Family Medicine
RCT: Sequential Oral Agents Not Noninferior to Insulin for Gestational Diabetes
8 Jan, 2025 | 11:05h | UTCBackground: Gestational diabetes mellitus (GDM) affects a growing number of pregnant individuals worldwide. While insulin has long been the standard pharmacological treatment, oral glucose-lowering agents (metformin and glyburide) have gained traction.
Objective: This trial investigated whether a sequential oral glucose-lowering regimen—beginning with metformin and adding glyburide as needed—was noninferior to an insulin-based strategy in reducing the risk of infants born large for gestational age (LGA).
Methods: This open-label, randomized, noninferiority trial enrolled 820 participants with singleton pregnancies at 16 to 34 weeks of gestation across 25 Dutch centers. Participants were randomized 1:1 to either (1) metformin initiated at 500 mg once daily and increased every three days up to 1000 mg twice daily or the highest tolerated dose with glyburide at 2.5 mg 30-60 minutes before each meal (with a dose increase up to a maximum of 5 mg three times per day) added if needed, and insulin added only if both failed, discontinuing glyburide, or (2) standard insulin therapy. The primary outcome was LGA (>90th percentile for gestational age and sex).
Results: Among those allocated to oral therapy (n=409), 79% achieved glycemic control without insulin. However, 23.9% of infants in the oral-therapy group were LGA vs 19.9% in the insulin group (absolute risk difference 4.0%; 95% CI, −1.7% to 9.8%). This exceeded the predefined 8% absolute risk difference noninferiority margin (P = .09 for noninferiority). Maternal hypoglycemia occurred more often with oral agents (20.9% vs 10.9%; absolute risk difference, 10.0%; 95% CI, 3.7%-21.2%), and neonatal intravenous glucose therapy was administered more frequently to those randomized to oral agents (6.4% vs 3.2%). Exploratory analysis not powered for definitive conclusions of participants requiring only metformin (no glyburide) showed a somewhat lower LGA rate (19.7%).
Conclusions: A sequential oral pharmacotherapy strategy—beginning with metformin and adding glyburide if needed—did not meet noninferiority criteria compared to insulin for preventing LGA births in GDM. While oral agents can reduce the overall need for insulin, the higher rate of maternal hypoglycemia, the higher rate of neonatal hypoglycemia requiring intravenous glucose therapy, and the borderline higher LGA incidence underscore the continued importance of insulin-based strategies, especially considering that the results support a larger body of evidence that glyburide is a suboptimal treatment for gestational diabetes. These results reinforce that insulin remains the preferred first-line pharmacological treatment for GDM, in line with current guidelines. Although patient satisfaction can be higher with oral agents, clinicians should carefully weigh the risks. Further research is needed to clarify the role of metformin-only approaches in GDM management.
Strengths and Limitations: Strengths include a large multicenter design and a clear noninferiority framework. Limitations include the open-label design, which introduces the possibility of bias in treatment allocation and outcome assessment, the reliance on local clinical protocols for insulin adjustments, and variations in diagnostic criteria.
Future Research: Ongoing trials are examining whether metformin alone might match insulin’s efficacy for GDM. Further studies should address long-term offspring outcomes.
Reference:
Rademaker D, de Wit L, Duijnhoven RG, et al. Oral Glucose-Lowering Agents vs Insulin for Gestational Diabetes: A Randomized Clinical Trial. JAMA. Published online January 6, 2025. DOI: http://doi.org/10.1001/jama.2024.23410
Powe CE. For Gestational Diabetes Pharmacotherapy, Insulin Reigns Supreme (Editorial). JAMA. Published online January 6, 2025. DOI: http://doi.org/10.1001/jama.2024.27148
Joint ATS/CDC/ERS/IDSA Guideline Recommends Shorter, All-Oral Regimens for Drug-Susceptible and Drug-Resistant TB
5 Jan, 2025 | 11:30h | UTCIntroduction: This summary outlines new clinical practice guidelines from the American Thoracic Society, U.S. Centers for Disease Control and Prevention, European Respiratory Society, and Infectious Diseases Society of America on updated treatment regimens for tuberculosis (TB) in low-incidence settings. These recommendations build on recent clinical trials, World Health Organization (WHO) guidance, and were developed using the GRADE and GRADE-ADOLOPMENT methodology. The guidelines aim to shorten treatment duration, reduce pill burden, and improve patient outcomes for both drug-susceptible (DS) and drug-resistant (DR) TB, and they apply to settings where mycobacterial cultures, molecular and phenotypic drug susceptibility tests, and radiographic studies are routinely available. A separate news release from CIDRAP highlights the significance of these shorter, all-oral regimens for adults and children. Directly observed therapy (DOT) remains the standard of care.
Key Recommendations:
Four-Month Regimen for DS-TB in Adults:
- For people aged 12 years or older with isoniazid- and rifampin-susceptible pulmonary TB, a new four-month regimen of isoniazid, rifapentine, moxifloxacin, and pyrazinamide (2HPZM/2HPM) is conditionally recommended. This shortened course is based on a large, randomized trial (Study 31/A5349) demonstrating noninferior efficacy compared to the standard six-month regimen (84.6% vs 85.4% cure, respectively), no increase in adverse events, and potential benefits in completion rates. Exclusions include TB meningitis and other complicated forms of extrapulmonary TB, and clinicians should obtain rapid fluoroquinolone susceptibility tests before initiating this regimen.
Four-Month Regimen for DS-TB in Children:
- For children and adolescents aged 3 months to 16 years with nonsevere, drug-susceptible pulmonary TB, a four-month regimen of isoniazid, rifampin, pyrazinamide, and ethambutol for the initial phase, followed by isoniazid and rifampin, is strongly recommended. Evidence from the SHINE trial showed high success (97.1% vs 96.9%) and similar safety with the shorter course compared to the 6-month regimen. Nonsevere TB generally excludes extensive cavitary disease, advanced extrapulmonary TB, or complicated forms. Close clinical and radiographic follow-up is important to confirm effective cure.
Six-Month BPaL Regimen for Rifampin-Resistant, Fluoroquinolone-Resistant or Intolerant TB:
- For rifampin-resistant (RR) pulmonary TB with resistance or patient intolerance to fluoroquinolones in adolescents aged 14 and older and adults, a six-month all-oral bedaquiline, pretomanid, and linezolid (BPaL) regimen is strongly recommended, replacing much longer regimens that often included injectables. Clinical trials (Nix-TB, ZeNix) demonstrated higher cure rates and lower toxicity with this regimen compared to longer regimens, though vigilance is needed for linezolid-related adverse events (e.g., neuropathy, myelosuppression). Baseline and monthly lab and ECG checks are advised.
Six-Month BPaLM Regimen for Rifampin-Resistant, Fluoroquinolone-Susceptible TB:
- For RR pulmonary TB that remains fluoroquinolone-susceptible in adolescents aged 14 and older and adults, a six-month bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaLM) regimen is strongly recommended over traditional 15-month or longer regimens in patients with MDR/RR-TB. Data from the TB-PRACTECAL trial showed high success rates and fewer serious adverse events. BPaLM is the first-line recommendation for this group. Close monitoring of cardiac status (QTc prolongation) and blood counts is advised.
Both BPaL and BPaLM regimens require detailed drug susceptibility testing and cautious management of potential drug–drug interactions, particularly for patients with comorbidities or HIV infection. Of note, the certainty of evidence for the outcomes in the DR-TB trials was rated as very low, due to multiple factors including bias, small event numbers, lack of blinding, and inconsistent outcomes.
Conclusion: These new recommendations markedly shorten TB treatment courses for adults and children in low-incidence settings with access to appropriate diagnostic tools, while avoiding injectables and reducing serious toxicities. By replacing older, more complex regimens with all-oral, shorter-duration therapy, and using DOT as the standard of care, the guidelines aim to improve adherence, lessen the burden on healthcare systems, and enhance patient quality of life. Ongoing research will further refine dosing, safety for special populations (e.g., pregnant individuals), and the role of advanced drug susceptibility testing.
Reference:
Jussi J. Saukkonen, Raquel Duarte, Sonal S. Munsiff, et al. “Updates on the Treatment of Drug-Susceptible and Drug-Resistant Tuberculosis: An Official ATS/CDC/ERS/IDSA Clinical Practice Guideline.” American Journal of Respiratory and Critical Care Medicine, (2025). https://doi.org/10.1164/rccm.202410-2096ST
News release commentary: “New guidelines expand recommendations for shorter, all-oral TB treatments” (CIDRAP). https://www.cidrap.umn.edu/tuberculosis/new-guidelines-expand-recommendations-shorter-all-oral-tb-treatments
Managing Autonomic Dysfunction, Pain, and Sleep Disturbances in Parkinson’s Disease: Key Points from the German Society of Neurology Guideline
5 Jan, 2025 | 11:00h | UTCIntroduction: This text summarizes a practice-oriented 2023 guideline from the German Society of Neurology addressing non-motor manifestations of Parkinson’s disease (PD). The guideline focuses on evidence-based approaches for diagnosing and treating autonomic failure (including urogenital, cardiovascular, and gastrointestinal dysfunction), pain, and sleep disturbances—problems that often reduce quality of life and accelerate disease progression. The guideline was developed using PICO (Patient, Intervention, Comparison, Outcome) questions, comprehensive literature searches, and a consensus process among German Parkinson’s experts. By presenting stepwise recommendations, the guideline aims to help clinicians manage these non-motor aspects more effectively and improve patient outcomes.
Key Recommendations:
Autonomic Failure
- Bladder Dysfunction: Encourage behavioral modifications (e.g., timed fluid intake, bladder training) and, if necessary, consider antimuscarinics (e.g., solifenacin, trospium) or β3 agonists (e.g., mirabegron 50 mg once daily). Specifically, solifenacin 5 mg once daily, trospium 15–30 mg twice daily or darifenacin 7.5–15 mg once daily are preferred, due to their lower risk of cognitive side effects.
- In patients who have responded inadequately to oral therapy, intravesical botulinum toxin A injection (200 U or customized) may be considered for treating severe urinary urge incontinence, if the individual motor and cognitive performance enables the subsequently likely necessary intermittent catheterization.
- For nocturia, limit evening fluid intake and consider a 10°–20° head-up tilt in bed. In nocturnal polyuria, desmopressin (5–40 µg once daily nasal spray or 100–800 µg once daily per os) may be used with close monitoring of blood pressure, serum electrolytes and body weight.
- Orthostatic Hypotension (OH): Apply a four-step approach: (1) address aggravating factors (e.g., infections, dehydration); (2) review medications; (3) use non-pharmacological measures (increased fluid/salt intake if no contraindications, abdominal binders, head-up tilt sleeping); (4) add medications to raise blood pressure (e.g., midodrine 2.5–10 mg two to three times a day, fludrocortisone 0.1–0.3 µg once daily). For the diagnosis of OH, a Schellong test or tilt table examination should be performed.
- Monitor for supine hypertension, which may require evening antihypertensives (e.g., low-dose losartan 25–100 mg or transdermal nitroglycerin 0.1–0.2 mg/h) and further adjustments. PD individuals with neurogenic OH should be screened for the presence of supine and nocturnal hypertension.
- Constipation: Follow the general German guideline on “Chronic Constipation.” Emphasize adequate hydration (1.5-2 L per day), fiber intake, and exercise.
- First-line drug therapy is macrogol (polyethylene glycol, PEG, 13–26 g once daily). Consider bisacodyl (5–10 mg once daily), sodium picosulfate (5–10 mg once daily), or prucalopride (1–2 mg once daily) if needed.
- Male Erectile Dysfunction: First-line treatment involves phosphodiesterase type 5 (PDE-5) inhibitors (e.g., sildenafil 50–100 mg on demand), used cautiously in patients with orthostatic hypotension. A multidisciplinary approach with urologists is necessary.
Pain Management
- Classification: Differentiate PD-related pain (nociceptive, neuropathic, or nociplastic) from pain arising independently of PD. Use PD-specific scales, such as the King’s Parkinson’s Disease Pain Scale (KPPS) or the Parkinson’s Disease Pain Classification System (PD-PCS), to clarify pain etiology and guide therapy.
- Approach: Optimize dopaminergic therapy, especially if pain correlates with wearing-off.
- Treat nociceptive pain per the WHO 3-step analgesic ladder (which recommends starting with non-opioid analgesics like acetaminophen or NSAIDs, then moving to mild opioids like codeine if needed, and finally to strong opioids like morphine for severe pain).
- For neuropathic pain, preference is given to anticonvulsants (e.g., gabapentin 300–1800 mg, especially in case of concomitant restless legs syndrome) or antidepressants (e.g., duloxetine 60–120 mg, in case of concomitant depression).
- Opioids (e.g., prolonged-release oxycodone/naloxone 5/2.5–20/10 mg, rarely up to 40/20 mg) may be considered in severe or refractory cases.
Sleep Disturbances
- Screening & Diagnosis: Use the Parkinson’s Disease Sleep Scale-2 (PDSS-2) to identify problems such as insomnia, nocturnal akinesia, restless legs, and REM sleep behavior disorder (RBD).
- Objective tests—actigraphy, polygraphy, or video-polysomnography—are recommended for complex or treatment-refractory sleep issues.
- Treatment: Address comorbid conditions (e.g., restless legs syndrome, sleep apnea) following standard guidelines.
- If motor fluctuations disturb sleep, adjust dopaminergic therapy (e.g., use long-acting levodopa or dopamine agonists at night).
- RBD management typically includes creating a safe sleep environment and considering clonazepam (0.125–3 mg) or melatonin (2–9 mg).
- Insomnia linked to circadian disruption may benefit from good sleep hygiene, bright light therapy, structured exercise, and (if indicated) low-dose agents such as eszopiclone (1 mg), doxepin (25 mg), zolpidem (5 mg), trazodone (50 mg), melatonin (2 mg), venlafaxine (37.5 mg, in case of comorbid depression), nortriptyline (25 mg) or mirtazapine (7.5 mg).
- Excessive daytime sleepiness calls for an etiology-driven approach, with non-pharmacological strategies (e.g., scheduled naps, light therapy, exercise) and possible use of modafinil (200–400 mg) if needed. Driving should be reassessed if sleep attacks occur.
Clinical Impact: Poor sleep worsens cognitive decline, motor deficits, caregiver burden, and overall disease progression. RBD in early PD often predicts faster deterioration and earlier cognitive complications. The guideline also addresses the prognostic implications of sleep disturbances.
Conclusion: This guideline underscores the critical importance of identifying and managing non-motor symptoms in Parkinson’s disease. A structured, practice-oriented, etiology-driven stepwise approach to autonomic failure, pain, and sleep problems helps reduce the risk of dangerous complications, alleviates patient distress, and may delay the progression of both motor and cognitive domains. By integrating evidence-based recommendations into daily practice—focusing on precise assessment, tailored interventions, and regular follow-up—clinicians can improve outcomes and quality of life for individuals with PD and their caregivers.
Reference: Fanciulli A, Sixel-Döring F, Buhmann C, Krismer F, Hermann W, Winkler C, Woitalla D, Jost WH, German Parkinson’s Guideline Group, Trenkwalder C & Höglinger G (2025). Diagnosis and treatment of autonomic failure, pain and sleep disturbances in Parkinson’s disease: guideline “Parkinson’s disease” of the German Society of Neurology. Journal of Neurology (2025). DOI: https://doi.org/10.1007/s00415-024-12730-5
Avian Influenza A(H5N1) Outbreak Among US Farm Exposures: Clinical Findings and Early Treatment Outcomes
2 Jan, 2025 | 17:01h | UTCBackground: Highly pathogenic avian influenza A(H5N1) has reemerged in the United States with documented infections in poultry and dairy cows since 2021. From March through October 2024, 46 human cases were identified, most of whom were workers engaged in poultry depopulation or dairy-farm activities where infected or presumably infected animals were present.
Objective: To characterize the clinical presentations, exposure settings, and outcomes of individuals with laboratory-confirmed H5N1 infection and to investigate potential routes of transmission, disease severity, and risk to public health.
Methods: Using a standardized case-report form, data were collected on exposure history, symptom onset, and use of personal protective equipment (PPE). Respiratory and conjunctival swabs from symptomatic persons underwent real-time RT-PCR for H5 subtyping at both state laboratories and the Centers for Disease Control and Prevention (CDC). Genetic sequencing was performed on available samples. Investigators also monitored close household contacts to evaluate the risk of secondary transmission. An additional hospitalized patient with no identifiable exposure source was detected through routine influenza surveillance.
Results: Of the 46 adult case patients, 20 were exposed to infected poultry, 25 to infected or presumably infected dairy cows, and 1 had unknown exposure. Among the 45 occupationally exposed patients, illness was mild, with no hospitalizations or deaths. Conjunctivitis was present in 93% of cases; 49% reported fever, and 36% had respiratory symptoms. Fifteen patients had only conjunctivitis, highlighting the utility of conjunctival specimens for detection. Early antiviral therapy with oseltamivir was common, initiated at a median of two days after symptom onset. No additional cases were found among 97 closely monitored household contacts, indicating no evidence of sustained human-to-human transmission. Genetic analyses revealed clade 2.3.4.4b viruses, with some genotypic differences between poultry-related (D1.1 genotype) and cow-related (B3.13 genotype) infections.
Conclusions: In this observational study, H5N1 infections in US adults were generally mild, self-limited, and predominantly associated with conjunctivitis. The absence of critical illness or fatalities contrasts with historical reports of more severe H5N1 disease. Although no ongoing person-to-person transmission was documented, continued vigilance is warranted, given the virus’s potential for rapid adaptation.
Implications for Practice: Occupational health measures, such as consistent PPE use (especially eye protection), timely surveillance, and prompt antiviral treatment, may reduce the impact of H5N1 infections among exposed workers. Clinicians should consider conjunctival sampling for symptomatic patients with relevant animal contact. Policy efforts should focus on improving biosecurity practices in both poultry and dairy settings.
Study Strengths and Limitations: Strengths include systematic surveillance, robust laboratory testing of both respiratory and conjunctival specimens, and early antiviral administration. Limitations involve possible underreporting of mild or asymptomatic cases, incomplete details on exposure duration, and limited data on specific routes of cow-to-human transmission.
Future Research: Further studies should explore viral evolution in cows, the significance of raw milk as a transmission vehicle, and the potential for more severe infections, as highlighted by sporadic reports of severe H5N1 illness worldwide.
Reference: Garg S, Reinhart K, Couture A, Kniss K, Davis CT, Kirby MK, Murray EL, et al. Highly Pathogenic Avian Influenza A(H5N1) Virus Infections in Humans. New England Journal of Medicine. Published December 31, 2024. Link: https://www.nejm.org/doi/full/10.1056/NEJMoa2414610
- Editorial: Ison MG, Marrazzo J. The Emerging Threat of H5N1 to Human Health. New England Journal of Medicine. Published December 31, 2024. Link: https://www.nejm.org/doi/full/10.1056/NEJMe2416323
Meta-Analysis: Glutamatergic Agents May Improve Obsessive-Compulsive and Related Disorder Symptoms
4 Jan, 2025 | 12:08h | UTCBackground: Obsessive-compulsive and related disorders (OCRDs) affect approximately 2% to 3% of the general population and encompass conditions such as OCD, skin-picking disorder, and trichotillomania, leading to substantial distress and impaired daily functioning. Glutamatergic dysfunction within cortico-striatal-thalamo-cortical circuits has emerged as a potential target, prompting investigations into whether glutamatergic agents can enhance outcomes either alone or alongside selective serotonin reuptake inhibitors (SSRIs).
Objective: To determine whether glutamatergic medications, used as monotherapy or as augmentation to SSRIs, can improve clinical symptoms across different OCRDs compared to placebo, with emphasis on changes in standardized measures such as the Yale-Brown Obsessive Compulsive Scale (Y-BOCS).
Methods: This systematic review and meta-analysis included 27 double-blind, placebo-controlled randomized clinical trials involving 1369 participants with OCRDs. Eligible studies examined agents including N-acetylcysteine (NAC), memantine, lamotrigine, riluzole, and topiramate, among others. Data extraction focused on changes in symptom severity, and pooled effect sizes were calculated using random-effects meta-analysis. Subgroup analyses evaluated potential moderators, such as disorder subtype, age group, refractoriness, and augmentation strategies, while sensitivity analyses and publication bias assessments (e.g. Egger test) were performed to ensure robustness.
Results: Overall, glutamatergic medications showed a large effect size in reducing OCRD symptoms (Cohen’s d = −0.80). Specifically for OCD (n=23 trials), a significant mean reduction in Y-BOCS scores (−4.17 points) indicated clinically meaningful improvement. Publication bias was detected in the broader OCRD meta-analysis but not in the OCD-specific analysis. Heterogeneity was high across studies, reflecting varied populations and treatment designs. Despite these findings, the certainty of evidence ranged from low to moderate, mandating cautious interpretation.
Conclusions: Glutamatergic interventions appear promising for OCRDs, particularly OCD, where moderate-certainty evidence suggests meaningful symptom improvement. Nevertheless, elevated heterogeneity and signs of publication bias highlight the need for larger, more rigorous trials to confirm optimal dosing parameters and elucidate which patient subsets may benefit most.
Implications for Practice: Clinicians might consider adding or switching to glutamatergic agents for individuals with inadequate response to SSRIs. However, these findings do not warrant unrestrained enthusiasm. Each case should be weighed individually, taking into account possible mild to moderate gastrointestinal side effects (particularly with NAC).
Study Strengths and Limitations: Strengths include the focus on double-blind RCTs, diverse glutamatergic agents, and robust statistical approaches. Limitations comprise high between-study heterogeneity, limited data for less common disorders (e.g., body dysmorphic disorder), and potential publication bias. Additionally, few trials specifically tested novel agents like ketamine.
Future Research: Studies with larger sample sizes, clearly defined outcomes, and detailed dose-response evaluations are needed. Future trials should explore underrepresented OCRDs, such as hoarding disorder, and newer glutamatergic compounds (e.g., troriluzole) to further optimize therapeutic strategies.
Reference: Coelho DRA, Yang C, Suriaga A, et al. Glutamatergic Medications for Obsessive-Compulsive and Related Disorders: A Systematic Review and Meta-Analysis. JAMA Netw Open. 2025;8(1):e2452963. DOI: http://doi.org/10.1001/jamanetworkopen.2024.52963
Meta-Analysis: Long Half-Life Phosphodiesterase Inhibitors Reduce HbA1c in Adults with Elevated Baseline Levels
6 Jan, 2025 | 08:00h | UTCBackground: Phosphodiesterase type 5 (PDE5) inhibitors are traditionally used to treat erectile dysfunction and pulmonary arterial hypertension. Recent evidence suggests that PDE5 inhibitors could also be repurposed to lower hemoglobin A1c (HbA1c) in patients with type 2 diabetes. Given the disparity in half-lives among these agents, this meta-analysis focused on whether longer half-life PDE5 inhibitors (tadalafil, PF-00489791) produce a more sustained HbA1c reduction compared to short half-life PDE5 inhibitors (sildenafil, avanafil).
Objective: To evaluate the effect of PDE5 inhibitors on HbA1c levels in individuals with baseline values above 6%, comparing agents with short and long half-lives to assess differential clinical benefits in glycemic control.
Methods: This systematic review and meta-analysis included only randomized controlled trials (RCTs) in which participants received any PDE5 inhibitor for at least four weeks, with control or placebo for comparison. Major databases (Cochrane CENTRAL, PubMed Central, ClinicalTrials.gov, and WHO ICTRP) were searched through September 2024 without language restrictions. Statistical analyses were performed using a random-effects model, reporting mean differences in HbA1c. Secondary outcomes (HOMA-IR, lipid profiles, fasting glucose, and others) were also explored.
Results: Thirteen RCTs were eligible (N=1083). Long half-life agents showed a significant mean reduction of approximately −0.40% in HbA1c (p=0.002) in the overall analysis, whereas short half-life PDE5 inhibitors exhibited no significant change. In more stringent subgroup analyses (≥8 weeks’ duration, exclusive type 2 diabetes, baseline HbA1c ≥6.5%), long half-life PDE5 inhibitors maintained a significant decrease (−0.50%), while short half-life agents paradoxically showed a slight but significant increase (+0.36%, p=0.03). In trials enrolling patients with poorly controlled diabetes (baseline HbA1c near 10%), tadalafil’s HbA1c reductions were considerably larger, aligning with the efficacy of other standard oral antidiabetic medications.
Conclusions: Long half-life PDE5 inhibitors appear to confer meaningful reductions in HbA1c, comparable to established oral antidiabetic agents, particularly in patients whose HbA1c is inadequately controlled. In contrast, short half-life PDE5 inhibitors did not show a consistent benefit and may paradoxically raise HbA1c in certain subgroups, although further large-scale studies are warranted to confirm these findings.
Implications for Practice: Long half-life PDE5 inhibitors could serve as an adjunctive therapy in type 2 diabetes management, especially in individuals with higher baseline HbA1c. Yet, caution is advised given limited data on adverse events and the short duration of most included trials. Physicians should remain prudent until more robust evidence, especially in populations with markedly elevated HbA1c, becomes available.
Study Strengths and Limitations: Strengths include a direct comparison between short and long half-life PDE5 inhibitors in a clinically relevant population, plus systematic subgroup analyses. Limitations involve heterogeneity in trial designs, relatively low baseline HbA1c in most participants, and a lack of long-term follow-up data or major clinical endpoints.
Future Research: Subsequent trials should target populations with poorly controlled diabetes (HbA1c ≥9.0%) and assess longer durations (≥3 months) to capture the full impact of PDE5 inhibitor therapy. A deeper examination of combination regimens, pharmacokinetic optimization, and clinical outcomes like cardiovascular events would further clarify the role of these agents in diabetes care.
Reference: Kim J, Zhao R, Kleinberg LR, Kim K. (2025) “Effect of long and short half-life PDE5 inhibitors on HbA1c levels: a systematic review and meta-analysis.” eClinicalMedicine, 80, 103035. Available at: DOI: http://doi.org/10.1016/j.eclinm.2024.103035
Cohort study: Higher Telehealth Use Linked to Lower Rates of Select Low-Value Services in Medicare
3 Jan, 2025 | 09:30h | UTCBackground: Telehealth has rapidly expanded in recent years, potentially transforming how primary care is delivered. However, questions remain regarding its impact on low-value services—tests or procedures that confer minimal benefit and might be wasteful. Previous research raised concerns that virtual encounters could either reduce or increase unnecessary care, but rigorous data on this matter have been limited.
Objective: To assess whether a primary care practice’s adoption of telehealth is associated with changes in the rate of eight established low-value services, comprising office-based procedures, laboratory tests, imaging studies, and mixed-modality interventions.
Methods: This retrospective cohort study used Medicare fee-for-service claims from 2019 through 2022 for 577,928 beneficiaries attributed to 2,552 primary care practices in Michigan. Practices were grouped into low, medium, or high tertiles of telehealth volume in 2022. A difference-in-differences approach was performed, comparing annualized low-value service rate changes between the prepandemic (2019) and postpandemic (2022) periods.
Results: Overall, high-telehealth practices demonstrated reduced rates of certain office-based low-value services, specifically cervical cancer screening (−2.9 services per 1000 beneficiaries, 95% CI −5.3 to −0.4) among older women. Additionally, high-telehealth practices showed lower rates of select low-value thyroid tests (−40 per 1000 beneficiaries, 95% CI −70 to −9). For five other measures—including imaging for low back pain, imaging for uncomplicated headache, and PSA tests in older men—no significant association was observed between greater telehealth use and low-value service rates. Notably, telehealth volume increased markedly from 2019 to 2022, while in-person visits generally decreased.
Conclusions: These findings suggest that widespread telehealth adoption in Michigan primary care was not associated with elevated low-value service use. In fact, certain office-based low-value tests appeared to decline, possibly owing to fewer face-to-face opportunities to perform unnecessary interventions. Nonetheless, caution is warranted in generalizing these findings, as telehealth’s effects may vary across different clinical contexts.
Implications for Practice: Health care systems should consider structured telehealth protocols that encourage judicious testing and minimize overuse. While telehealth can broaden access, clinicians must remain vigilant to avoid missing necessary care. Clear guidelines, effective triage, and patient education might help balance convenience with quality.
Study Strengths and Limitations: Strengths include a large Medicare population and established low-value service metrics, enhancing the study’s validity. Limitations include a single-state focus (Michigan) and reliance on claims data without detailed clinical information, restricting the scope of outcomes assessed.
Future Research: Further investigation is needed to verify whether these trends extend to other states, different insurance models, and additional low-value services (including medications). Evaluations of telehealth’s role in both low-value and high-value care could offer deeper insights into its broader effects on cost and quality.
Reference: Liu T, Zhu Z, Thompson MP, et al. Primary Care Practice Telehealth Use and Low-Value Care Services. JAMA Network Open. 2024;7(11):e2445436. DOI: http://doi.org/10.1001/jamanetworkopen.2024.45436
RCT: Chlorthalidone Shows No Renal Advantage Over Hydrochlorothiazide Under Equivalent Dosing in Older Adults With Hypertension
3 Jan, 2025 | 09:00h | UTCBackground: Hypertension is a critical factor in chronic kidney disease (CKD) progression and cardiovascular risk. Thiazide-type diuretics, such as chlorthalidone and hydrochlorothiazide, are first-line antihypertensive treatments. However, whether one agent confers stronger renal protection remains contested, especially at doses considered pharmacologically comparable. Prior observational studies suggested potential discrepancies in kidney outcomes and hypokalemia incidence. This secondary analysis of the Diuretic Comparison Project (DCP) further clarifies the comparative effectiveness of chlorthalidone versus hydrochlorothiazide on renal endpoints.
Objective: To evaluate whether chlorthalidone (12.5–25 mg/day) prevents CKD progression more effectively than hydrochlorothiazide (25–50 mg/day) in adults ≥65 years with hypertension and no pre-specified exclusion by renal function.
Methods: The DCP is a pragmatic, open-label randomized clinical trial embedded in Veterans Affairs (VA) facilities across the United States. Between June 1, 2016, and December 31, 2023, patients already receiving hydrochlorothiazide (25 or 50 mg/day) for hypertension were randomized either to continue that medication or switch to chlorthalidone (12.5–25 mg/day), reflecting equivalent potency.
The prespecified primary kidney outcome was a composite of doubling of serum creatinine, a terminal estimated glomerular filtration rate (eGFR) <15 mL/min, or dialysis initiation. Secondary measures included ≥40% eGFR decline, incident CKD (new eGFR <60 mL/min), eGFR slope, and relevant adverse events. Laboratory data were obtained through usual clinical care rather than protocol-driven testing.
Results: Among 13,523 randomized participants, 12,265 had analyzable renal data (mean [SD] age, 71 [4] years; 96.8% male). The mean (SD) follow-up was 3.9 (1.3) years. Chlorthalidone did not demonstrate superiority over hydrochlorothiazide for the composite kidney endpoint (6.0% vs 6.4%; hazard ratio, 0.94; 95% CI, 0.81–1.08; P=.37). Additional analyses showed no differences in CKD incidence, ≥40% eGFR decline, or eGFR slope. Hypokalemia occurred more frequently in chlorthalidone users (overall ~2% higher rate of low potassium measurements), and hospitalizations for hypokalemia also trended higher.
Conclusions: Under dosing regimens designed to achieve equivalent antihypertensive potency, chlorthalidone provided no measurable renal benefit over hydrochlorothiazide but posed a modestly elevated risk of hypokalemia. These findings reinforce the clinical interchangeability of both agents for long-term blood pressure management in older adults, provided serum potassium is monitored.
Implications for Practice: Clinicians can confidently employ either chlorthalidone or hydrochlorothiazide in older patients with hypertension, including those with mild or moderate CKD, since renal deterioration rates did not differ significantly. Importantly, the trial used half the milligram amount of chlorthalidone (12.5–25 mg/day) to match the usual doses of hydrochlorothiazide (25–50 mg/day). Recognizing this equivalence helps guide therapy transitions and dosing decisions. Vigilant monitoring of electrolytes remains essential, particularly when prescribing chlorthalidone, given the slightly higher incidence of hypokalemia.
Study Strengths and Limitations: Strengths include the randomized design, broad participant inclusion, and pragmatic structure that mirrors real-world prescribing. Limitations involve potential underestimation or overestimation of renal events due to reliance on routine (rather than scheduled) lab tests. Also, nearly all participants had prior hydrochlorothiazide exposure, which may have influenced tolerance and adherence patterns.
Future Research: Further clinical trials focusing on more advanced CKD stages, distinct comorbidities, or combination regimens (e.g., with potassium-sparing agents) would expand our understanding of how thiazide-type diuretics influence long-term kidney outcomes. Extended follow-up or additional subgroup analyses could also shed light on the interplay of dose-response effects in highly vulnerable populations.
Reference: Ishani A, Hau C, Raju S, et al. “Chlorthalidone vs Hydrochlorothiazide and Kidney Outcomes in Patients With Hypertension: A Secondary Analysis of a Randomized Clinical Trial.” JAMA Netw Open. 2024;7(12):e2449576. DOI: http://doi.org/10.1001/jamanetworkopen.2024.49576
Dose-Response Meta-Analysis: At Least 150 Weekly Minutes of Aerobic Exercise Needed for Significant Waist and Fat Reduction
2 Jan, 2025 | 09:30h | UTCBackground: Elevated body weight and adiposity remain major public health concerns worldwide, with overweight and obesity affecting nearly half of the adult population. Although various guidelines advocate for aerobic exercise as a core strategy in weight management, robust meta-analyses exploring dose-response relationships are scarce.
Objective: To clarify how different doses and intensities of supervised aerobic exercise affect body weight, waist circumference, and body fat in adults with overweight or obesity.
Methods: This systematic review and meta-analysis encompassed 116 randomized clinical trials (RCTs) including a total of 6880 participants (mean [SD] age, 46 [13] years). All studies involved supervised continuous aerobic interventions (e.g., walking or running) for at least 8 weeks. Comparisons were made against sedentary or usual-activity controls. Frequency, duration (minutes per week), and intensity (moderate, vigorous, or combined) of aerobic sessions were extracted.
Results: Across all trials, each additional 30 minutes per week of aerobic exercise was linked to a mean reduction of 0.52 kg in body weight (95% CI, −0.61 to −0.44), 0.56 cm in waist circumference, and 0.37 percentage points in body fat. Body weight and waist circumference showed largely linear decreases with increasing weekly exercise, whereas body fat percentage displayed a pattern suggesting that at least 150 minutes per week may be required to achieve clinically meaningful reductions (>2% reduction in body fat). Aerobic training was generally well tolerated, although a modest increase in mild musculoskeletal complaints was noted (risk difference, 2 more events per 100 participants).
Conclusions: Engaging in up to 300 minutes per week of aerobic exercise was associated with progressively greater benefits for weight control, waist circumference, and body fat. While even small doses yielded modest improvements, these findings suggest that an intensity of at least moderate level and a duration of at least 150 minutes per week may be necessary to achieve clinically important reductions in central obesity and fat percentage.
Implications for Practice: Clinicians managing patients with overweight or obesity can recommend a minimum of 150 minutes per week of moderate-to-vigorous aerobic training to achieve significant anthropometric changes. Gradual progression is essential to balance effectiveness and safety, especially in individuals with musculoskeletal constraints.
Study Strengths and Limitations: Strengths include the large number of RCTs, robust dose-response analyses, and consistent directions of effects. However, high heterogeneity, publication bias for certain fat measures, and limited data on medication use and health-related quality of life in longer trials were noted.
Future Research: Further trials should explore additional subgroup analyses (e.g., older adults, individuals with chronic comorbidities), longer durations of follow-up, and the integration of resistance training to optimize cardiometabolic outcomes.
Reference: Jayedi A, Soltani S, Emadi A, et al. Aerobic Exercise and Weight Loss in Adults: A Systematic Review and Dose-Response Meta-Analysis. JAMA Network Open. 2024;7(12):e2452185. DOI: http://doi.org/10.1001/jamanetworkopen.2024.52185
Cohort Study: Higher Telehealth Intensity May Reduce Certain Office-Based Low-Value Services in Medicare Primary Care
2 Jan, 2025 | 08:00h | UTCBackground: The rapid expansion of telehealth has raised concerns about its potential to foster wasteful services, especially in primary care. While telehealth can eliminate certain in-person interventions, it might also increase unnecessary laboratory or imaging requests, given the more limited physical exam. Evaluating how telehealth intensity affects the provision of low-value care is crucial for guiding future policy and clinical practice.
Objective: To determine whether higher telehealth utilization at the practice level is associated with changes in the rates of common low-value services among Medicare fee-for-service beneficiaries in Michigan.
Methods: Using Medicare claims data from January 1, 2019, to December 31, 2022, this retrospective cohort employed a difference-in-differences design. A total of 577,928 beneficiaries attributed to 2,552 primary care practices were included. Practices were stratified into low, medium, or high telehealth tertiles based on the volume of virtual visits per 1,000 beneficiaries in 2022. Eight low-value services relevant to primary care were grouped into four main categories: office-based (e.g., cervical cancer screening in women older than 65), laboratory-based, imaging-based, and mixed-modality services.
Results: Among the 577,928 beneficiaries (332,100 women; mean age, 76 years), practices with high telehealth utilization had a greater reduction in office-based cervical cancer screening (−2.9 [95% CI, −5.3 to −0.4] services per 1,000 beneficiaries) and low-value thyroid testing (−40 [95% CI, −70 to −9] tests per 1,000 beneficiaries), compared with low-utilization practices. No significant association emerged for other laboratory- or imaging-based low-value services, including PSA testing for men over 75 or imaging for uncomplicated low back pain. These findings suggest that while telehealth can lower certain office-based low-value services, it does not appear to substantially increase other types of wasteful care.
Conclusions: High telehealth intensity was linked to reductions in specific low-value procedures delivered in-office, without raising the overall rates of other potentially unnecessary interventions. These data may alleviate some policy concerns that telehealth drives excessive or wasteful care due to its convenience. Instead, substituting certain in-person visits with virtual encounters might curtail opportunities for procedures with minimal clinical benefit.
Implications for Practice: For clinicians and policymakers, these results underscore the possibility that carefully implemented telehealth may reduce some low-value services. Nonetheless, sustained monitoring is needed to confirm whether telehealth encourages or discourages appropriate clinical decision-making across a broader range of interventions.
Study Strengths and Limitations: Strengths include a sizable cohort, a pre- versus post-pandemic time frame, and comprehensive analysis of multiple low-value outcomes. Limitations involve the exclusive focus on beneficiaries in Michigan, the inability to capture prescription-related low-value practices (e.g., antibiotic overuse), and the reliance on claims-based measures, which lack clinical details.
Future Research: Subsequent studies should expand to different geographic areas, assess additional low-value endpoints such as overtreatment with medications, and explore whether demographic or socioeconomic factors modify telehealth’s impact on care quality.
Reference: Liu T, Zhu Z, Thompson MP, et al. Primary Care Practice Telehealth Use and Low-Value Care Services. JAMA Netw Open. 2024;7(11):e2445436. DOI: http://doi.org/10.1001/jamanetworkopen.2024.45436
Meta-analysis: One-day Low-residue Diet Achieves Comparable Bowel Cleansing Compared to Multi-day Regimens
26 Dec, 2024 | 18:21h | UTCBackground: Colorectal cancer remains a leading cause of cancer-related morbidity worldwide, making early detection through colonoscopy essential. Adequate bowel preparation is crucial to maximize mucosal visibility and detect lesions effectively. Although low-residue diets (LRDs) are commonly recommended before colonoscopy, guidelines vary regarding the optimal duration (one day versus multiple days). This systematic review and meta-analysis evaluated whether a one-day LRD regimen is non-inferior to multi-day protocols in achieving satisfactory bowel cleansing and lesion detection.
Objective: To compare the efficacy of 1-day versus >1-day LRD regimens for bowel preparation in adult patients undergoing elective colonoscopy, focusing on bowel cleanliness, polyp detection, and adenoma detection rates.
Methods: A comprehensive search of PubMed, Cochrane Central Register of Controlled Trials, ScienceDirect, Scopus, and ClinicalTrials.gov was conducted for randomized controlled trials (RCTs) comparing 1-day with >1-day LRD regimens. Six RCTs involving 2,469 participants met inclusion criteria. Patients were randomized to either a 1-day LRD (n=1,237) or a multi-day LRD (n=1,232). Adequate bowel preparation was primarily defined by a Boston Bowel Preparation Scale (BBPS) score ≥2 in each segment or total BBPS ≥6. Secondary outcomes included polyp detection rate (PDR), adenoma detection rate (ADR), withdrawal time, cecal intubation rate, and cecal intubation time.
Results: Both groups demonstrated similar rates of adequate bowel preparation (87.2% in the 1-day LRD vs. 87.1% in the multi-day group), with no significant difference (OR=1.03, 95% CI, 0.76–1.41; p=0.84; I2=0%). PDR was likewise comparable (OR=0.91, 95% CI, 0.76–1.09; p=0.29; I2=16%), as was ADR (OR=0.87, 95% CI, 0.71–1.08; p=0.21; I2=0%). Withdrawal time did not differ (MD=–0.01 minutes, 95% CI, –0.25 to 0.24; p=0.97; I2=63%), and cecal intubation parameters were also statistically similar. Across studies, the pooled mean global BBPS revealed minimal difference (MD=0.16, 95% CI, –0.02 to 0.34; p=0.08; I2=15%), confirming the non-inferiority of a shorter LRD protocol.
Conclusions: A one-day LRD achieves bowel cleansing outcomes comparable to those of multi-day LRDs, without compromising polyp or adenoma detection. This shorter regimen may help optimize patient adherence, reduce dietary restriction burden, and simplify procedural logistics, especially for busy endoscopy practices.
Implications for Practice: Adopting a 1-day LRD can streamline preparation, improve patient satisfaction, and maintain high-quality visualization. Clinicians should weigh individual patient factors such as chronic constipation or comorbidities but may generally favor a shorter dietary restriction period to enhance compliance and comfort.
Study Strengths and Limitations: This meta-analysis included only RCTs, strengthening its internal validity. Heterogeneity for primary outcomes was minimal. However, the included trials employed varied dietary protocols and bowel preparation solutions. Additionally, some studies lacked uniform reporting of cecal intubation endpoints, limiting direct comparisons. Future investigations with standardized outcome measures could offer more definitive guidance.
Future Research: Further large-scale RCTs should assess cost-effectiveness, patient-reported outcomes, and LRD composition in specific populations. Identifying optimal dietary instructions for individuals with slower colonic transit or specific nutritional needs would refine colonoscopy preparation guidelines and potentially increase detection of precancerous lesions.
Reference: Putri RD, et al. One-day low-residue diet is equally effective as the multiple-day low-residue diet in achieving adequate bowel cleansing: a meta-analysis of randomized controlled trials. Clinical Endoscopy. 2024. DOI: https://doi.org/10.5946/ce.2024.061
Three Phase 3, Placebo-Controlled Trials Show Rapid Benefits of Oral Atogepant for Migraine Prevention
26 Dec, 2024 | 12:17h | UTCBackground: Preventive therapies for migraine often require long titration and may take weeks to achieve their full effect. This analysis integrates data from three randomized, placebo-controlled Phase 3 trials (ADVANCE, ELEVATE, PROGRESS) assessing atogepant 60 mg once daily (QD) over 12 weeks, focusing on the first four weeks. A key point is that atogepant was compared only to placebo, not to other well-established migraine preventives.
Objective: To determine whether atogepant provides early efficacy in reducing migraine frequency and improving functional outcomes within the initial weeks of therapy, for both episodic and chronic migraine.
Methods: All three studies enrolled participants aged 18–80 years with a ≥1-year history of migraine. ADVANCE and ELEVATE focused on episodic migraine (EM; 4–14 monthly migraine days), while PROGRESS studied chronic migraine (CM; ≥15 monthly headache days, ≥8 of which met migraine criteria). In ELEVATE, participants had previously failed 2–4 classes of oral migraine preventives. Throughout each trial, patients recorded daily migraine-related data and completed validated functional assessments (AIM-D and EQ-5D-5L). For this pooled analysis, only the atogepant 60 mg QD and placebo arms were examined.
Results: Atogepant recipients had a significantly lower proportion of patients with a migraine day on day 1 in all three trials, suggesting a rapid onset of benefit. Reductions in weekly migraine days (WMDs) emerged as early as week 1 and remained consistently greater than placebo over the first four weeks. Functional measures improved within this same timeframe, with patients on atogepant reporting reductions in activity impairment and enhanced self-rated health. These positive findings were observed in EM (with or without prior prophylaxis failures) and in CM populations.
Conclusions: Atogepant 60 mg QD was linked to early and significant reductions in migraine days, as well as enhancements in physical functioning and daily activities, across three placebo-controlled studies. The data suggest that atogepant may offer clinically meaningful, rapid-onset prophylactic benefits.
Implications for Practice: Clinicians may consider atogepant for patients seeking a preventive migraine therapy that demonstrates a potentially faster impact on symptom frequency and daily functioning. However, direct comparisons with established active treatments are lacking, and appropriate caution in interpreting the early onset of benefit is recommended.
Study Strengths and Limitations: Major strengths include robust, double-blind methodologies and consistent findings across diverse migraine populations. A key limitation is the exclusive use of placebo as the comparator, so the relative advantage over standard preventives remains unknown. The predominantly female and White study cohorts also restrict generalizability.
Future Research: Further investigations should evaluate atogepant in direct comparisons with existing active migraine preventives, examine long-term outcomes, and recruit more diverse populations. Such efforts could better define the therapy’s place in routine migraine care.
Reference: Lipton RB, et al. Early Improvements With Atogepant for the Preventive Treatment of Migraine: Results From 3 Randomized Phase 3 Trials. Neurology. 2025;104(2). DOI: https://doi.org/10.1212/WNL.0000000000210212
VisionFM: A Generalist AI Surpasses Single-Modality Models in Ophthalmic Diagnostics
25 Dec, 2024 | 13:41h | UTCBackground: Ophthalmic AI models typically address single diseases or modalities. Their limited generalizability restricts broad clinical application. This study introduces VisionFM, a novel foundation model trained on 3.4 million images from over 500,000 individuals. It covers eight distinct ophthalmic imaging modalities (e.g., fundus photography, OCT, slit-lamp, ultrasound, MRI) and encompasses multiple diseases. Compared with prior single-task or single-modality approaches, VisionFM’s architecture and large-scale pretraining enable diverse tasks such as disease screening, lesion segmentation, prognosis, and prediction of systemic markers.
Objective: To develop and validate a generalist ophthalmic AI framework that can handle multiple imaging modalities, recognize multiple diseases, and adapt to new clinical tasks through efficient fine-tuning, potentially easing the global burden of vision impairment.
Methods: VisionFM employs individual Vision Transformer–based encoders for each of the eight imaging modalities, pretrained with self-supervised learning (iBOT) focused on masked image modeling. After pretraining, various task-specific decoders were fine-tuned for classification, segmentation, and prediction tasks. The model was evaluated on 53 public and 12 private datasets, covering eight disease categories (e.g., diabetic retinopathy, glaucoma, cataract), five imaging modalities (fundus photographs, OCT, etc.), plus additional tasks (e.g., MRI-based orbital tumor segmentation). Performance metrics included AUROCs, Dice similarity coefficients, F1 scores, and comparisons with ophthalmologists of varying clinical experience.
Results: VisionFM achieved an average AUROC of 0.950 (95% CI, 0.941–0.959) across eight disease categories in internal validation. External validation showed AUROCs of 0.945 (95% CI, 0.934–0.956) for diabetic retinopathy and 0.974 (95% CI, 0.966–0.983) for AMD, surpassing baseline deep learning approaches. In a 12-disease classification test involving 38 ophthalmologists, VisionFM’s accuracy matched intermediate-level specialists. It successfully handled modality shifts (e.g., grading diabetic retinopathy on previously unseen OCTA), with an AUROC of 0.935 (95% CI, 0.902–0.964). VisionFM also predicted glaucoma progression (F1, 72.3%; 95% CI, 55.0–86.3) and flagged possible intracranial tumors (AUROC, 0.986; 95% CI, 0.960–1.00) from fundus images.
Conclusions: VisionFM offers a versatile, scalable platform for comprehensive ophthalmic tasks. Through self-supervised learning and efficient fine-tuning, it extends specialist-level performance to multiple clinical scenarios and imaging modalities. The study demonstrates that large-scale, multimodal pretraining can enable robust generalization to unseen data, potentially reducing data annotation burdens and accelerating AI adoption worldwide.
Implications for Practice: VisionFM may help address global shortages of qualified ophthalmologists and expand care in low-resource settings, though clinical decision-making still requires appropriate human oversight. Further multicenter studies are needed before widespread implementation, especially for higher-risk use cases such as tumor detection.
Study Strengths and Limitations: Strengths include its unique multimodal design, large-scale pretraining, and extensive external validation. Limitations involve demographic bias toward Chinese datasets, the need for larger cohorts in certain applications (e.g., intracranial tumor detection), and the challenges of matching real-world clinical complexity when only image-based data are used.
Future Research: Further validation in diverse populations, integration of new imaging modalities (e.g., widefield imaging, ultrasound variants), and expansion to additional diseases are planned. Hybridization with large language models could facilitate automatic generation of clinical reports.
Reference: Qiu J, Wu J, Wei H, et al. Development and Validation of a Multimodal Multitask Vision Foundation Model for Generalist Ophthalmic Artificial Intelligence. NEJM AI 2024;1(12). DOI: http://doi.org/10.1056/AIoa2300221
Meta-analysis: Incidence Rate Difference of Adverse Events from Canabinoids in Middle-Aged and Older Adults
25 Dec, 2024 | 12:19h | UTCBackground: Growing evidence suggests that cannabinoid-based medicines (CBMs) are increasingly prescribed to individuals aged 50 years and above for various clinical conditions. While these agents may offer therapeutic benefits, questions remain about the incidence of adverse events (AEs), particularly in older adults with multiple comorbidities. This systematic review and meta-analysis aims to quantify the incidence rate difference (IRD) of AEs and determine whether weekly doses of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are associated with any dose-dependent increase in risk.
Objective: To evaluate whether adults aged ≥50 years exposed to CBMs, including THC-alone formulations and THC combined with CBD, experience a higher incidence of AEs than controls, and to assess how variations in weekly THC and CBD doses might affect AE rates.
Methods: Researchers searched MEDLINE, PubMed, EMBASE, CINAHL, PsychInfo, Cochrane Library, and ClinicalTrials.gov from January 1, 1990, to June 12, 2023. Randomized clinical trials involving middle-aged and older adults (mean age ≥50 years) using medicinal CBMs for all indications were included. Data on common and serious AEs, withdrawals, and deaths were extracted and pooled using a random-effects model. Further meta-regression analyses examined THC and CBD weekly doses as predictors of AEs in THC-only and THC:CBD trials.
Results: Fifty-eight randomized clinical trials (n=6611) met inclusion criteria, with 3450 participants receiving CBMs. Compared to controls, individuals on THC-alone experienced significantly higher incidence of dizziness, somnolence, impaired coordination, dissociative symptoms, and dry mouth, often in a dose-dependent manner. Similarly, THC:CBD combinations increased nausea, vomiting, fatigue, dizziness, and disorientation. The incidence of serious AEs, withdrawals, or mortality did not differ significantly between CBM and control groups, although neurological or psychiatric side effects were more pronounced with higher THC doses.
Conclusions: THC-containing CBMs can provoke dose-related gastrointestinal, neurological, and psychiatric adverse events, posing additional risks in older adults susceptible to falls and cognitive disturbances. However, the meta-analysis found no significant increases in serious AEs or deaths. Clinicians should weigh potential benefits against the likelihood of common side effects, especially when prescribing higher THC doses or combining cannabinoids with other medications frequently used by older patients.
Implications for Practice:
- Physicians should exercise caution when initiating or escalating THC-based therapies in middle-aged and older adults, monitoring for neurological or psychiatric AEs.
- Using lower THC doses, titrating gradually, and adding CBD may mitigate some side effects.
- Though severe AEs are uncommon, vigilance is warranted in individuals with complex medication regimens.
Study Strengths and Limitations:
- Strength: This review merges diverse clinical conditions and provides a comprehensive assessment of THC vs. THC:CBD. Its large pooled population allows for more precise IRD estimates.
- Limitation: Short treatment durations in many trials limit understanding of long-term toxicity, and some studies lacked rigorous reporting of randomization and outcome measures, potentially introducing bias.
Future Research:
- Longer-duration trials focused on older populations are needed to clarify chronic safety profiles.
- Studies exploring drug-drug interactions between CBMs and medications commonly prescribed to older adults will further elucidate real-world tolerability.
Reference: Velayudhan L, Pisani S, Dugonjic M, McGoohan K, Bhattacharyya S. Adverse events caused by cannabinoids in middle aged and older adults for all indications: a meta-analysis of incidence rate difference. Age and Ageing. 2024;53(11):afae261. DOI: https://doi.org/10.1093/ageing/afae261
Bayesian Network Meta-Analysis: Chlorpromazine IV/IM Emerges as a Top Choice for Acute Migraine Relief in the ED
25 Dec, 2024 | 11:18h | UTCBackground: Acute migraine is a prevalent cause of emergency department (ED) visits, necessitating prompt pain control. Although numerous drugs are available, there is debate about the most effective and safest options. Traditional pairwise meta-analyses fail to capture all treatment comparisons in a single framework, making network meta-analyses, particularly Bayesian, an appealing approach to inform clinical decision-making.
Objective: This systematic review and Bayesian network meta-analysis aimed to compare multiple pharmacologic therapies—single agents or combinations—for acute migraine relief in adults presenting to the ED. The goal was to identify those most likely to achieve adequate pain relief, reduce rescue medication use, and minimize significant adverse reactions.
Methods: The authors searched MEDLINE, Embase, and Web of Science from inception to February 9, 2024, for randomized controlled trials comparing any pharmacologic therapy to another or to placebo in ED patients with migraine. Four primary outcomes were analyzed: (1) adequate pain relief at two hours, (2) change in pain intensity at one hour, (3) need for rescue drug at two hours, and (4) significant adverse reaction (eg, sedation, akathisia, hypotension).
Results: Twenty-four to twenty-seven trials contributed to each outcome network. Chlorpromazine IV/IM was ranked highest for adequate pain relief (SUCRA=87.3%) and also significantly reduced the need for rescue medication (SUCRA=93.2%). Ibuprofen IV and valproate IV emerged among the least effective for pain relief, while dexamethasone IV was the most probable to cause fewer serious adverse reactions (SUCRA=79.5%). However, most comparisons were of low or very low certainty, limiting the strength of the findings.
Conclusions: Chlorpromazine IV/IM appears among the most effective single agents for acute migraine in the ED, although it may carry higher risks of sedation or hypotension. Certain analgesics (eg, ibuprofen IV, valproate IV, and possibly ketorolac IV/IM) demonstrated lower efficacy. Due to variability in trial size, dosing, and participant characteristics, the overall certainty of evidence remains limited.
Implications for Practice: Clinicians may consider parenteral chlorpromazine for rapid migraine relief, balancing its adverse event profile with potential efficacy. Dexamethasone’s lower probability of serious side effects could make it a complementary option. The findings highlight the need for individualized treatment, taking into account patient comorbidities and preferences.
Study Strengths and Limitations: This network meta-analysis offers a broad comparative perspective on diverse pharmacologic interventions for ED-based migraine management. Nonetheless, there is notable heterogeneity in study methodologies, small sample sizes, and sparse direct comparisons for many interventions, all of which reduce certainty in the estimates.
Future Research: Larger, more standardized trials are needed to confirm these results and directly compare drugs like chlorpromazine, prochlorperazine, and metoclopramide-NSAID combinations. Rigorous safety reporting is crucial to clarify adverse reaction risks for various agents, especially those with less available evidence.
Reference: deSouza IS, Anthony N, Thode H Jr, et al. Effectiveness and Safety of Pharmacologic Therapies for Migraine in the Emergency Department: A Systematic Review and Bayesian Network Meta-analysis. Annals of Emergency Medicine. DOI: http://doi.org/10.1016/j.annemergmed.2024.11.004
AGA Clinical Practice Update on Screening and Surveillance in High-Risk US Populations for Gastric Cancer: Expert Review
25 Dec, 2024 | 11:02h | UTCIntroduction:
This American Gastroenterological Association (AGA) Clinical Practice Update provides guidance on primary and secondary prevention strategies for gastric cancer (GC) among high-risk groups in the United States. GC disproportionately affects racial and ethnic minorities, certain first-generation immigrants from countries with elevated GC incidence, and individuals with specific hereditary syndromes or family histories of GC. Given ongoing disparities in diagnosis and outcomes, this document outlines best practices for recognizing at-risk individuals, performing high-quality endoscopic screening, and establishing surveillance protocols for gastric precancerous conditions.
Key Recommendations:
- Identify High-Risk Groups: Consider screening among first-generation immigrants from high-incidence regions, people with a family history of GC in a first-degree relative, individuals with hereditary gastrointestinal syndromes, and patients with multiple risk factors (eg, chronic Helicobacter pylori infection, smoking, diets high in salt and processed meats).
- Preferred Screening Modality: Upper endoscopy is considered the best method for detecting precancerous lesions (atrophic gastritis and intestinal metaplasia) and early malignancies. It allows direct visualization of the gastric mucosa, systematic biopsy, and accurate histologic staging.
- High-Quality Endoscopic Examination: Essential elements include high-definition endoscopes, optimal mucosal cleansing and insufflation, adequate inspection time, systematic photodocumentation, and biopsy protocols (such as the updated Sydney System) to detect and characterize precancerous changes or early cancer.
- H. pylori Eradication: Opportunistic screening for H. pylori and its eradication are key adjunctive measures in preventing GC development. Family-based testing—screening adult household members of H. pylori–positive individuals—may further reduce reinfection rates and disease progression.
- Systematic Biopsy Protocols: When atrophic gastritis or intestinal metaplasia is suspected, obtain at least five biopsies (antrum/incisura and corpus in separate containers). Any suspicious lesion should be sampled independently.
- Recognition of Metaplasia and Dysplasia: Endoscopists should be trained to accurately identify visual patterns associated with gastric intestinal metaplasia (GIM) and dysplasia. Artificial intelligence may hold promise, but current data are insufficient to recommend routine use.
- Risk Stratification and Surveillance Intervals: Patients with confirmed GIM or dysplasia, especially those with severe or extensive metaplasia, may require follow-up endoscopy every three years. Individuals with multiple risk factors or severe metaplastic changes could benefit from shorter intervals.
- Management of Dysplasia and Early GC: All dysplasia should be reviewed by an expert gastrointestinal pathologist. Visible high-grade dysplasia or early GC lesions generally warrant endoscopic submucosal dissection (ESD) at specialized centers to achieve en bloc, R0 resection and enable accurate pathology.
- Post-Resection Surveillance: Individuals with successfully resected dysplasia or early cancer need ongoing endoscopic surveillance to detect metachronous lesions. Surveillance intervals vary depending on pathology results and patient-level factors.
- De-Escalation of Screening: Discontinue screening or surveillance when the patient is no longer fit for potential endoscopic or surgical treatment.
- Equity and Sustainability: To reduce GC mortality, it is crucial to address modifiable risk factors, enhance patient access to endoscopy and skilled practitioners, and integrate research advances, especially in noninvasive biomarker development and improved endoscopic technologies.
Conclusion:
An effective US-based GC screening and surveillance program requires robust preprocedural identification of high-risk individuals, intraprocedural adherence to quality endoscopy standards, and consistent postprocedural follow-up to ensure equitable access to treatment. By refining these clinical practices and prioritizing research, meaningful reductions in GC incidence and mortality can be achieved, ultimately improving patient outcomes and addressing healthcare disparities.
Reference:
Shah SC, Wang AY, Wallace MB, Hwang JH. AGA Clinical Practice Update on Screening and Surveillance in Individuals at Increased Risk for Gastric Cancer in the United States: Expert Review. Gastroenterology. Published online December 23, 2024.
https://doi.org/10.1053/j.gastro.2024.11.001
RCT: Levofloxacin for the Prevention of Multidrug-Resistant Tuberculosis in Vietnam
24 Dec, 2024 | 12:53h | UTCBackground:
Multidrug-resistant (MDR) and rifampin-resistant tuberculosis pose significant global health challenges. Preventing active disease among contacts exposed to resistant strains is critical, yet limited evidence exists on targeted chemopreventive interventions. This study investigated whether a six-month course of daily levofloxacin could reduce the incidence of bacteriologically confirmed tuberculosis among household contacts of individuals with confirmed MDR or rifampin-resistant tuberculosis in Vietnam.
Objective:
To assess if levofloxacin prophylaxis decreases the 30-month incidence of active tuberculosis among high-risk contacts. Primary endpoints included bacteriologically confirmed disease, and secondary outcomes encompassed adverse events, mortality, and development of fluoroquinolone-resistant Mycobacterium tuberculosis.
Methods:
Researchers conducted a double-blind, placebo-controlled, randomized trial. Eligible participants were household contacts of persons who had started MDR tuberculosis treatment within the previous three months, had a positive tuberculin skin test or immunosuppressive condition, and showed no clinical or radiographic signs of active disease. Enrolled individuals received weight-based oral levofloxacin (up to 750 mg/day) or an identical placebo for 180 days. Monthly visits supported adherence and monitored adverse events. Participants underwent follow-up visits every six months until 30 months for tuberculosis screening, chest radiography, and sputum testing where indicated.
Results:
Of 2041 randomized contacts, 1995 (97.7%) completed 30 months of follow-up or reached a primary endpoint. Confirmed tuberculosis was diagnosed in 6 participants (0.6%) in the levofloxacin group and 11 (1.1%) in the placebo group (incidence rate ratio, 0.55; 95% CI, 0.19–1.62), a difference that did not achieve statistical significance. Severe (grade 3 or 4) adverse events were infrequent in both groups, while mild adverse events were more common with levofloxacin (31.9% vs. 13.0%). Acquired fluoroquinolone resistance was not detected.
Conclusions:
Daily levofloxacin for six months showed a numerically lower incidence of tuberculosis than placebo, but the difference was not statistically significant due to lower-than-expected case counts. Treatment was generally well tolerated; however, higher discontinuation rates occurred among levofloxacin recipients, often due to mild musculoskeletal complaints. Further studies may clarify the role of fluoroquinolone-based regimens in preventing MDR tuberculosis across diverse epidemiologic contexts.
Implications for Practice:
These findings suggest that levofloxacin prophylaxis could benefit contacts at high risk of MDR tuberculosis, albeit with caution regarding adherence challenges and low-grade side effects. Broader implementation would require diligent screening, consideration of background fluoroquinolone resistance, and strategies to manage mild adverse events that could undermine treatment completion.
Study Strengths and Limitations:
Strengths include a rigorous double-blind, placebo-controlled design, nearly complete follow-up, and thorough exclusion of prevalent tuberculosis at baseline. Limitations involve an unexpectedly low incidence of confirmed disease, limiting statistical power, and a study population with low HIV prevalence, which may reduce generalizability.
Future Research:
Further research is necessary to confirm these findings in diverse settings, explore alternative or shorter regimens (including newer agents like delamanid), and investigate optimal approaches for patients with fluoroquinolone-resistant strains. The long-term impact on transmission dynamics and microbiome shifts also warrants additional investigation.
Guideline: Metformin to Prevent Antipsychotic-Induced Weight Gain
23 Dec, 2024 | 20:55h | UTCIntroduction:
This guideline was developed to address a pressing need for strategies to prevent antipsychotic-induced weight gain (AIWG), a frequent and troubling adverse effect of treatment in individuals with severe mental illness (SMI). Although metformin has shown consistent benefits in mitigating weight gain when initiated alongside antipsychotics, clinical uptake remains limited. The guideline follows the AGREE II framework and synthesizes both randomized and observational research, including Cochrane and meta-analytic data. The primary objective is to outline explicit indications, dosing approaches, and duration for using metformin to avert AIWG.
Key Recommendations:
- Co-initiation With High-Risk Agents: In patients requiring higher-risk antipsychotics (olanzapine, clozapine), start metformin simultaneously. Evidence suggests that concurrent treatment may lessen weight gain by 3 to 5 kg in the early months, potentially yielding greater benefits over time.
- Co-initiation With Medium-Risk Agents: For individuals prescribed quetiapine, paliperidone, or risperidone who have at least one cardiometabolic risk factor (such as diabetes, prediabetes, hypertension, or BMI above 25) or who are 10 to 25 years old, begin metformin at antipsychotic initiation to curb rapid weight changes.
- Initiation During the First Year: If, at any point in the first year of antipsychotic treatment, weight gain exceeds 3% over baseline, consider adding metformin regardless of the antipsychotic being used.
- Titration Schedule and Safety: The guideline advises starting at 500 mg once daily, then moving to 500 mg twice daily after about two weeks, with subsequent increases every two weeks up to 1 g twice daily (2 g/day) as tolerated. Metformin must be discontinued if lactic acidosis is suspected, if BMI falls below 20, or if the antipsychotic is stopped. Avoid its use in harmful alcohol consumption.
- Additional Treatment Options: In cases of obesity (BMI ≥30) or comorbid metabolic disorders, clinicians should consider adding glucagon-like peptide-1 receptor agonists (GLP-1) where available. If cost, supply, or access is limited, metformin remains a practical alternative.
Conclusion:
This is the first evidence-based guideline focused on preventing AIWG by starting metformin at the time of antipsychotic initiation or upon early weight gain signs. By reducing the magnitude of weight increase, metformin may alleviate health risks tied to obesity, as well as psychological distress and nonadherence to treatment. Implementing the guideline involves continuous weight monitoring, structured dose adjustments, and shared decision-making. Ensuring clear communication about benefits and potential side effects will be crucial for sustaining adherence and improving patient outcomes.
Reference:
Carolan A, Hynes-Ryan C, Agarwal SM, Bourke R, Cullen W, Gaughran F, Hahn MK, Krivoy A, Lally J, Leucht S, et al. Metformin for the Prevention of Antipsychotic-Induced Weight Gain: Guideline Development and Consensus Validation. Schizophrenia Bulletin. 2024; sbae205.
DOI: https://doi.org/10.1093/schbul/sbae205
Additional Commentaries:
- Psychiatric News Alert: https://alert.psychnews.org/2024/12/new-guideline-advises-metformin-to.html
- Zagorski N. Metformin May Reduce Weight Gain in Youth Taking Antipsychotics. Psychiatric News. 2024; 59(01). https://psychiatryonline.org/doi/full/10.1176/appi.pn.2024.01.1.22
Guideline: Doxycycline Postexposure Prophylaxis to Reduce Bacterial STI Incidence in High-Risk Populations
19 Dec, 2024 | 22:32h | UTCIntroduction: This summary presents key recommendations from the 2024 Centers for Disease Control and Prevention (CDC) guidelines on using doxycycline postexposure prophylaxis (doxyPEP) to prevent bacterial sexually transmitted infections (STIs), including syphilis, gonorrhea, and chlamydia. Targeting men who have sex with men (MSM) and transgender women with at least one bacterial STI in the past 12 months, these guidelines aim to reduce recurrence rates and improve sexual health outcomes through timely prophylactic intervention.
Key Recommendations:
- Offer doxyPEP counseling to MSM and transgender women with a recent bacterial STI history, addressing the benefits, harms, and uncertainties of prophylactic doxycycline use.
- Advise eligible patients to take a single 200 mg dose of doxycycline as soon as possible (ideally within 72 hours) following condomless oral, anal, or vaginal sexual exposure to reduce their subsequent STI risk.
- Reinforce periodic screening (every 3–6 months) for STI markers, including syphilis and HIV serologies, as well as nucleic acid amplification tests for gonorrhea and chlamydia at relevant anatomical sites.
- Integrate doxyPEP into comprehensive sexual health services that include risk-reduction counseling, condom use, recommended immunizations, and linkage to HIV preexposure prophylaxis (PrEP) or HIV care, thereby enhancing overall prevention strategies.
- Consider extending doxyPEP to other high-risk groups, including heterosexual individuals with recurrent STIs, guided by clinical judgment and shared decision-making.
- Monitor and address adverse events, particularly gastrointestinal symptoms, and acknowledge the potential for antimicrobial resistance. Continued vigilance is warranted given the risk of resistance in commensal flora and key STI pathogens, such as Neisseria gonorrhoeae.
- Assess social and ethical dimensions of doxyPEP implementation, ensuring equitable access and minimizing potential harms, including stigma or intimate partner violence related to prophylaxis disclosure.
Conclusion: Implementing doxyPEP for MSM and transgender women who have experienced a recent bacterial STI can substantially lower the incidence of recurrent infections. By combining prophylactic doxycycline with routine surveillance, comprehensive preventive services, and careful consideration of resistance patterns, clinicians may enhance patient care and strengthen STI control efforts. Further investigation is needed to establish efficacy in cisgender women, transgender men, nonbinary persons, and other populations at risk. Longer-term, population-based studies focused on antimicrobial resistance and community-level effects will help guide sustainable and equitable use of this prevention strategy.
Review: New and Emerging Treatments for Major Depressive Disorder
19 Dec, 2024 | 22:21h | UTCIntroduction: This is a summary of a review on new and emerging treatments for major depressive disorder (MDD), a globally prevalent condition with substantial morbidity and socioeconomic burden. While conventional monoaminergic antidepressants often provide benefit, many patients do not achieve remission, leading to treatment-resistant depression. Novel approaches, including psychedelics (psilocybin, ketamine/esketamine), anti-inflammatory agents, opioid modulators, neuropeptides, botulinum toxin injections, and various neuromodulatory techniques (newer forms of transcranial magnetic stimulation and light-based therapies), are under investigation. This summary highlights their potential efficacy, tolerability, and current limitations.
Key Recommendations:
- Ketamine and Esketamine: Consider these as adjunctive treatments for patients with refractory MDD, given their rapid antidepressant and anti-suicidal effects. Carefully monitor for blood pressure elevations and potential habituation. Long-term cost-effectiveness and sustained benefits remain uncertain.
- Psychedelics (Psilocybin, Ayahuasca): Psilocybin-assisted therapy may produce rapid symptom improvement, but scalability, required therapeutic support, and possible increases in suicidality raise concern. Ayahuasca shows early promise, yet lacks robust long-term data and standardized administration protocols.
- Neuromodulation (rTMS, TBS, Accelerated TMS, Light Therapy): Repetitive transcranial magnetic stimulation (rTMS) and its variants (theta burst stimulation, accelerated protocols) demonstrate modest efficacy with good tolerability. Bright light therapy may enhance neuromodulation outcomes. Optimal protocols and positioning in treatment pathways are not well established.
- Anti-inflammatory and Other Agents: Preliminary findings suggest potential adjunctive roles for minocycline, NSAIDs, statins, omega-3 fatty acids, and a buprenorphine-samidorphan combination. However, larger, high-quality trials are needed to confirm their efficacy and safety profiles.
- Onabotulinumtoxin A: A single glabellar injection may confer antidepressant effects, but the underlying mechanism and durability are unclear. Methodological issues, including difficulties with blinding, limit strong recommendations.
- More Invasive Interventions (DBS, MST): Deep brain stimulation (DBS) and magnetic seizure therapy (MST) are invasive approaches supported by limited evidence, restricting their use to highly refractory cases. The balance of benefit, risk, and resource intensity remains uncertain.
Conclusion: Although these emerging treatments offer potential avenues beyond traditional antidepressants, most remain investigational. Key challenges include limited comparative data, uncertain long-term outcomes, and scaling difficulties. Further rigorous research, including head-to-head trials, long-term follow-ups, and clarity regarding optimal psychotherapeutic support, is required. As evidence matures, these novel interventions may become more integrated into standard care, potentially improving outcomes for patients with difficult-to-treat MDD.
Review: Nonsurgical Management of Chronic Venous Insufficiency
19 Dec, 2024 | 16:45h | UTCIntroduction: This summary highlights key points from a recent review on the nonsurgical management of chronic venous insufficiency, a condition characterized by persistent venous hypertension leading to edema, skin changes, and venous ulcers. Chronic venous insufficiency is influenced by both structural factors (e.g., venous reflux, obstruction) and functional elements (e.g., obesity, impaired calf-muscle pump). While interventional procedures may improve symptoms in patients with significant structural abnormalities, most cases require comprehensive nonsurgical strategies targeting venous hypertension and improving quality of life.
Key Recommendations:
- Comprehensive Assessment: Distinguish between structural and functional components of venous disease. Structural issues may warrant endovenous procedures, whereas functional insufficiency (e.g., due to obesity, weak calf muscles) requires behavioral and medical interventions.
- Compression Therapy (Class 1A for Venous Ulcers): Use tailored compression stockings or wraps to reduce venous pressure, alleviate swelling, and aid ulcer healing. Compression levels above 30 mm Hg can facilitate healing, but lower levels (20–30 mm Hg) may improve adherence.
- Lifestyle Modifications: Implement weight reduction measures in obese patients to lower central venous pressure and improve venous return. Consider evaluating and managing obstructive sleep apnea or cardiac dysfunction that may elevate venous pressure.
- Exercise and Leg Elevation: Encourage exercises that strengthen calf and foot muscles, thereby enhancing the venous pump function and reducing stasis. Advise regular leg elevation to alleviate edema and discomfort.
- Medication Review: Assess current medications (e.g., calcium-channel blockers, gabapentinoids) that may cause edema and consider alternatives. Avoid unnecessary diuretics unless true volume overload is confirmed.
- Venous Interventions for Structural Lesions (Class IB for Varicose Veins): In patients with symptomatic varicose veins and axial reflux, procedural interventions (e.g., endovenous ablation, sclerotherapy, or surgical stripping) can be more effective than long-term compression alone. Early intervention may expedite ulcer healing in selected cases.
- Cautious Use of Venoactive Agents: Although certain supplements (e.g., flavonoids, horse chestnut) are widely available, current guidelines provide only weak recommendations, with limited evidence for clinically meaningful outcomes.
Conclusion: Nonsurgical management of chronic venous insufficiency emphasizes reducing venous hypertension, improving calf muscle pump function, and addressing central factors such as obesity and cardiac conditions. By combining compression therapy, exercise, weight reduction, and appropriate medication adjustments, clinicians can alleviate symptoms, enhance patient comfort, and potentially improve wound healing. Procedural interventions remain essential adjuncts for selected structural abnormalities, but long-term functional management is key to sustained clinical benefit.
Review: Management of Atrial Fibrillation
18 Dec, 2024 | 14:22h | UTCIntroduction: This summary of a comprehensive review on atrial fibrillation (AF) focuses on an increasingly prevalent arrhythmia affecting more than 10 million adults in the United States. AF significantly elevates the risks of stroke, heart failure (HF), cognitive decline, and mortality. This guideline-based overview examines the pathophysiology, detection, prevention, and treatment strategies for AF, emphasizing risk factor modification, appropriate anticoagulation, and early rhythm control interventions to improve clinical outcomes and quality of life.
Key Recommendations:
- Risk Factor and Lifestyle Modification: Implement weight reduction, regular exercise, optimal blood pressure control, smoking cessation, and reduced alcohol intake at all AF stages to prevent new-onset AF, reduce recurrences, and mitigate complications.
- Screening and Diagnosis: Consider AF screening in high-risk patients using wearable devices or implantable loop recorders. Confirm suspected AF with electrocardiography and extended rhythm monitoring in those with cryptogenic stroke.
- Stroke Prevention: Assess stroke risk using CHA2DS2-VASc. For patients with annual stroke risk ≥2%, initiate oral anticoagulation (preferably direct oral anticoagulants over warfarin) to lower stroke risk by up to 80%. Avoid aspirin monotherapy for AF-related stroke prevention due to inferior efficacy.
- Early Rhythm Control: Begin rhythm control within one year of AF diagnosis, particularly in symptomatic patients or those with HF and reduced ejection fraction (HFrEF). Early use of antiarrhythmic drugs or catheter ablation can improve symptoms, cardiac function, and reduce hospitalizations.
- Catheter Ablation: Utilize ablation as a first-line therapy in symptomatic paroxysmal AF to maintain sinus rhythm and prevent progression. In patients with AF and HFrEF, ablation enhances quality of life, improves left ventricular function, and lowers mortality and HF hospitalization rates.
- Rate Control Strategies: For patients who are not candidates for rhythm control, use beta-blockers or nondihydropyridine calcium channel blockers to achieve satisfactory ventricular rate control. Consider atrioventricular nodal ablation plus pacemaker implantation if pharmacologic therapy is inadequate.
- Staging and Long-Term Management: Recognize four AF stages (at risk, pre-AF, clinically apparent AF, and permanent AF) to tailor management. After ablation, continue anticoagulation for at least three months, then reassess stroke risk before considering discontinuation.
- Addressing Inequities: Improve access to guideline-directed AF therapies, including ablation and specialized care, and address social determinants of health that influence disparities in diagnosis, treatment, and outcomes.
Conclusion: Guideline-directed AF management, encompassing comprehensive risk factor modification, appropriate anticoagulation, and timely rhythm control strategies, can reduce stroke incidence, improve HF outcomes, and prolong life. Catheter ablation is a key intervention for appropriate patients, especially those with symptomatic paroxysmal AF or HFrEF, while striving for equitable and evidence-based care across diverse populations remains a critical priority.
Review: Diagnosis and Management of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)
18 Dec, 2024 | 11:08h | UTCIntroduction: DRESS is a severe T-cell–mediated hypersensitivity reaction triggered by prolonged exposure to certain medications, characterized by extensive rash, fever, hematologic abnormalities (notably eosinophilia or atypical lymphocytosis), lymphadenopathy, and involvement of internal organs such as the liver, kidneys, and lungs. Common culprits include aromatic anticonvulsants, allopurinol, and specific antibiotics. Although relatively rare, DRESS accounts for a substantial proportion of severe cutaneous adverse drug reactions (SCARs) in hospitalized patients and can be life-threatening, with mortality rates around 5%. Its pathogenesis involves complex immune dysregulation, including Th2 predominance, possible viral reactivation (e.g., HHV-6), and genetic predispositions related to certain HLA alleles. Diagnosis typically relies on clinical criteria, such as the validated RegiSCAR scoring system, and on excluding other SCARs like Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and acute generalized exanthematous pustulosis (AGEP).
Key Recommendations:
- Identify and Discontinue the Culprit Drug: Prompt removal of the offending medication is the cornerstone of therapy.
- Supportive Care and Monitoring: Hospitalization, often in an intensive care setting, may be required for organ function support and close monitoring of disease progression. Regular assessment of liver enzymes, renal function, blood counts, and cardiac and pulmonary status is critical.
- Systemic Glucocorticoids: High-dose corticosteroids (e.g., prednisone 0.5–1 mg/kg/day) are first-line therapy. A gradual taper over 6–12 weeks is recommended to minimize relapse.
- Steroid-Sparing and Targeted Therapies: In refractory cases or when steroids are contraindicated, consider other immunosuppressants (e.g., cyclosporine, mycophenolate mofetil) or targeted biologic agents (e.g., anti–IL-5 therapies) to control persistent eosinophilia and organ involvement.
- Diagnostic Testing and Specialist Involvement: Although no single test confirms DRESS, dermatology or allergy/immunology consultation may help identify culprit drugs and safer therapeutic alternatives. Patch testing, delayed intradermal testing, and HLA genotyping can sometimes clarify drug causality.
- Long-Term Follow-Up: Patients require prolonged observation due to risks of relapse, potential autoimmune sequelae (e.g., thyroiditis, type 1 diabetes), and psychological distress. Ongoing multidisciplinary care and support are essential.
Conclusion: Early recognition of DRESS, prompt discontinuation of the offending drug, and initiation of systemic corticosteroids are key steps in management. Emerging therapies offer additional treatment options for severe or refractory cases. Long-term follow-up is vital to address relapses, organ damage, and autoimmune complications. A coordinated, multidisciplinary approach improves clinical outcomes and quality of life for affected patients.
Guidelines for the Management of Hyperglycemic Crises in Adult Patients with Diabetes
15 Dec, 2024 | 13:18h | UTCIntroduction: Diabetic ketoacidosis (DKA) and hyperglycemic hyperosmolar state (HHS) are critical, acute complications of type 1 and type 2 diabetes. Recent data show a global rise in DKA and HHS admissions, driven by factors such as psychosocial challenges, suboptimal insulin use, infection, and certain medications (e.g., SGLT2 inhibitors). This consensus report, developed by leading diabetes organizations (ADA, EASD, JBDS, AACE, DTS), provides updated recommendations on epidemiology, pathophysiology, diagnosis, treatment, and prevention of DKA and HHS in adults, aiming to guide clinical practice and improve outcomes.
Key Recommendations:
- Diagnosis and Classification:
- DKA is defined by hyperglycemia (>11.1 mmol/l [200 mg/dl] or known diabetes), elevated ketone levels (β-hydroxybutyrate ≥3.0 mmol/l), and metabolic acidosis (pH <7.3 or bicarbonate <18 mmol/l).
- HHS is characterized by marked hyperglycemia, severe hyperosmolality (>320 mOsm/kg), significant dehydration, and minimal ketonaemia or acidosis.
- Consider euglycemic DKA, especially with SGLT2 inhibitor use.
- Classify DKA severity (mild, moderate, severe) to guide the setting of care.
- Fluid and Electrolyte Management:
- Initiate isotonic or balanced crystalloid solutions to restore intravascular volume, enhance renal perfusion, and reduce hyperglycemia.
- Adjust fluids based on hydration, sodium levels, and glucose trends.
- Add dextrose when glucose falls below ~13.9 mmol/l (250 mg/dl) to allow ongoing insulin therapy until ketoacidosis resolves.
- Carefully monitor potassium and provide adequate replacement to prevent severe hypokalemia.
- Insulin Therapy:
- Start a continuous intravenous infusion of short-acting insulin as soon as feasible after confirming adequate potassium.
- For mild or moderate DKA, subcutaneous rapid-acting insulin analogs may be used under close supervision.
- Continue insulin until DKA resolves (pH ≥7.3, bicarbonate ≥18 mmol/l, β-hydroxybutyrate <0.6 mmol/l) or HHS improves (osmolality <300 mOsm/kg, improved mental status).
- Overlap subcutaneous basal insulin by 1–2 hours before discontinuing intravenous insulin to prevent rebound hyperglycemia.
- Additional Considerations:
- Avoid routine bicarbonate; use only if pH <7.0.
- Phosphate supplementation is not routinely recommended unless levels are severely low.
- Identify and treat underlying precipitating causes (infection, psychological factors, medication-related triggers).
- Address social determinants of health and mental health conditions to reduce recurrence.
Conclusion: By implementing these evidence-based recommendations—early diagnosis, structured fluid and insulin therapy, careful electrolyte management, and addressing precipitating factors—clinicians can improve patient care, reduce morbidity and mortality, and enhance the quality of life for adults experiencing DKA and HHS.
Prospective Cohort: Combined CRP, LDL Cholesterol, and Lipoprotein(a) Levels Predict 30-Year Cardiovascular Risk in Women
8 Dec, 2024 | 20:58h | UTCBackground: Current 10-year risk models do not fully capture lifetime cardiovascular disease (CVD) risk. Inflammation, low-density lipoprotein (LDL) cholesterol, and lipoprotein(a) are distinct pathways associated with atherosclerosis. While their value in predicting 5- to 10-year cardiovascular risk is established, data on their combined long-term predictive utility, particularly over three decades in women, are limited.
Objective: To determine whether a single baseline measurement of high-sensitivity C-reactive protein (CRP), LDL cholesterol, and lipoprotein(a) provides additive and independent predictive value for 30-year cardiovascular outcomes in initially healthy women.
Methods: This prospective cohort study included 27,939 initially healthy U.S. women (mean age, 54.7 years) from the Women’s Health Study, enrolled between 1992 and 1995. Baseline levels of high-sensitivity CRP, LDL cholesterol, and lipoprotein(a) were measured. Participants were followed for 30 years for a first major adverse cardiovascular event (myocardial infarction, coronary revascularization, stroke, or cardiovascular death). Adjusted hazard ratios (HRs) for each biomarker’s quintiles were estimated, as well as combined models including all three biomarkers simultaneously.
Results: Over 30 years, 3,662 first major cardiovascular events occurred. Higher baseline quintiles of CRP, LDL cholesterol, and lipoprotein(a) were each associated with elevated 30-year risk. Compared to the lowest quintile, adjusted HRs for the top quintile were 1.70 (95% CI, 1.52–1.90) for CRP, 1.36 (95% CI, 1.23–1.52) for LDL cholesterol, and 1.33 (95% CI, 1.21–1.47) for lipoprotein(a). Each marker contributed independently, and models incorporating all three showed the greatest risk discrimination. Participants with all three biomarkers in the highest quintile had a HR of 2.63 (95% CI, 2.16–3.19) for the primary endpoint.
Conclusions: A single combined baseline assessment of high-sensitivity CRP, LDL cholesterol, and lipoprotein(a) strongly predicted CVD events over 30 years. These findings suggest extending beyond traditional 10-year estimates to identify long-term risk, reinforcing the need for early prevention strategies addressing multiple biological pathways.
Implications for Practice: Measuring these three biomarkers early may inform more personalized, prolonged preventive efforts. While lowering LDL cholesterol remains foundational, addressing inflammation and lipoprotein(a) could further optimize long-term CVD prevention. Nonetheless, caution is advised before embracing new interventions lacking robust long-term data.
Study Strengths and Limitations: Strengths include the extended 30-year follow-up, a large, well-characterized cohort, and standardized biomarker assessments. Limitations include a predominantly White, female population, limiting generalizability. Single-time-point biomarker measurements and evolving statin use over time add complexity. Despite these constraints, the study underscores the multifactorial nature of long-term CVD risk.
Future Research: Further investigations should evaluate targeted interventions on inflammation and lipoprotein(a), potentially through long-term clinical trials and more diverse populations. Such research could clarify the benefits of a multimodal risk-reduction strategy.