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Daily Archives: January 2, 2025

Avian Influenza A(H5N1) Outbreak Among US Farm Exposures: Clinical Findings and Early Treatment Outcomes

2 Jan, 2025 | 17:01h | UTC

Background: 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

 

Phase 2 RCT: CRISPR-Based Therapy Reduces Attacks in Hereditary Angioedema

2 Jan, 2025 | 10:00h | UTC

Background: Hereditary angioedema (HAE) is a rare autosomal dominant disorder characterized by unpredictable attacks of angioedema involving cutaneous tissues, the gastrointestinal tract, and, potentially, the larynx, posing a risk of asphyxiation. Current prophylactic treatments require frequent administration, often leading to suboptimal adherence and ongoing disease burden. NTLA-2002 is an in vivo CRISPR-Cas9–based therapy designed to permanently inactivate the KLKB1 gene in hepatocytes, thereby reducing plasma kallikrein levels and, hypothetically, lowering attack frequency in patients with HAE.

Objective: To evaluate whether a single intravenous infusion of NTLA-2002 (25 mg or 50 mg) would safely and effectively decrease HAE attack rates and reduce plasma kallikrein protein levels over a 16-week primary observation period, as compared with placebo.

Methods: This phase 2, randomized, double-blind, placebo-controlled trial included 27 adults with confirmed type 1 or type 2 HAE. Participants were assigned in a 2:2:1 ratio to receive a one-time dose of 25 mg or 50 mg of NTLA-2002 or placebo. The primary endpoint was the investigator-confirmed number of angioedema attacks per month from Week 1 through Week 16. Secondary endpoints included the number of moderate-to-severe attacks, use of on-demand therapy, adverse events, and changes in total plasma kallikrein protein levels (analyzed by immunoassays). Exploratory measures encompassed patient-reported outcomes using the Angioedema Quality of Life (AE-QoL) questionnaire.

Results: During the 16-week period, the mean monthly attack rate decreased by 75% in the 25 mg group and 77% in the 50 mg group relative to placebo (estimated rates of 0.70 vs. 0.65 vs. 2.82 attacks per month, respectively). Notably, 4 of 10 patients (40%) in the 25 mg group and 8 of 11 (73%) in the 50 mg group reported no attacks or further prophylaxis use after dosing. Placebo recipients showed only a 16% reduction from baseline. Adverse events were predominantly mild to moderate; headache, fatigue, and nasopharyngitis were most common. Infusion-related reactions occurred in a few patients but resolved without sequelae. A single transient grade 2 elevation in alanine aminotransferase was recorded in one participant given 25 mg of NTLA-2002. By Week 16, total plasma kallikrein levels decreased by 55% in the 25 mg group and 86% in the 50 mg group, with no meaningful changes in placebo.

Conclusions: A single intravenous infusion of NTLA-2002 significantly lowered attack frequency and reduced total plasma kallikrein levels in HAE. Most patients treated at 50 mg experienced no attacks, suggesting that long-term prophylaxis might be unnecessary for many. Longer observation supports durability, yet cost and potential long-term effects of gene editing warrant cautious interpretation.

Implications for Practice: If confirmed by larger phase 3 trials, this gene-editing approach could alter the management of HAE, reducing or eliminating the need for continuous prophylaxis. However, clinicians must weigh the high upfront cost, possible unpredictable immune responses, and the novelty of CRISPR-based therapies before integrating them into standard care.

Study Strengths and Limitations: Strengths include a placebo-controlled design, meaningful improvement in patient-reported outcomes, and robust plasma kallikrein protein reduction. Limitations are the small sample size, short primary observation period, and uncertain long-term safety in diverse populations.

Future Research: Ongoing phase 3 studies with larger cohorts and extended follow-up are essential to confirm safety, long-term efficacy, and cost-effectiveness.

Reference: Cohn DM, Gurugama P, Magerl M, et al. CRISPR-Based Therapy for Hereditary Angioedema. New England Journal of Medicine. 2024; DOI: http://doi.org/10.1056/NEJMoa2405734

 

Dose-Response Meta-Analysis: At Least 150 Weekly Minutes of Aerobic Exercise Needed for Significant Waist and Fat Reduction

2 Jan, 2025 | 09:30h | UTC

Background: 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

 

RCT: Pembrolizumab with Preoperative Radiotherapy Shows Potential in Stage III Soft Tissue Sarcoma

2 Jan, 2025 | 09:00h | UTC

Background: Patients with locally advanced, high-grade soft tissue sarcomas of the extremity often face a high risk of metastatic disease, despite curative-intent surgery and radiotherapy. Traditional doxorubicin-based chemotherapy provides variable benefits and can cause considerable toxicity, prompting investigations into alternative strategies. Emerging data from smaller trials hinted that immune checkpoint inhibitors might offer targeted benefit in sarcomas, but robust evidence in the neoadjuvant setting remains limited.

Objective: To assess whether adding neoadjuvant and adjuvant pembrolizumab to preoperative radiotherapy and surgical resection could enhance disease-free survival (DFS) in individuals with resectable grade 2 or 3, stage III undifferentiated pleomorphic sarcoma or liposarcoma of the extremity and limb girdle.

Methods: This open-label, randomized trial (SU2C-SARC032) enrolled 143 participants at 20 academic centers in Australia, Canada, Italy, and the USA. Eligible patients were 12 years or older, presented with primary tumors >5 cm, and did not receive chemotherapy as part of this protocol. Participants were randomized 1:1 to standard preoperative radiotherapy (50 Gy/25 fractions) plus surgery (control) or the same radiotherapy combined with pembrolizumab (200 mg every three weeks) in the neoadjuvant setting, followed by up to 14 adjuvant cycles. The primary endpoint was disease-free survival, analyzed in a modified intention-to-treat cohort of 127 evaluable patients, with a median follow-up of 43 months.

Results: The pembrolizumab group demonstrated a higher 2-year DFS rate (67%) compared with controls (52%), suggesting a favorable hazard ratio (0.61) for recurrence or death. Nonetheless, grade 3 or higher adverse events were more common in the pembrolizumab arm (56% vs 31%). Secondary endpoints, including distant disease-free survival and overall survival, also appeared to favor the pembrolizumab arm, but these comparisons were not powered for definitive conclusions.

Conclusions: Neoadjuvant and adjuvant pembrolizumab in combination with radiotherapy and surgery demonstrated a DFS advantage in stage III undifferentiated pleomorphic sarcoma or liposarcoma, reinforcing the potential role of immunotherapy in high-risk settings. However, given the increased incidence of adverse events and the relatively short follow-up for overall survival, cautious interpretation is warranted. Further evidence is required to determine long-term benefits and confirm whether these findings extend to other sarcoma subtypes.

Implications for Practice: These data suggest that incorporating pembrolizumab could be considered in selected patients, particularly those with large, high-grade tumors unresponsive to or unsuitable for traditional chemotherapy. Clinicians must balance the incremental risk of immunotherapy-induced side effects against the observed gains in disease-free survival and the ongoing need for extended follow-up.

Study Strengths and Limitations: Strengths include a multicenter randomized design, focus on a high-risk population, and a robust primary endpoint. Limitations encompass a relatively small sample size, inherent to rare cancers, underpowered subgroup analyses, and absence of long-term survival data. Confirmation of these early signals in larger cohorts and over more extended follow-up periods remains necessary.

Future Research: Additional trials should explore optimal radiotherapy fractionation, potential synergies with cytotoxic or targeted agents, and predictive biomarkers of response. Understanding immune correlates, including circulating tumor DNA and tumor microenvironmental factors, may refine treatment selection and enhance therapeutic outcomes.

Reference: Mowery YM, et al. Safety and efficacy of pembrolizumab, radiation therapy, and surgery versus radiation therapy and surgery for stage III soft tissue sarcoma of the extremity (SU2C-SARC032): an open-label, randomised clinical trial. The Lancet. 2024;404(10467). DOI: http://doi.org/10.1016/S0140-6736(24)01812-9

 

Systematic Review and Bayesian Meta-Analysis: Higher Protein Delivery May Increase Mortality in Critically Ill Patients

2 Jan, 2025 | 08:30h | UTC

Background: Nutritional guidelines often recommend higher protein doses (approximately 1.2–2.0 g/kg/d) to mitigate muscle loss in critically ill patients. However, recent multicenter trials have raised concerns that elevated protein targets might increase mortality and adversely affect patient-centered outcomes. This study applied a Bayesian approach to synthesize current evidence regarding the effect of higher versus lower protein delivery on mortality, infections, mechanical ventilation duration, and health-related quality of life in critically ill adults.

Objective: To estimate the probability of beneficial or harmful effects of increased protein delivery on clinically important outcomes, with emphasis on quantifying the likelihood of mortality benefit versus risk.

Methods: A systematic review and Bayesian meta-analysis were conducted according to a preregistered protocol (PROSPERO CRD42024546387) and PRISMA 2020 guidelines. Twenty-two randomized controlled trials comparing higher (mean 1.5 g/kg/d) versus lower (mean 0.9 g/kg/d) protein delivery in adult ICU patients were included, ensuring similar energy intake in both groups. A hierarchical random-effects Bayesian model was applied, using vague priors to estimate relative risks for mortality and infections, mean differences for ventilator days, and standardized mean differences for quality of life.

Results: A total of 4,164 patients were analyzed. The posterior probability that higher protein intake increases mortality was 56.4%, compared with a 43.6% probability of any mortality benefit. Probabilities for a clinically relevant (≥5%) mortality decrease were low (22.9%), while the probability of at least a 5% increase reached 32.4%. Infections were slightly more likely with higher protein, although the likelihood of a major detrimental effect remained modest. The probability of a clinically meaningful difference in ventilator days was negligible, suggesting near equivalence for that endpoint. Conversely, quality of life might be negatively impacted by higher protein dosing, although few trials measured this outcome.

Conclusions: Under a Bayesian framework, current evidence suggests that high protein delivery in critically ill patients might pose a meaningful risk of increased mortality. Although a beneficial effect cannot be fully excluded, its probability appears comparatively small. These findings challenge the longstanding assumption that more protein universally translates to better outcomes.

Implications for Practice: Clinicians should exercise caution when aiming for higher protein targets. Individual patient characteristics, such as severity of illness, renal function, and underlying comorbidities, may modulate outcomes. The data support considering a personalized protein prescription rather than routinely pushing intake beyond conventional targets.

Study Strengths and Limitations: Strengths include a robust Bayesian analysis that evaluates probabilities of both benefit and harm across multiple thresholds, as well as the inclusion of recently published large trials. Limitations involve heterogeneity in protein dosing strategies, potential publication bias (indicated by Egger’s test), and limited data on quality of life.

Future Research: Ongoing trials, such as TARGET Protein and REPLENISH, will provide valuable insights into optimal protein dosing, particularly in specific subgroups. Further investigation should explore mechanistic underpinnings of how high protein intake could adversely affect recovery in critically ill patients.

Reference: Heuts S, Lee ZY, Lew CCH, et al. Higher Versus Lower Protein Delivery in Critically Ill Patients: A Systematic Review and Bayesian Meta-Analysis. Critical Care Medicine. December 27, 2024. DOI: http://doi.org/10.1097/CCM.0000000000006562

 

Cohort Study: Higher Telehealth Intensity May Reduce Certain Office-Based Low-Value Services in Medicare Primary Care

2 Jan, 2025 | 08:00h | UTC

Background: 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

 

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