A common allele of HLA is associated with asymptomatic SARS-CoV-2 infection.

Studies have demonstrated that at least 20% of individuals infected with SARS-CoV-2 remain asymptomatic1-4. Although most global efforts have focused on severe illness in COVID-19, examining asymptomatic infection provides a unique opportunity to consider early immunological features that promote rapid viral clearance. Here, postulating that variation in the human leukocyte antigen (HLA) loci may underly processes mediating asymptomatic infection, we enrolled 29,947 individuals, for whom high-resolution HLA genotyping data were available, in a smartphone-based study designed to track COVID-19 symptoms and outcomes. Our discovery cohort (n = 1,428) comprised unvaccinated individuals who reported a positive test result for SARS-CoV-2. We tested for association of five HLA loci with disease course and identified a strong association between HLA-B*15:01 and asymptomatic infection, observed in two independent cohorts. Suggesting that this genetic association is due to pre-existing T cell immunity, we show that T cells from pre-pandemic samples from individuals carrying HLA-B*15:01 were reactive to the immunodominant SARS-CoV-2 S-derived peptide NQKLIANQF. The majority of the reactive T cells displayed a memory phenotype, were highly polyfunctional and were cross-reactive to a peptide derived from seasonal coronaviruses. The crystal structure of HLA-B*15:01-peptide complexes demonstrates that the peptides NQKLIANQF and NQKLIANAF (from OC43-CoV and HKU1-CoV) share a similar ability to be stabilized and presented by HLA-B*15:01. Finally, we show that the structural similarity of the peptides underpins T cell cross-reactivity of high-affinity public T cell receptors, providing the molecular basis for HLA-B*15:01-mediated pre-existing immunity.

Metformin use associated with lower rate of hospitalization for influenza in individuals with diabetes.

AIM: To investigate if patients with diabetes taking metformin have better outcomes versus those not taking metformin following an emergency room visit for influenza. METHODS: Using electronic medical records, we performed a retrospective chart review of all adult patients with a diagnosis of diabetes seen in any Duke University Medical Center-affiliated emergency department for influenza over a 6-year period. We documented patient characteristics and comorbidities, and compared outcomes for patients taking metformin versus patients not taking metformin using both univariable and multivariable analyses. Our primary outcome was hospital admission rate. Secondary outcomes were in-hospital length of stay and in-hospital death. RESULTS: Our cohort included 1023 adult patients with diabetes, of whom 59.9% were female. The mean age was 62.9 years, 58.4% were African American, 36.1% were White, and 81.9% were obese or overweight. Of these patients, 347 (34%) were taking metformin. Patients with diabetes taking metformin were less likely to be hospitalized following an emergency department visit for influenza than patients with diabetes not taking metformin (56.8% vs. 70.1%; p < 0.001). Of those patients admitted, there was no statistically significant difference in length of stay or death. CONCLUSIONS: In patients with diabetes, metformin use is associated with lower rate of hospitalization following an emergency department visit for influenza.

Static Versus Articulating Spacer: Does Infectious Pathogen Type Affect Treatment Success?

BACKGROUND: Treatment with a static or an articulating antibiotic-containing spacer is a common strategy for treating periprosthetic joint infection (PJI), yet many patients have persistent infections after spacer treatment. Although previous studies have compared the efficacy of a static and articulating spacer for treating PJI, few studies have assessed infection control from the time of spacer implantation, or they defined treatment failure as including reinfection, reoperation, or chronic suppressive therapy. Additionally, few studies have examined whether there is an interaction between spacer and pathogen type with respect to treatment success. QUESTIONS/PURPOSES: (1) Is there a difference in failure-free survival (defined as no reoperation, reinfection, or suppressive antibiotic therapy) between static and articulating spacers after spacer implantation for PJI? (2) Did the relationship between spacer type and failure-free survival differ by pathogen type (staphylococcal versus nonstaphylococcal and difficult-to-treat [including methicillin-resistant Staphylococcus aureus, methicillin-susceptible S. aureus, Corynebacterium, Mycobacterium, Enterococcus spp, and other gram-negative bacterium] versus not-difficult-to-treat organisms)? METHODS: Between January 2014 and January 2022, a convenience sample of 277 patients was identified as having knee PJIs treated with an articulating (75% [208 of 277]) or static (25% [69 of 277]) antibiotic spacer and potentially eligible for this study. During that time, providers at our institution generally used spacers for later-presenting or chronic infections. Spacer choice was determined by surgeon preference, with static spacers used more often in instances of higher bone loss and poor soft tissue coverage. Thirty-one patients (8 static and 23 articulating spacers) were considered lost to follow-up or had incomplete datasets and were excluded from the analysis, resulting in a final analysis cohort of 246 patients: 25% (61 of 246) received a static spacer and 75% (185 of 246) received an articulating spacer. The mean ± standard deviation age of patients was 66 ± 9.9 years, BMI was 33.3 ± 6.9 kg/m2, and Elixhauser score was 18.1 ± 16.9. Demographic and clinical characteristics were similar between the two groups. Pathogen type was collected and categorized as staphylococcal versus nonstaphylococcal, and difficult-to-treat (including methicillin-resistant Staphylococcus aureus, methicillin-susceptible S. aureus, Corynebacterium, Mycobacterium, Enterococcus spp, and other gram-negative bacterium) versus not-difficult-to-treat, as defined by an infectious disease physician. Other variables we collected included sex, age, American Society of Anesthesiologists classification, BMI, and Elixhauser score. The primary outcome of interest was failure-free survival, which was a composite time-to-event outcome, with failure defined as reoperation, reinfection, death owing to infection, or chronic antibiotic use at a minimum of 1 year after the completion of the patient's Stage 1 postoperative antibiotic course, whichever came first. Reinfection was determined by the treating physicians in accordance with the Musculoskeletal Infection Society guidelines and included an evaluation of infectious laboratory values, cultures, and clinical signs of infection. We compared static and articulating spacers using a Cox proportional hazards model, with spacer type as the primary predictor variable. We compared staphylococcal versus nonstaphylococcal and difficult-to-treat versus not-difficult-to-treat infections by running additional models with interaction terms between spacer type and pathogen type. RESULTS: No difference was observed in the cause-specific hazard ratio for static versus articulating (reference) spacers (HR 1.45 [95% confidence interval 0.94 to 2.22]; p = 0.09), after adjusting for covariates. Additionally, no difference in the association between spacer type and failure-free survival was found between pathogen types or treatment difficulty after evaluating interactions (staphylococcal HR 0.37 [95% CI 0.15 to 0.91], nonstaphylococcal HR 0.79 [95% CI 0.49 to 1.28]; p value for interaction = 0.14; difficult-to-treat HR 0.37 [95% CI 0.14 to 0.99], not-difficult-to-treat HR 0.75 [95% CI 0.47 to 1.20]; p value for interaction = 0.20). CONCLUSION: The lack of a difference in failure-free survival and insufficient evidence of a difference in the association between spacer type and treatment failure by pathogen type suggests that infectious organism may not be an important consideration in the decision about spacer treatment type. Further studies should aim to elucidate which patient factors are the most influential in surgeon decision-making when choosing a spacer type in patients with PJI of the knee.Level of Evidence Level III, therapeutic study.

Outcomes after total ankle arthroplasty with an average follow-up of 10 years: A systematic review and meta-analysis.

BACKGROUND: The literature demonstrating positive outcomes after total ankle arthroplasty (TAA) is mounting. However, the long-term outcomes of TAA (≥ 10 years) remain minimally reported. The purpose of this systematic review and meta-analysis was to evaluate outcome metrics over multiple TAA studies with greater than 10 years of average follow-up. METHODS: TAA studies were searched in Medline, Embase, and Scopus from the date of inception to September 12, 2022. Inclusion criteria included 1) studies of patients that underwent uncemented TAA, and 2) studies with an average follow-up time of at least ten years. Manuscripts in non-English languages and isolated abstracts were excluded. We collected American Orthopaedic Foot and Ankle Score (AOFAS) and Visual Analog Scale (VAS) scores from the included studies for pooled meta-analysis. Due to the varying definition of survivability between studies, this metric was not assessed in our final evaluation. RESULTS: Our data included approximately 3651 patients (3782 ankles). Of the 25 studies with an average follow-up of 10 years included in the systematic review, 5 provided pre- and post-operative AOFAS means and 5 provided pre- and post-operative VAS means with associated measures of variability and were included in our meta-analysis. The weighted mean difference between pre-and post-operative AOFAS and VAS scores was -40.36 (95% CI -47.24 to -33.47) and 4.52 (95% CI: 2.26-6.43), respectively. The risk of bias was low to moderate for the included studies. CONCLUSION: Outcomes following TAA are favorable and indicate patient-reported outcome improvement over long-term follow-up. However, a significant amount of heterogeneity exists between studies. Future, prospective, randomized research should focus on standardizing outcome measures, survivorship, and complication reporting methodologies to allow for pooled meta-analyses of these important outcome metrics.

Incidence and associated risk factors for systemic drug levels with inhaled aminoglycoside therapy.

OBJECTIVES: To characterize the incidence of and risk factors for a detectable drug level (DDL) in patients that received inhaled aminoglycoside therapy. METHODS: This retrospective, single-centre study included adult patients who received at least one dose of an inhaled aminoglycoside with a drug level during inpatient hospitalization. Patients were excluded if they received an aminoglycoside intravenously within 7 days or if the drug level was not drawn within 4 h of the next dose. A repeated measures logistic regression model evaluated the association between potential risk factors and a DDL. RESULTS: Among 286 drug levels, 88 (30.8%) drug levels were detectable. In multivariable analysis, cystic fibrosis (CF) (OR: 3.03; 95% CI: 1.10-8.35), chronic kidney disease (CKD) (OR: 4.25; 95% CI: 1.84-9.83), lung transplant recipient (OR: 3.08; 95% CI: 1.09-8.73), mechanical ventilation (OR: 2.99; 95% CI: 1.25-7.15) and tobramycin (OR: 5.26; 95% CI: 2.35-11.78) were associated with higher odds of a DDL. Among those with a DDL, inhaled aminoglycoside type and drug level concentration were not associated with acute kidney injury (P = 0.161). CONCLUSIONS: Among 286 drug levels identified among inpatients receiving inhaled aminoglycoside therapy, 88 (30.8%) unique drug levels were detectable. Based on the results of this study, periodic trough concentrations should be considered for patients receiving inhaled aminoglycoside therapy with CF, CKD, lung transplantation, mechanical ventilation or tobramycin.

Timing and Magnitude of Peak Body Mass Index and Peak Weight Velocity in Infancy Predict Body Mass Index at 2 Years in a Retrospective Cohort of Electronic Health Record Data.

OBJECTIVES: To use growth data from electronic health records to describe and model infant growth (weight velocity and peak body mass index [pBMI]) characteristics. STUDY DESIGN: We extracted data from all children born at ≥34 weeks of gestation within one health system between 2014 and 2017. After excluding implausible growth data with an algorithm created for childhood growth, we estimated pBMI, peak weight and length velocities, and the odds of obesity at 2 years, adjusted for race, sex, ethnicity, and birth weight, by the magnitude of peak weight velocity, peak length velocity, and pBMI. RESULTS: Among 6425 children (41% White, 28% Black, 26% other race; 16% Hispanic ethnicity), mean pBMI was 17.9 kg/m2 (SD 1.5) and mean age at pBMI was 9.6 months (SD 2.7). Mean peak weight velocity was 949 g (SD 165) per 2 weeks, and the mean peak length velocity was 3.4 cm (SD 0.3) per 2 weeks. Children with obesity at 2 years (n = 931, 14.5%) were more likely to be Hispanic, had greater peak weight and peak length velocities, and had 2 kg/m2 greater magnitude of pBMI than children without obesity. For each unit increase in pBMI, children had more than 4 times greater odds of obesity at age 2 years. CONCLUSIONS: In a large sample of infants with clinical growth data tracked via electronic health records, we found associations between the magnitude and timing of peak infant BMI and obesity at 2 years of age.

Improved Outcomes in Severe Primary Graft Dysfunction After Heart Transplantation Following Donation After Circulatory Death Compared With Donation After Brain Death.

BACKGROUND: Primary graft dysfunction (PGD), the leading cause of early mortality after heart transplantation, is more common following donation after circulatory death (DCD) than donation after brain death (DBD). We conducted a single-center, retrospective cohort study to compare the incidence, severity and outcomes of patients experiencing PGD after DCD compared to DBD heart transplantation. METHODS AND RESULTS: Medical records were reviewed for all adult heart transplant recipients at our institution between March 2016 and December 2021. PGD was diagnosed within 24 hours after transplant according to modified International Society for Heart and Lung Transplant criteria. A total of 459 patients underwent isolated heart transplantation during the study period, 65 (14%) following DCD and 394 (86%) following DBD. The incidence of moderate or severe PGD in DCD and DBD recipients was 34% and 23%, respectively (P = 0.070). DCD recipients were more likely to experience severe biventricular PGD than DBD recipients (19% vs 7.4%; P = 0.004). Among patients with severe PGD, DCD recipients experienced shorter median (Q1, Q3) duration of post-transplant mechanical circulatory support (6 [4, 7] vs 9 [5, 14] days; P = 0.039), shorter median post-transplant hospital length of stay (17 [15, 29] vs 52 [26, 83] days; P = 0.004), and similar 60-day survival rates (100% [95% CI: 76.8%-100%] vs 80.0% [63.1%-91.6%]; P = 0.17) and overall survival (log-rank; P = 0.078) compared with DBD recipients. CONCLUSIONS: DCD heart transplant recipients were more likely to experience severe, biventricular PGD than DBD recipients. Despite this, DCD recipients with severe PGD spent fewer days on mechanical circulatory support and in the hospital than similar DBD patients. These findings suggest that patterns of graft dysfunction and recovery may differ between donor types, and they support the expansion of the heart-donor pool with DCD.

Multicenter study of universal prophylaxis versus pre-emptive therapy for patients at intermediate risk (R+) for CMV following heart transplantation.

INTRODUCTION: Heart transplant (HT) recipients with prior exposure to cytomegalovirus (CMV R+) are considered intermediate risk for CMV-related complications. Consensus guidelines allow for either universal prophylaxis (UP) or preemptive therapy (PET) (serial CMV testing) approaches to CMV prevention in such patients. Whether an optimal approach to mitigate CMV related risks exists in this setting remains uncertain. We therefore assessed the utility of PET as compared to UP in CMV R+ HT recipients. METHODS: Retrospective analysis of all CMV R+ HT recipients from 6 U.S. centers between 2010 and 2018 was performed. The primary outcome was the development of CMV DNAemia or end-organ disease resulting in the initiation/escalation of anti-CMV therapy. The secondary outcome was CMV-related hospitalization. Additional outcomes included incidence of acute cellular rejection (ACR) ≥ grade 2R, death, cardiac allograft vasculopathy (CAV), and leukopenia. RESULTS: Of 563 CMV R+ HT recipients, 344 (61.1%) received UP. PET was associated with increased risk for the primary (adjusted HR 3.95, 95% CI: 2.65-5.88, p < .001) and secondary (adjusted HR 3.19, 95% CI: 1.47-6.94, p = .004) outcomes, and with increased ACR ≥ grade 2R (PET 59.4% vs. UP 34.4%, p < .001). Incidence of detectable CAV was similar at 1 year (PET 8.2% vs. UP 9.5%, p = .698). UP was associated with increased incidence of leukopenia within 6 months post-HT (PET 34.7% vs. UP 43.6%, p = .036). CONCLUSION: The use of a PET CMV prophylaxis strategy in intermediate risk HT recipients associated with increased risk of CMV infection and CMV-related hospitalization, and may associate with worse post-HT graft outcomes.

Chronological trends in the causation of malignant mesothelioma: Fiber burden analysis of 619 cases over four decades.

Malignant mesothelioma is a relatively rare malignancy with a strong association with prior asbestos exposure. A percentage of cases is not related to asbestos, and fiber analysis of lung tissue is a useful methodology for identifying idiopathic or spontaneous cases. We have performed fiber analyses in more than 600 cases of mesothelioma over the past four decades and were interested in looking for trends in terms of fiber types and concentrations as well as percentages of cases not related to asbestos. Demographic information was also considered including patient age, gender, and tumor location (pleural vs. peritoneal). The histologic pattern of the tumor and the presence or absence of pleural plaques or asbestosis were noted. Fiber analysis was performed in 619 cases, using the sodium hypochlorite technique for digestion of lung tissue samples. Asbestos bodies were counted by light microscopy (LM) and coated and uncoated fibers by scanning electron microscopy (EM). The results were stratified over four decades. Trends that were observed included increasing patient age, increasing percentage of women, increasing percentage of peritoneal cases, and increasing percentage of epithelial histological type. There was a decreasing trend in the percentage of patients with concomitant asbestosis (p < 0.001). The percentage of cases with an elevated lung asbestos content decreased from 90.5% in the 1980s to 54.1% in the 2010s (p < 0.001). This trend also held when the analysis was limited to 490 cases of pleural mesothelioma in men (91.8% in the 1980s vs. 65.1% in the 2010s). There was a decrease in the median asbestos body count by LM from 1390 asbestos bodies per gram of wet lung in the 1980s to 38 AB/gm in the 2010s. Similar trends were observed for each of the asbestos fiber types as detected by EM. We conclude that there has been a progressive decrease in lung fiber content of mesothelioma patients during the past four decades, with an increasing percentage of cases not related to asbestos and an increase in median patient age.

Sudden cardiac arrest response preparedness in Durham County schools.

Sudden cardiac arrest is an uncommon event with high morbidity and mortality. There are improved outcomes with early access to an automated external defibrillator and cardiopulmonary resuscitation. We assessed the availability of automated external defibrillators and emergency cardiac arrest plans in schools. A cross-sectional electronic survey was conducted to determine the status of emergency cardiac arrest plans and automated external defibrillator presence. Most schools (88%) had access to an automated external defibrillator; however, trained staff and maintenance plans were highly variable. Automated external defibrillator availability did not differ by racial/ethnic or socio-economic composition; however, there was a relationship between number of automated external defibrillators and student population (p = 0.0030). The majority of schools either did not have (28%) or did not know if they had (36%) an emergency cardiac arrest plan. Even without state legislation, automated external defibrillators were largely available in schools. However, there remains a paucity of emergency cardiac arrest plans and automated external defibrillator maintenance plans.

A validated preoperative risk prediction tool for extended inpatient length of stay following anatomic or reverse total shoulder arthroplasty.

BACKGROUND: Recent work has shown inpatient length of stay (LOS) following shoulder arthroplasty to hold the second strongest association with overall cost (after implant cost itself). In particular, a preoperative understanding for the patients at risk of extended inpatient stays (≥3 days) can allow for counseling, optimization, and anticipating postoperative adverse events. METHODS: A multicenter retrospective review was performed of 5410 anatomic (52%) and reverse (48%) total shoulder arthroplasties done at 2 large, tertiary referral health systems. The primary outcome was extended inpatient LOS of at least 3 days, and over 40 preoperative sociodemographic and comorbidity factors were tested for their predictive ability in a multivariable logistic regression model based on the patient cohort from institution 1 (derivation, N = 1773). External validation was performed using the patient cohort from institution 2 (validation, N = 3637), including area under the receiver operator characteristic curve (AUC), sensitivity, specificity, and positive and negative predictive values. RESULTS: A total of 814 patients, including 318 patients (18%) in the derivation cohort and 496 patients (14%) in the validation cohort, experienced an extended inpatient LOS of at least 3 days. Four hundred forty-five (55%) were discharged to a skilled nursing or rehabilitation facility. Following parameter selection, a multivariable logistic regression model based on the derivation cohort (institution 1) demonstrated excellent preliminary accuracy (AUC: 0.826), with minimal decrease in accuracy under external validation when tested against the patients from institution 2 (AUC: 0.816). The predictive model was composed of only preoperative factors, in descending predictive importance as follows: age, marital status, fracture case, ASA (American Society of Anesthesiologists) score, paralysis, electrolyte disorder, body mass index, gender, neurologic disease, coagulation deficiency, diabetes, chronic pulmonary disease, peripheral vascular disease, alcohol dependence, psychoses, smoking status, and revision case. CONCLUSION: A freely-available, preoperative online clinical decision tool for extended inpatient LOS (≥ 3 days) after shoulder arthroplasty reaches excellent predictive accuracy under external validation. As a result, this tool merits consideration for clinical implementation, as many risk factors are potentially modifiable as part of a preoperative optimization strategy.

Cast or Nail? Using a Preference-Based Tool for Shared Decision-Making in Pediatric Femoral Shaft Fracture Treatment.

BACKGROUND: Femoral shaft fractures are common injuries in children 2 to 7 years of age, with treatments ranging from casting to flexible intramedullary nails (FIN). Each treatment has unique attributes and outcomes are overall similar. Given equivalent outcomes, we hypothesized that a shared decision-making process, using adaptive conjoint analysis (ACA), can be used to assess individual family situations to determine ultimate treatment choice. METHODS: An interactive survey incorporating an ACA exercise to elicit the preferences of individuals was created. Amazon Mechanical Turk was used to recruit survey respondents simulating the at-risk population. Basic demographic information and family characteristics were collected. Sawtooth Software was utilized to generate relative importance values of five treatment attributes and determine subjects' ultimate treatment choice. Student's t-test or Wilcoxon rank sum test was used to compare relative importance between groups. RESULTS: The final analysis included 186 subjects with 147 (79%) choosing casting as their ultimate treatment choice, while 39 (21%) chose FIN. Need for second surgery had the highest overall average relative importance (42.0), followed by a chance of serious complications (24.6), time away from school (12.9), effort required by caregivers (11.0), and return to activities (9.6). Most respondents (85%) indicated the generated relative importance of attributes aligned "very well or well" with their preferences. For those who chose casting instead of FIN, the need for secondary surgery (43.9 vs. 34.8, P <0.001) and the chance of serious complications (25.9 vs. 19.6, P <0.001) were the most important factors. In addition, returning to activities, the burden to caregivers, and time away from school were all significantly more important to those choosing surgery versus casting (12.6 vs. 8.7 P <0.001, 12.6 vs. 9.8 P =0.014, 16.6 vs. 11.7 P <0.001, respectively). CONCLUSIONS: Our decision-making tool accurately identified subjects' treatment preferences and appropriately aligned them with a treatment decision. Given the increased emphasis on shared decision-making in health care, this tool may have the potential to improve shared decision-making and family understanding, leading to improved satisfaction rates and overall outcomes. LEVEL OF EVIDENCE: Level-III.

A Validated Pre-operative Risk Prediction Tool for Extended Inpatient Length of Stay Following Primary Total Hip or Knee Arthroplasty.

BACKGROUND: As value-based reimbursement models mature, understanding the potential trade-off between inpatient lengths of stay and complications or need for costly postacute care becomes more pressing. Understanding and predicting a patient's expected baseline length of stay may help providers understand how best to decide optimal discharge timing for high-risk total joint arthroplasty (TJA) patients. METHODS: A retrospective review was conducted of 37,406 primary total hip (17,134, 46%) and knee (20,272, 54%) arthroplasties performed at two high-volume, geographically diverse, tertiary health systems during the study period. Patients were stratified by 3 binary outcomes for extended inpatient length of stay: 72 + hours (29%), 4 + days (11%), or 5 + days (5%). The predictive ability of over 50 sociodemographic/comorbidity variables was tested. Multivariable logistic regression models were created using institution #1 (derivation), with accuracy tested using the cohort from institution #2 (validation). RESULTS: During the study period, patients underwent an extended length of stay with a decreasing frequency over time, with privately insured patients having a significantly shorter length of stay relative to those with Medicare (1.9 versus 2.3 days, P < .0001). Extended stay patients also had significantly higher 90-day readmission rates (P < .0001), even when excluding those discharged to postacute care (P < .01). Multivariable logistic regression models created from the training cohort demonstrated excellent accuracy (area under the curve (AUC): 0.755, 0.783, 0.810) and performed well under external validation (AUC: 0.719, 0.743, 0.763). Many important variables were common to all 3 models, including age, sex, American Society of Anesthesiologists (ASA) score, body mass index, marital status, bilateral case, insurance type, and 13 comorbidities. DISCUSSION: An online, freely available, preoperative clinical decision tool accurately predicts risk of extended inpatient length of stay after TJA. Many risk factors are potentially modifiable, and these validated tools may help guide clinicians in preoperative patient counseling, medical optimization, and understanding optimal discharge timing.

Monthly sulfadoxine/pyrimethamine-amodiaquine or dihydroartemisinin-piperaquine as malaria chemoprevention in young Kenyan children with sickle cell anemia: A randomized controlled trial.

BACKGROUND: Children with sickle cell anemia (SCA) in areas of Africa with endemic malaria transmission are commonly prescribed malaria chemoprevention. Chemoprevention regimens vary between countries, and the comparative efficacy of prevention regimens is largely unknown. METHODS AND FINDINGS: We enrolled Kenyan children aged 1 to 10 years with homozygous hemoglobin S (HbSS) in a randomized, open-label trial conducted between January 23, 2018, and December 15, 2020, in Homa Bay, Kenya. Children were assigned 1:1:1 to daily Proguanil (the standard of care), monthly sulfadoxine/pyrimethamine-amodiaquine (SP-AQ), or monthly dihydroartemisinin-piperaquine (DP) and followed monthly for 12 months. The primary outcome was the cumulative incidence of clinical malaria at 12 months, and the main secondary outcome was the cumulative incidence of painful events by self-report. Secondary outcomes included other parasitologic, hematologic, and general events. Negative binomial models were used to estimate incidence rate ratios (IRRs) per patient-year (PPY) at risk relative to Proguanil. The primary analytic population was the As-Treated population. A total of 246 children were randomized to daily Proguanil (n = 81), monthly SP-AQ (n = 83), or monthly DP (n = 82). Overall, 53.3% (n = 131) were boys and the mean age was 4.6 ± 2.5 years. The clinical malaria incidence was 0.04 episodes/PPY; relative to the daily Proguanil group, incidence rates were not significantly different in the monthly SP-AQ (IRR: 3.05, 95% confidence interval [CI]: 0.36 to 26.14; p = 0.39) and DP (IRR: 1.36, 95% CI: 0.21 to 8.85; p = 0.90) groups. Among secondary outcomes, relative to the daily Proguanil group, the incidence of painful events was not significantly different in the monthly SP-AQ and DP groups, while monthly DP was associated with a reduced rate of dactylitis (IRR: 0.47; 95% CI: 0.23 to 0.96; p = 0.038). The incidence of Plasmodium falciparum infection relative to daily Proguanil was similar in the monthly SP-AQ group (IRR 0.46; 95% CI: 0.17 to 1.20; p = 0.13) but reduced with monthly DP (IRR 0.21; 95% CI: 0.08 to 0.56; p = 0.002). Serious adverse events were common and distributed between groups, although compared to daily Proguanil (n = 2), more children died receiving monthly SP-AQ (n = 7; hazard ratio [HR] 5.44; 95% CI: 0.92 to 32.11; p = 0.064) but not DP (n = 1; HR 0.61; 95% CI 0.04 to 9.22; p = 0.89), although differences did not reach statistical significance for either SP-AQ or DP. Study limitations include the unexpectedly limited transmission of P. falciparum in the study setting, the high use of hydroxyurea, and the enhanced supportive care for trial participants, which may limit generalizability to higher-transmission settings where routine sickle cell care is more limited. CONCLUSIONS: In this study with limited malaria transmission, malaria chemoprevention in Kenyan children with SCA with monthly SP-AQ or DP did not reduce clinical malaria, but DP was associated with reduced dactylitis and P. falciparum parasitization. Pragmatic studies of chemoprevention in higher malaria transmission settings are warranted. TRIAL REGISTRATION: clinicaltrials.gov (NCT03178643). Pan-African Clinical Trials Registry: PACTR201707002371165.

A Randomized Controlled Trial of Mobile Health Intervention in Patients With Heart Failure and Diabetes.

BACKGROUND: Mobile health (mHealth) platforms can affect health behaviors but have not been rigorously tested in randomized trials. OBJECTIVES: We sought to evaluate the effectiveness of a pragmatic mHealth intervention in patients with heart failure (HF) and diabetes (DM). METHODS: We conducted a multicenter randomized trial in 187 patients with both HF and DM to assess an mHealth intervention to improve physical activity and medication adherence compared to usual care. The primary endpoint was change in mean daily step count from baseline through 3 months. Other outcomes included medication adherence, health-related quality of life and metabolomic profiling. RESULTS: The mHealth group had an increase in daily step count of 151 steps/day at 3 months, whereas the usual-care group had a decline of 162 steps/day (least squares mean between-group difference = 313 steps/day; 95% CI: 8 619; P = 0.044). Medication adherence, measured using the Voils Adherence Questionnaire, did not change from baseline to 3 months (LS-mean change -0.08 in mHealth vs -0.15 in usual care; P = 0.47). The mHealth group had an improvement in Kansas City Cardiomyopathy Questionnaire Overall Summary Score compared to the usual-care group (LS-mean difference = 5.5 points, 95% CI: 1.4, 9.6; P = 0.009). Thirteen metabolites, primarily medium- and long-chain acylcarnitines, changed differently between treatment groups from baseline to 3 months (P < 0.05). CONCLUSIONS: In patients with HF and DM, a 3-month mHealth intervention significantly improved daily physical activity, health-related quality of life and metabolomic markers of cardiovascular health but not medication adherence. CONDENSED ABSTRACT: Heart failure (HF) and diabetes (DM) have overlapping biological and behavioral risk factors. We conducted a multicenter randomized, clinical trial in 187 patients with both HF (regardless of ejection fraction) and DM to assess whether an mHealth intervention could improve physical activity and medication adherence. The mHealth group had an increase in mean daily step count and quality of life but not in medication adherence. Medium- and long-chain acylcarnitines changed differently in treatment groups from baseline to 3 months (P < 0.05). These data have important implications for designing effective lifestyle interventions in HF and DM.

High-dose, high-frequency ustekinumab therapy for patients with severe hidradenitis suppurativa.

In this case series, ustekinumab therapy demonstrated efficacy in some patients with severe hidradenitis suppurativa previously treated with adalimumab and/or infliximab. Larger prospective studies are needed to evaluate ustekinumab as a treatment option for recalcitrant hidradenitis suppurativa.

Appropriate patient selection for outpatient shoulder arthroplasty: a risk prediction tool.

BACKGROUND: The transition from inpatient to outpatient shoulder arthroplasty critically depends on appropriate patient selection, both to ensure safety and to counsel patients preoperatively regarding individualized risk. Cost and patient demand for same-day discharge have encouraged this transition, and a validated predictive tool may help decrease surgeon liability for complications and help select patients appropriate for same-day discharge. We hypothesized that an accurate predictive model could be created for short inpatient length of stay (discharge at least by postoperative day 1), potentially serving as a useful proxy for identifying patients appropriate for true outpatient shoulder arthroplasty. METHODS: A multicenter cohort of 5410 shoulder arthroplasties (2805 anatomic and 2605 reverse shoulder arthroplasties) from 2 geographically diverse, high-volume health systems was reviewed. Short inpatient stay was the primary outcome, defined as discharge on either postoperative day 0 or 1, and 49 patient outcomes and factors including the Elixhauser Comorbidity Index, sociodemographic factors, and intraoperative parameters were examined as candidate predictors for a short stay. Factors surviving parameter selection were incorporated into a multivariable logistic regression model, which underwent internal validation using 10,000 bootstrapped samples. RESULTS: In total, 2238 patients (41.4%) were discharged at least by postoperative day 1, with no difference in rates of 90-day readmission (3.5% vs. 3.3%, P = .774) between cohorts with a short length of stay and an extended length of stay (discharge after postoperative day 1). A multivariable logistic regression model demonstrated high accuracy (area under the receiver operator characteristic curve, 0.762) for discharge by postoperative day 1 and was composed of 13 variables: surgery duration, age, sex, electrolyte disorder, marital status, American Society of Anesthesiologists score, paralysis, diabetes, neurologic disease, peripheral vascular disease, pulmonary circulation disease, cardiac arrhythmia, and coagulation deficiency. The percentage cutoff maximizing sensitivity and specificity was calculated to be 47%. Internal validation showed minimal loss of accuracy after bias correction for overfitting, and the predictive model was incorporated into a freely available online tool to facilitate easy clinical use. CONCLUSIONS: A risk prediction tool for short inpatient length of stay after shoulder arthroplasty reaches very good accuracy despite requiring only 13 variables and was derived from an underlying database with broad geographic diversity in the largest institutional shoulder arthroplasty cohort published to date. Short inpatient length of stay may serve as a proxy for identifying patients appropriate for same-day discharge, although perioperative care decisions should always be made on an individualized and holistic basis.

Current Trends in Revision Hip Arthroplasty: Indications and Types of Components Revised.

BACKGROUND: The materials and techniques for both primary and revision total hip arthroplasty (THA) have changed over time. This study evaluated if the indications for revision THA, rates of components utilized (femoral or acetabulum, both, or head/liner exchange), length of stay (LOS), and payments to surgeons and facilities have also changed. METHODS: A retrospective study, utilizing the PearlDiver database, of 38,377 revision THA patients from January 2010 through December 2018 was performed. Data included the indication for revision, components revised (femoral or acetabulum, both, or head/liner exchange), LOS, and payments. Indications and components were analyzed by logistic regression (Dunnett's post hoc test). Revision totals were analyzed with a linear regression model. Analysis of variance assessed changes in LOS and payments. RESULTS: Patients' median age was 67 years (Q1-Q3: 59-74), and 58.7% were female. Revisions for dislocation decreased between 2010 and 2018 (odds ratio [OR] 0.82, 95% confidence interval [CI] 0.68-0.98). Revisions for component loosening increased (OR 1.54, 95% CI 1.25-1.91). Dislocation remained the most common indication (19.3%), followed by PJI (17.3%) and loosening (17.1%). Both-component (OR:1.45; 95% CI:1.25-1.67) and femoral component only revisions increased; acetabular component only and head/liner exchanges decreased. Acetabular (OR 0.57, 95% CI 0.47-0.70) and head/liner exchange (OR 0.29, 95% CI 0.20-0.43) revisions decreased, while both component exchange (OR 1.45, 95% CI 1.25-1.67) and femoral revisions (OR 1.17, 95% CI 0.99-1.37) increased. Average LOS (-0.68 days; P < .001) and surgeon payments decreased (-$261.8; P < .001) while facility payments increased ($4,211; P < .001). CONCLUSION: Indications for revision THA in this database study changed over time, with revision for dislocation decreasing and revision for loosening increasing over time. Both component and femoral revisions increased, and acetabular component and head/liner exchanges decreased. It is possible that these associations could be attributed to a number of details, the method of femoral fixation, surgical approach, and cementing, all of which require additional study.

Tracheostomy for COVID-19 Respiratory Failure: Multidisciplinary, Multicenter Data on Timing, Technique, and Outcomes.

OBJECTIVE: The aim of this study was to assess the outcomes of tracheostomy in patients with COVID-19 respiratory failure. SUMMARY BACKGROUND DATA: Tracheostomy has an essential role in managing COVID-19 patients with respiratory failure who require prolonged mechanical ventilation. However, limited data are available on how tracheostomy affects COVID-19 outcomes, and uncertainty surrounding risk of infectious transmission has led to divergent recommendations and practices. METHODS: It is a multicenter, retrospective study; data were collected on all tracheostomies performed in COVID-19 patients at 7 hospitals in 5 tertiary academic medical systems from February 1, 2020 to September 4, 2020. RESULT: Tracheotomy was performed in 118 patients with median time from intubation to tracheostomy of 22 days (Q1-Q3: 18-25). All tracheostomies were performed employing measures to minimize aerosol generation, 78.0% by percutaneous technique, and 95.8% at bedside in negative pressure rooms. Seventy-eight (66.1%) patients were weaned from the ventilator and 18 (15.3%) patients died from causes unrelated to tracheostomy. No major procedural complications occurred. Early tracheostomy (≤14 days) was associated with decreased ventilator days; median ventilator days (Q1-Q3) among patients weaned from the ventilator in the early, middle and late groups were 21 (21-31), 34 (26.5-42), and 37 (32-41) days, respectively with P = 0.030. Compared to surgical tracheostomy, percutaneous technique was associated with faster weaning for patients weaned off the ventilator [median (Q1-Q3): 34 (29-39) vs 39 (34-51) days, P = 0.038]; decreased ventilator-associated pneumonia (58.7% vs 80.8%, P = 0.039); and among patients who were discharged, shorter intensive care unit duration [median (Q1-Q3): 33 (27-42) vs 47 (33-64) days, P = 0.009]; and shorter hospital length of stay [median (Q1-Q3): 46 (33-59) vs 59.5 (48-80) days, P = 0.001]. CONCLUSION: Early, percutaneous tracheostomy was associated with improved outcomes compared to surgical tracheostomy in a multi-institutional series of ventilated patients with COVID-19.

Early Identification of Patients at Risk for Incident Heart Failure With Preserved Ejection Fraction: Novel Approach to Echocardiographic Trends.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) continues to increase in prevalence with a 50% mortality rate within 3 years of diagnosis, but lacking effective evidence-based therapies. Specific echocardiographic markers are not typically used to trigger alarm before acute HFpEF decompensation. The goal of this study was to retrospectively track changes in echocardiographic markers leading to the time of incident HFpEF hospitalization. METHODS AND RESULTS: In a single-center, retrospective analysis, patients with HFpEF admitted between 2007 and 2014 were identified using the International Classification of Diseases, 9th Revision with search refined using the European Society of Cardiology HFpEF guidelines. Using linear mixed effects models, changes in echocardiographic markers preceding acute HF decompensation owing to incident HFpEF were analyzed. We report on an incident HFpEF cohort of 242 patients, extending 18 years retrospectively, and including 675 echocardiograms analyzed from the overall sample at 14 distinct time intervals before acute decompensation. The regression models demonstrated 3 echocardiographic markers with statistically significant increases across multiple time intervals including, arterial elastance (P = .006), right atrial pressure estimate (P < .001), and right ventricular systolic pressure (P = .006). Other echocardiographic markers had individual time intervals with significant increases before acute decompensation, including (a) left atrial diameter, 8 to 10 years before HFpEF diagnosis, (b) left ventricular filling pressure 2 to 6 years before HFpEF diagnosis, (c) ventricular elastance 3 to 6 months before HFpEF diagnosis, and (d) ventricular elastance/arterial elastance as early as 10 to 20 years and as late as 3 to 6 months before HFpEF diagnosis. Furthermore, African Americans presented with incident HFpEF at an average younger age than White patients (65.6 ± 15.2 years vs. 76.7 years ± 11.7, P < .001). CONCLUSIONS: Noninvasive echocardiographic markers associated with incident HFpEF diagnosis showed long, mid, and acute range, significant changes as far back as 10 to 20 years and as close as 3 to 6 months before acute HFpEF decompensation. Including a diverse study cohort is critical to understanding the phenotypic differences of HFpEF. This hypothesis-generating study identified a novel approach to identifying trends in echocardiographic markers that may be used as a signal of impending incident HFpEF.