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IMPORTANCE: There is an urgent need to identify treatments for postacute sequelae of SARS-CoV-2 infection (PASC). OBJECTIVE: To assess the efficacy of a 15-day course of nirmatrelvir-ritonavir in reducing the severity of select PASC symptoms. DESIGN, SETTING, AND PARTICIPANTS: This was a 15-week blinded, placebo-controlled, randomized clinical trial conducted from November 2022 to September 2023 at Stanford University (California). The participants were adults with moderate to severe PASC symptoms of 3 months or longer duration. INTERVENTIONS: Participants were randomized 2:1 to treatment with oral nirmatrelvir-ritonavir (NMV/r, 300 mg and 100 mg) or with placebo-ritonavir (PBO/r) twice daily for 15 days. MAIN OUTCOMES AND MEASURES: Primary outcome was a pooled severity of 6 PASC symptoms (fatigue, brain fog, shortness of breath, body aches, gastrointestinal symptoms, and cardiovascular symptoms) based on a Likert scale score at 10 weeks. Secondary outcomes included symptom severity at different time points, symptom burden and relief, patient global measures, Patient-Reported Outcomes Measurement Information System (PROMIS) measures, orthostatic vital signs, and sit-to-stand test change from baseline. RESULTS: Of the 155 participants (median [IQR] age, 43 [34-54] years; 92 [59%] females), 102 were randomized to the NMV/r group and 53 to the PBO/r group. Nearly all participants (n = 153) had received the primary series for COVID-19 vaccination. Mean (SD) time between index SARS-CoV-2 infection and randomization was 17.5 (9.1) months. There was no statistically significant difference in the model-derived severity outcome pooled across the 6 core symptoms at 10 weeks between the NMV/r and PBO/r groups. No statistically significant between-group differences were found at 10 weeks in the Patient Global Impression of Severity or Patient Global Impression of Change scores, summative symptom scores, and change from baseline to 10 weeks in PROMIS fatigue, dyspnea, cognitive function, and physical function measures. Adverse event rates were similar in NMV/r and PBO/r groups and mostly of low grade. CONCLUSIONS AND RELEVANCE: The results of this randomized clinical trial showed that a 15-day course of NMV/r in a population of patients with PASC was generally safe but did not demonstrate a significant benefit for improving select PASC symptoms in a mostly vaccinated cohort with protracted symptom duration. Further studies are needed to determine the role of antivirals in the treatment of PASC. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05576662

Alterations of the gut microbiota after allogeneic hematopoietic cell transplantation (allo-HCT) are a key factor in the development of transplant-related complications such as graft-versus-host disease (GVHD). Interventions that preserve the gut microbiome hold promise to improve HCT-associated morbidity and mortality. Murine models demonstrate that prebiotics such as fructo-oligosaccharides (FOSs) may increase gut levels of short-chain fatty acids (SCFAs) such as butyrate and consequently induce proliferation of immunomodulatory FOXP3+CD4+regulatory T cells (Tregs), which impact GVHD risk. We conducted a pilot phase I trial to investigate the maximum tolerated dose of FOS in patients undergoing reduced-intensity allo-HCT (n = 15) compared with concurrent controls (n = 16). We administered the FOS starting at pretransplant conditioning and continuing for a total of 21 days. We characterized the gut microbiome using shotgun metagenomic sequencing, measured stool short-chain fatty acids (SCFAs) using liquid chromatography–mass spectrometry, and determined peripheral T cell concentrations using cytometry by time-of-flight. We found that FOS was safe and well-tolerated at 10 g/d without significant adverse effects in patients undergoing allo-HCT. Community-level gut microbiota composition differed significantly on the day of transplant (day 0) between patients receiving FOS and concurrent controls; however, FOS-associated alterations of the gut microbiota were not sustained after transplant. Although the impact of FOS was fleeting, transplantation itself impacted a substantial number of taxa over time. In our small pilot trial, no significant differences were observed in gut microbial metabolic pathways, stool SCFAs, or peripheral Tregs, although Tregs trended higher in those patients who received FOS. A marker of CD4+T cell activation (namely, CTLA4+) was significantly higher in patients receiving FOS, whereas a non-significant trend existed for FOP3+CD4+Treg cells, which were higher in those receiving FOS compared with controls. FOS is well tolerated at 10 g/d in patients undergoing reduced-intensity allo-HCT. Although the alterations in gut microbiota and peripheral immune cell composition in those receiving FOS are intriguing, additional studies are required to investigate the use of prebiotics in HCT recipients.

To investigate whether dual-energy x-ray absorptiometry (DXA) estimates of adiposity improve risk prediction for cardiometabolic diseases over traditional surrogates, body mass index (BMI), waist circumference (WC), and waist-to-hip ratio (WHR) in older women.

To compare the pregnancy outcomes of lesbian women undergoing donor sperm intrauterine insemination (IUI) with that of heterosexual women undergoing IUI using partner or donor sperm.

Lung transplant candidates can be waitlisted at more than one transplant center, a practice known as multiple listing. The factors associated with multiple listing and whether multiple listing modifies waitlist mortality or likelihood of lung transplant is unknown. US lung transplant waitlist candidates were identified as either single or multiple listed using data from the Scientific Registry of Transplant Recipients. Characteristics of single and multiple listed candidates were compared and multivariable logistic regression was used to estimate associations with multiple listing. Multiple listed candidates were matched to single listed candidates using a combination of exact and propensity score matching methods. Cox proportional hazard models were used to estimate the relationship of multiple listing on waitlist mortality and receiving a transplant. Multiple listing occurred in 2.3% of lung transplant waitlist candidates. Younger age, female gender, white race, short stature, high antibody sensitization, college or postcollege education, lower lung allocation score, and a cystic fibrosis diagnosis were independently associated with multiple listing. Multiple listing was associated with an increased likelihood of lung transplant (adjusted hazard ratio [aHR] 2.74, 95% CI 2.37 to 3.16) but was not associated with waitlist mortality (aHR 0.99, 95% CI 0.68 to 1.44).

Lung transplant candidates can be waitlisted at more than one transplant center, a practice known as multiple listing. The factors associated with multiple listing and whether multiple listing modifies waitlist mortality or likelihood of lung transplant is unknown. USlung transplant waitlist candidates were identified as either single or multiple listed using data from the Scientific Registry of Transplant Recipients. Characteristics of single and multiple listed candidates were compared and multivariable logistic regression was used to estimate associations with multiple listing. Multiple listed candidates were matched to single listed candidates using a combination of exact and propensity score matching methods. Cox proportional hazard models were used to estimate the relationship of multiple listing on waitlist mortality and receiving a transplant. Multiple listing occurred in 2.3% of lung transplant waitlist candidates. Younger age, female gender, white race, short stature, high antibody sensitization, college or postcollege education, lower lung allocation score, and a cystic fibrosis diagnosis were independently associated with multiple listing. Multiple listing was associated with an increased likelihood of lung transplant (adjusted hazard ratio [aHR] 2.74, 95% CI2.37 to 3.16) but was not associated with waitlist mortality (aHR0.99, 95% CI0.68 to 1.44). Multiple listing in US lung transplant candidates is associated with specific clinical and socioeconomic characteristics, with multiple‐listing candidates having a greater adjusted likelihood of undergoing lung transplant as compared to single‐listing candidates.

Calls-to-action in health research have described a need to improve research on race, ethnicity, and structural racism. Well-established cohort studies typically lack access to novel structural and social determinants of health (SSDOH) or precise race and ethnicity categorization, contributing to a loss of rigor to conduct informative analyses and a gap in prospective evidence on the role of structural racism in health outcomes. We propose and implement methods that prospective cohort studies can use to begin to rectify this, using the Women's Health Initiative (WHI) cohort as a case study. To do so, we evaluated the quality, precision, and representativeness of race, ethnicity, and SSDOH data compared with the target US population and operationalized methods to quantify structural determinants in cohort studies. Harmonizing racial and ethnic categorization to the current standards set by the Office of Management and Budget improved measurement precision, aligned with published recommendations, disaggregated groups, decreased missing data, and decreased participants reporting “some other race”. Disaggregation revealed sub-group disparities in SSDOH, including a greater proportion of Black-Latina (35.2%) and AIAN-Latina (33.3%) WHI participants with income below the US median compared with White-Latina (42.5%) participants. We found similarities in the racial and ethnic patterning of SSDOH disparities between WHI and US women but less disparity overall in WHI. Despite higher individual-level advantage in WHI, racial disparities in neighborhood resources were similar to the US, reflecting structural racism. Median neighborhood income was comparable between Black WHI ($39,000) and US ($34,700) women. WHI SSDOH-associated outcomes may be generalizable on the basis of comparing across race and ethnicity but may quantitatively (but not qualitatively) underestimate US effect sizes. This paper takes steps towards data justice by implementing methods to make visible hidden health disparity groups and operationalizing structural-level determinants in prospective cohort studies, a first step to establishing causality in health disparities research.

Kidney disease disproportionately affects minority populations, including African Americans and Hispanics; therefore, understanding the relationship of kidney function to cardiovascular (CV) outcomes within different racial/ethnic groups is of considerable interest. We investigated the relationship between kidney function and CV events and assessed effect modification by race/ethnicity in the Women’s Health Initiative.

Introduction:The burden of bedside alarms is a well-established patient safety hazard with >85% of alarms in ICU settings considered non-actionable or “false alarms”. Healthcare providers risk developing alarm fatigue with potential for prolonged response times and silencing of clinically meaningful alarms. Additionally, alarms disrupt care and cause stress for patients and families.Hypothesis:Creating conditional alarm triggers for bedside monitors can decrease the frequency of non-actionable alarms without compromising safety. The decreased burden of alarms on nurses, patients, and families may promote increased satisfaction.Methods:Single center, quality improvement initiative in a 26-bed cardiac acute care unit and 36-bed pediatric ICU, modeled after successful iterative effort at another tertiary children’s hospital. After 1 month pre-intervention observation of bedside monitor alarm burden, monitors were programmed with hierarchical time delay and conditional pulse oximetry, respiratory rate, and premature ventricular contractions alarm triggers. Bedside alarms were tallied for 1-month follow-up. The primary outcome was alarms per monitored patient day (MPD).Results:A total of 1394 and 776 MPD were evaluated in the pre- and post-intervention periods, respectively. The median number of cardiorespiratory monitor alarms per MPD decreased by 73% (15 to 4, p < 0.001) in both acute care and ICU. Alarm burden in RR, SpO2, and PVC categories also decreased. No increase in frequency of rapid response or code events occurred in either unit. Nursing surveys (n=253) reported positive trends of more manageable alarm burden and decreased perceived number of alarms. Family surveys (n=160), however, reported decreased sleep quality and increased perceived alarms.Conclusions:Implemented changes to bedside monitor alarm conditions decreased total alarm frequency in both cardiac acute care and pediatric ICU without compromising safety.

Insulin resistance is associated with diabetes mellitus, but it is uncertain whether it improves cardiovascular disease (CVD) risk prediction beyond traditional cardiovascular risk factors.

COVID-19 manifests with respiratory, systemic, and gastrointestinal (GI) symptoms.1,2SARS-CoV-2 RNA is detected in respiratory and fecal samples, and recent reports demonstrate viral replication in both the lung and intestinal tissue.3–5Although much is known about early fecal RNA shedding, little is known about the long-term shedding, especially in those with mild COVID-19. Furthermore, most reports of fecal RNA shedding do not correlate these findings with GI symptoms.6

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Acute GVHD is a major cause of morbidity and mortality following NST. A high incidence of aGVHD occurs when CSA alone is used as prophylaxis. We investigated the effect of combining either mycophenolate mofetil (MMF) or an abbreviated course of low dose MTX with CSA on the incidence and severity of aGVHD. Between 11/97 and 07/07, 230 consecutive patients (pts) (solid tumors n=127, hematologic malignancies n=57, non-malignant hematologic disorders n=46) underwent conditioning with fludarabine (125mg/m2) and cyclophosphamide (120mg/kg), followed by a G-CSF mobilized PBSC transplant from an HLA identical (n=222: 96%) or 5/6 HLA-matched (n=8: 4%) related donor. Forty-eight pts with a history of heavy RBC transfusions or those receiving a 5/6 HLA-matched transplant had ATG (40mg/kg/d × 4 days) added to their conditioning. The initial cohort of pts (Group 1, n=66), received CSA alone (dose adjusted to maintain therapeutic serum levels) as GVHD prophylaxis. Due to the high incidence of severe aGVHD in this group, subsequent pts received CSA with either MMF (1 gram po bid; Group 2, n=82) or an abbreviated course of mini-dose MTX (5mg/m2 days +1, +3, +6; Group 3, n=82). In all three groups, decisions regarding discontinuation of CSA and MMF were based on donor T cell chimerism, presence of GVHD, and disease status. With a median follow-up of 2963, 2317 and 894 days in the three consecutive cohorts, a comparison was undertaken using competing risk analysis. The incidence of grades II–IV and III–IV GVHD was significantly higher in pts receiving CSA alone or CSA+MMF compared to those receiving CSA+MTX; the cumulative incidence of grades II–IV GVHD in the three groups was 56%, 59%, and 37% (p=0.05) while grades III–IV GVHD occurred in 30%, 34%, and 15% (p=0.019) respectively. The incidence of chronic GVHD (45% vs. 57% vs. 46%, p=0.27) was similar in the three groups. The lower incidence of aGVHD associated with MTX use was accompanied by a significantly improved TRM in group 3 pts; transplant related mortality was 21% in group 1, 21% in group 2 and 5% in group 3 pts (p=0.019). The impact of adding MMF or MTX to CSA on disease-specific outcome in pts with different malignant diseases could not be assessed due to small sample sizes. Conclusion: The addition of an abbreviated course of mini-dose methotrexate to CSA was associated with a significantly lower incidence of grades II–IV and III–IV aGVHD as well as lower TRM compared with CSA used alone or in combination with MMF in pts undergoing NST. To our knowledge this is the first report demonstrating a benefit of adding mini-dose MTX for GVHD prophylaxis in patients undergoing NST. Group 1 (N=66) Group 2 (N=82) Group 3 (N=82) P value Cumulative Incidence of Grade II–IV aGVHD (95% CI) 56% (44%–68%) 59%(48%–70%) 37%(25%–49%) 0.05 Cumulative Incidence of Grade III–IV aGVHD (95% CI) 30%(19%–41%) 34%(22%–46%) 15%(7%–23%) 0.019 Transplant Related Mortality(95% CI) 21%(11%–31%) 21%(12%–30%) 5%(0%–7%) 0.019 Proportion of Evaluable Pts with Chronic GVHD (%) 24/53 (45%) 43/75(57%) 34/74(46%) 0.274

Acute GVHD is a major cause of morbidity and mortality following NST. A high incidence of aGVHD occurs when CSA alone is used as prophylaxis. We investigated the effect of combining either mycophenolate mofetil (MMF) or an abbreviated course of low dose MTX with CSA on the incidence and severity of aGVHD. Between 11/97 and 07/07, 230 consecutive patients (pts) (solid tumors n=127, hematologic malignancies n=57, non-malignant hematologic disorders n=46) underwent conditioning with fludarabine (125mg/m2) and cyclophosphamide (120mg/kg), followed by a G-CSF mobilized PBSC transplant from an HLA identical (n=222: 96%) or 5/6 HLA-matched (n=8: 4%) related donor. Forty-eight pts with a history of heavy RBC transfusions or those receiving a 5/6 HLA-matched transplant had ATG (40mg/kg/d × 4 days) added to their conditioning. The initial cohort of pts (Group 1, n=66), received CSA alone (dose adjusted to maintain therapeutic serum levels) as GVHD prophylaxis. Due to the high incidence of severe aGVHD in this group, subsequent pts received CSA with either MMF (1 gram po bid; Group 2, n=82) or an abbreviated course of mini-dose MTX (5mg/m2days +1, +3, +6; Group 3, n=82). In all three groups, decisions regarding discontinuation of CSA and MMF were based on donor T cell chimerism, presence of GVHD, and disease status. With a median follow-up of 2963, 2317 and 894 days in the three consecutive cohorts, a comparison was undertaken using competing risk analysis. The incidence of grades II–IV and III–IV GVHD was significantly higher in pts receiving CSA alone or CSA+MMF compared to those receiving CSA+MTX; the cumulative incidence of grades II–IV GVHD in the three groups was 56%, 59%, and 37% (p=0.05) while grades III–IV GVHD occurred in 30%, 34%, and 15% (p=0.019) respectively. The incidence of chronic GVHD (45% vs. 57% vs. 46%, p=0.27) was similar in the three groups. The lower incidence of aGVHD associated with MTX use was accompanied by a significantly improved TRM in group 3 pts; transplant related mortality was 21% in group 1, 21% in group 2 and 5% in group 3 pts (p=0.019). The impact of adding MMF or MTX to CSA on disease-specific outcome in pts with different malignant diseases could not be assessed due to small sample sizes.