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PURPOSE This randomized, open-label trial compared the efficacy and safety of adjuvant nab-paclitaxel + gemcitabine with those of gemcitabine for resected pancreatic ductal adenocarcinoma (ClinicalTrials.gov identifier: NCT01964430 ). METHODS We assigned 866 treatment-naive patients with pancreatic ductal adenocarcinoma to nab-paclitaxel (125 mg/m 2 ) + gemcitabine (1,000 mg/m 2 ) or gemcitabine alone to one 30-40 infusion on days 1, 8, and 15 of six 28-day cycles. The primary end point was independently assessed disease-free survival (DFS). Additional end points included investigator-assessed DFS, overall survival (OS), and safety. RESULTS Two hundred eighty-seven of 432 patients and 310 of 434 patients completed nab-paclitaxel + gemcitabine and gemcitabine treatment, respectively. At primary data cutoff (December 31, 2018; median follow-up, 38.5 [interquartile range [IQR], 33.8-43 months), the median independently assessed DFS was 19.4 ( nab-paclitaxel + gemcitabine) versus 18.8 months (gemcitabine; hazard ratio [HR], 0.88; 95% CI, 0.729 to 1.063; P = .18). The median investigator-assessed DFS was 16.6 (IQR, 8.4-47.0) and 13.7 (IQR, 8.3-44.1) months, respectively (HR, 0.82; 95% CI, 0.694 to 0.965; P = .02). The median OS (427 events; 68% mature) was 40.5 (IQR, 20.7 to not reached) and 36.2 (IQR, 17.7-53.3) months, respectively (HR, 0.82; 95% CI, 0.680 to 0.996; P = .045). At a 16-month follow-up (cutoff, April 3, 2020; median follow-up, 51.4 months [IQR, 47.0-57.0]), the median OS (511 events; 81% mature) was 41.8 ( nab-paclitaxel + gemcitabine) versus 37.7 months (gemcitabine; HR, 0.82; 95% CI, 0.687 to 0.973; P = .0232). At the 5-year follow-up (cutoff, April 9, 2021; median follow-up, 63.2 months [IQR, 60.1-68.7]), the median OS (555 events; 88% mature) was 41.8 versus 37.7 months, respectively (HR, 0.80; 95% CI, 0.678 to 0.947; P = .0091). Eighty-six percent ( nab-paclitaxel + gemcitabine) and 68% (gemcitabine) of patients experienced grade ≥ 3 treatment-emergent adverse events. Two patients per study arm died of treatment-emergent adverse events. CONCLUSION The primary end point (independently assessed DFS) was not met despite favorable OS seen with nab-paclitaxel + gemcitabine.

Advances in computer science and data-analytic methods are driving a new era in mental health research and application. Artificial intelligence (AI) technologies hold the potential to enhance the assessment, diagnosis, and treatment of people experiencing mental health problems and to increase the reach and impact of mental health care. However, AI applications will not mitigate mental health disparities if they are built from historical data that reflect underlying social biases and inequities. AI models biased against sensitive classes could reinforce and even perpetuate existing inequities if these models create legacies that differentially impact who is diagnosed and treated, and how effectively. The current article reviews the health-equity implications of applying AI to mental health problems, outlines state-of-the-art methods for assessing and mitigating algorithmic bias, and presents a call to action to guide the development of fair-aware AI in psychological science.

Abstract Background Image-guided biopsies in patients with suspected native vertebral osteomyelitis (NVO) are recommended to establish the microbiological diagnosis and guide antibiotic therapy. Despite recent advances, the microbiological yield of this procedure remains between 48% and 52%. A better understanding of factors associated with this low yield may lead to improved microbiological diagnosis. Methods We retrospectively identified patients with suspected NVO undergoing image-guided biopsies from January 2011 to June 2021 at our institution. Two hundred nine patients undergoing 248 percutaneous biopsies were included. Demographic data, biopsy and microbiologic techniques, clinical characteristics, and antibiotic use were collected. Multivariable logistic regression analysis was conducted to determine factors associated with microbiological yield. Results A total of 110 of 209 (52.6%) initial image-guided biopsies revealed positive microbiological results. This number increased to 121 of 209 (57.9%) when repeat image-guided biopsies were included. In multivariable analysis, aspiration of fluid was associated with a 3-fold increased odds of yielding a positive result (odds ratio [OR], 3.13; 95% confidence interval [CI], 1.39–7.04; P = .006), whereas prior antibiotic use was associated with a 3-fold decreased yield (OR, 0.32; 95% CI, .16–.65; P = .002). A univariate subgroup analysis revealed a significant association between the length of the antibiotic-free period and microbiological yield, with the lowest rates of pathogen detection at 0–3 days and higher rates as duration increased (P = .017). Conclusions Prior antibiotic use in patients with suspected NVO was associated with a decrease in the microbiological yield of image-guided biopsies. An antibiotic-free period of at least 4 days is suggested to maximize yield. Successful fluid aspiration during the procedure also increases microbiological yield.

Previously we showed the generation of a protein trap library made with the gene-break transposon (GBT) in zebrafish ( Danio rerio ) that could be used to facilitate novel functional genome annotation towards understanding molecular underpinnings of human diseases (Ichino et al, 2020). Here, we report a significant application of this library for discovering essential genes for heart rhythm disorders such as sick sinus syndrome (SSS). SSS is a group of heart rhythm disorders caused by malfunction of the sinus node, the heart’s primary pacemaker. Partially owing to its aging-associated phenotypic manifestation and low expressivity, molecular mechanisms of SSS remain difficult to decipher. From 609 GBT lines screened, we generated a collection of 35 zebrafish insertional cardiac (ZIC) mutants in which each mutant traps a gene with cardiac expression. We further employed electrocardiographic measurements to screen these 35 ZIC lines and identified three GBT mutants with SSS-like phenotypes. More detailed functional studies on one of the arrhythmogenic mutants, GBT411 , in both zebrafish and mouse models unveiled Dnajb6 as a novel SSS causative gene with a unique expression pattern within the subpopulation of sinus node pacemaker cells that partially overlaps with the expression of hyperpolarization activated cyclic nucleotide gated channel 4 (HCN4), supporting heterogeneity of the cardiac pacemaker cells.

Importance In patients with severe aortic valve stenosis at intermediate surgical risk, transcatheter aortic valve replacement (TAVR) with a self-expanding supra-annular valve was noninferior to surgery for all-cause mortality or disabling stroke at 2 years. Comparisons of longer-term clinical and hemodynamic outcomes in these patients are limited. Objective To report prespecified secondary 5-year outcomes from the Symptomatic Aortic Stenosis in Intermediate Risk Subjects Who Need Aortic Valve Replacement (SURTAVI) randomized clinical trial. Design, Setting, and Participants SURTAVI is a prospective randomized, unblinded clinical trial. Randomization was stratified by investigational site and need for revascularization determined by the local heart teams. Patients with severe aortic valve stenosis deemed to be at intermediate risk of 30-day surgical mortality were enrolled at 87 centers from June 19, 2012, to June 30, 2016, in Europe and North America. Analysis took place between August and October 2021. Intervention Patients were randomized to TAVR with a self-expanding, supra-annular transcatheter or a surgical bioprosthesis. Main Outcomes and Measures The prespecified secondary end points of death or disabling stroke and other adverse events and hemodynamic findings at 5 years. An independent clinical event committee adjudicated all serious adverse events and an independent echocardiographic core laboratory evaluated all echocardiograms at 5 years. Results A total of 1660 individuals underwent an attempted TAVR (n = 864) or surgical (n = 796) procedure. The mean (SD) age was 79.8 (6.2) years, 724 (43.6%) were female, and the mean (SD) Society of Thoracic Surgery Predicted Risk of Mortality score was 4.5% (1.6%). At 5 years, the rates of death or disabling stroke were similar (TAVR, 31.3% vs surgery, 30.8%; hazard ratio, 1.02 [95% CI, 0.85-1.22]; P = .85). Transprosthetic gradients remained lower (mean [SD], 8.6 [5.5] mm Hg vs 11.2 [6.0] mm Hg; P < .001) and aortic valve areas were higher (mean [SD], 2.2 [0.7] cm 2 vs 1.8 [0.6] cm 2 ; P < .001) with TAVR vs surgery. More patients had moderate/severe paravalvular leak with TAVR than surgery (11 [3.0%] vs 2 [0.7%]; risk difference, 2.37% [95% CI, 0.17%- 4.85%]; P = .05). New pacemaker implantation rates were higher for TAVR than surgery at 5 years (289 [39.1%] vs 94 [15.1%]; hazard ratio, 3.30 [95% CI, 2.61-4.17]; log-rank P < .001), as were valve reintervention rates (27 [3.5%] vs 11 [1.9%]; hazard ratio, 2.21 [95% CI, 1.10-4.45]; log-rank P = .02), although between 2 and 5 years only 6 patients who underwent TAVR and 7 who underwent surgery required a reintervention. Conclusions and Relevance Among intermediate-risk patients with symptomatic severe aortic stenosis, major clinical outcomes at 5 years were similar for TAVR and surgery. TAVR was associated with superior hemodynamic valve performance but also with more paravalvular leak and valve reinterventions.

Abstract Background This study investigated breast cancer‐related lymphedema (BCRL) and its correlation with the incidence of cellulitis and mortality in the National Health Insurance (NHI) database in Taiwan. Methods Between 2004 and 2014, the NHI database of patients with breast cancer who underwent surgical procedures, adjuvant therapies, BCRL, cellulitis, and mortality were retrospectively reviewed. Cox regression was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for incidence of BCRL and cellulitis in different treatment groups. The associations of BCRL with the incidence of cellulitis and mortality were further analyzed using the Kaplan–Meier curve. Results Among 100 301 patients, 5464 (5.4%) developed BCRL with a median onset of 1.3 years. At a mean follow‐up of 4.77 years, the incidence of cellulitis in the BCRL group (12.7%, 694/5464 patients) was significantly higher than in the no‐BCRL group (2.73%, 2589/94 837 patients) (HR: 3.74; 95% CI: 3.43–4.08; p < 0.0001). At a mean follow‐up of 5.77 years, the mortality rate in the cellulitis group (34.21%, 1123/3283 patients) was significantly greater than in the no‐cellulitis group (16.29%, 15 804/97 018 patients) (HR: 1.17; 95% CI: 1.1–1.24; p < 0.0001). Conclusions BCRL had a significantly higher incidence of cellulitis and mortality.

Abstract Background The optimal duration of antibiotic therapy after debridement and implant retention (DAIR) for periprosthetic joint infections (PJIs) is debated. Furthermore, the best antibiotic regimens for staphylococcal PJI are also unclear. In this study, we evaluated the impact of antibiotic therapy duration on the risk of failure. We assessed the utility of rifampin-based regimens for staphylococcal PJI managed with DAIR. Methods We performed a retrospective cohort study of patients 18 years and older diagnosed with hip and knee PJI who underwent DAIR between January 1, 2008 and 31 December 31, 2018 at Mayo Clinic, USA. The outcome was failure of DAIR. For statistical analysis, joint-stratified Cox regression models adjusted for age, sinus tract, symptom duration, and primary/revision arthroplasty were performed. Results We examined 247 cases of PJI with a median follow-up of 4.4 years (interquartile range [IQR], 2.3–7) after DAIR. The estimated 5-year cumulative incidence of failure was 28.1% (n = 65). There was no association between the duration of intravenous (IV) antibiotics (median 42 days; IQR, 38–42) and treatment failure (P = .119). A shorter duration of subsequent oral antibiotic therapy was associated with a higher risk of failure (P = .005; eg, 90-day vs 1-year duration; hazard ratio [HR], 3.50; 95% confidence interval [CI], 1.48–8.25). For staphylococcal knee PJI, both the use and longer duration of a rifampin-based regimen were associated with a lower risk of failure (both P = .025). There was no significant association between fluoroquinolone (FQ) use and failure (HR, 0.62; 95% CI, .31–1.24; P = .172). Conclusions The duration of initial IV antibiotic therapy did not correlate with treatment failure in this cohort of patients. Rifampin use is recommended for staphylococcal knee PJI. There was no apparent benefit of FQ use in staphylococcal PJI.

Introduction: The 6-hour threshold to revascularization of an ischemic limb is ubiquitous in the trauma literature, however, contemporary evidence suggests that this threshold should be less. This study aims to characterize the relationship between the duration of limb ischemia and successful limb salvage following lower extremity arterial trauma. Methods: This is a cohort study of the United States and UK military service members injured while serving in Iraq or Afghanistan between 2003 and 2013. Consecutive patients who sustained iliac, femoral, or popliteal artery injuries, and underwent surgery to attempt revascularization, were included. The association between limb outcome and the duration of limb ischemia was assessed using the Kaplan-Meier method. Results: One hundred twenty-two patients (129 limbs) who sustained iliac (2.3%), femoral (56.6%), and popliteal (41.1%) arterial injuries were included. Overall, 87 limbs (67.4%) were successfully salvaged. The probability of limb salvage was 86.0% when ischemia was ≤1 hour; 68.3% when between 1 and 3 hours; 56.3% when between 3 and 6 hours; and 6.7% when >6 hours ( P <0.0001). Shock more than doubled the risk of failed limb salvage [hazard ratio=2.42 (95% confidence interval: 1.27–4.62)]. Conclusions: Limb salvage is critically dependent on the duration of ischemia with a 10% reduction in the probability of successful limb salvage for every hour delay to revascularization. The presence of shock significantly worsens this relationship. Military trauma systems should prioritize rapid hemorrhage control and early limb revascularization within 1 hour of injury.

Abstract Background Corynebacterium periprosthetic joint infection (PJI) is a poorly described infectious syndrome. Prior studies included cases of polymicrobial infections. This series describes the clinical characteristics, management, and outcomes of monomicrobial Corynebacterium PJI. Methods We queried the Mayo Clinic Total Joint Registry for cases of monomicrobial Corynebacterium knee and hip PJI in adults (age ≥18 years) between 2010 and 2019. Results A total of 20 (1%) out of 2067 PJI cases met our inclusion criteria. Most were males (55%), and the median age was 64 years. Seventy percent had chronic symptoms (&gt;4 weeks). PJI was delayed to late (&gt;3 months postimplantation) in 90%. Three species were identified: C. striatum (70%), C. jeikeium (20%), and C. amycolatum (10%). All tested isolates were susceptible to vancomycin (100%) and linezolid (100%), and most had a minimum inhibitory concentration ≤0.06 mcg/mL to daptomycin (75%). Other agents were less reliable, with high resistance to oral agents commonly used for suppression. Nineteen patients were treated: 37% debridement and implant retention (DAIR), 47% 2-stage exchange, and 16% resection without reimplantation. Of these, failure occurred in 29%, 11%, and 0%, respectively. Conclusions Corynebacterium PJIs pose a therapeutic challenge due to limited antimicrobial armamentarium and undefined optimal surgical intervention. Vancomycin and linezolid remain the most reliable agents for treatment. DAIR may be attempted for acute PJI, but verification of durable chronic suppression options will be critical for this approach.