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Key Points Question Are results of universal and selective screening for suicide risk implemented in a pediatric emergency department associated with future suicidal behaviors? Findings In this cohort study of 15 003 youths aged 8 to 18 years, positive screens were significantly associated with subsequent suicide-related hospital visits compared with standard emergency department procedures. Screening also more than doubled the detection of suicide risk compared with treatment as usual. Meaning These findings suggest that screening for suicide risk in pediatric emergency departments is an effective approach to identify risk for subsequent suicide-related emergency department visits., This cohort study examines the association between results of universal and selective screening for suicide risk in a pediatric emergency department using the Ask Suicide-Screening Questions (ASQ) instrument and subsequent suicide-related outcomes., Importance According to National Patient Safety Goal 15.01.01, all individuals being treated or evaluated for behavioral health conditions as their primary reason for care in hospitals and behavioral health care organizations accredited by The Joint Commission should be screened for suicide risk using a validated tool. Existing suicide risk screens have minimal or no high-quality evidence of association with future suicide-related outcomes. Objective To test the association between results of the Ask Suicide-Screening Questions (ASQ) instrument in a pediatric emergency department (ED), implemented through selective and universal screening approaches, and subsequent suicide-related outcomes. Design, Setting, and Participants In this retrospective cohort study at an urban pediatric ED in the United States, the ASQ was administered to youths aged 8 to 18 years with behavioral and psychiatric presenting problems from March 18, 2013, to December 31, 2016 (selective condition), and then to youths aged 10 to 18 years with medical presenting problems (in addition to those aged 8-18 years with behavioral and psychiatric presenting problems) from January 1, 2017, to December 31, 2018 (universal condition). Exposure Positive ASQ screen at baseline ED visit. Main Outcomes and Measures The main outcomes were subsequent ED visits with suicide-related presenting problems (ie, ideation or attempts) based on electronic health records and death by suicide identified through state medical examiner records. Association with suicide-related outcomes was calculated over the entire study period using survival analyses and at 3-month follow-up for both conditions using relative risk. Results The complete sample was 15 003 youths (7044 [47.0%] male; 10 209 [68.0%] black; mean [SD] age, 14.5 [3.1] years at baseline). The follow-up for the selective condition was a mean (SD) of 1133.7 (433.3) days; for the universal condition, it was 366.2 (209.2) days. In the selective condition, there were 275 suicide-related ED visits and 3 deaths by suicide. In the universal condition, there were 118 suicide-related ED visits and no deaths during the follow-up period. Adjusting for demographic characteristics and baseline presenting problem, positive ASQ screens were associated with greater risk of suicide-related outcomes among both the universal sample (hazard ratio, 6.8 [95% CI, 4.2-11.1]) and the selective sample (hazard ratio, 4.8 [95% CI, 3.5-6.5]). Conclusions and Relevance Positive results of both selective and universal screening for suicide risk in pediatric EDs appear to be associated with subsequent suicidal behavior. Screening may be a particularly effective way to detect suicide risk among those who did not present with ideation or attempt. Future studies should examine the impact of screening in combination with other policies and procedures aimed at reducing suicide risk.

BACKGROUND: The aim of this study was to evaluate the effect of a virtual reality video on preoperative anxiety, hemodynamic parameters, and patient satisfaction in patients undergoing septorhinoplasty. METHODS: This was a prospective, observational cohort trial. Forty patients between the ages of 18...65 who were scheduled for elective septorhinoplasty, with an American Society of Anesthesiologists (ASA) physical status I...II were included in the study. Patients experienced a 15-minute virtual reality (VR) video via a phone using a VR device. A three-dimensional, 360.. video depicted the beauty of nature and was accompanied by meditation music. Patients... oxygen saturation values, heart rate, and blood pressure were monitored and recorded. Using the State-Trait Anxiety Inventory scale, anxiety scores and hemodynamic parameters were compared before and after VR application. RESULTS: Median anxiety scores decreased significantly from 40.5 to 34 (p.ß

BACKGROUND: Malignant Hyperthermia (MH) is a pharmacogenetic disorder triggered by halogenated anesthesia agents/succinylcholine and characterized by hypermetabolism crisis during anesthesia, but also by day-to-day symptoms, such as exercise intolerance, that may alert the health professional. OBJECTIVE: The study aimed to analyze the incidence of fatigue in MH susceptible patients and the variables that can impact perception of fatigue, such as the level of routine physical activity and depression. METHODS: A cross-sectional observational study was carried out with three groups ... 22 patients susceptible to MH (positive in vitro muscle contracture test), 13 non-susceptible to MH (negative in vitro muscle contracture test) and 22 controls (no history of MH). Groups were assessed by a demographic/clinical questionnaire, a fatigue severity scale (intensity, specific situations, psychological consequences, rest/sleep response), and the Beck depression scale. Subgroups were re-assessed with the Baecke habitual physical exercise questionnaire (occupational physical activity, leisure physical exercise, leisure/locomotion physical activity). RESULTS: There were no significant differences among the three groups regarding fatigue intensity, fatigue related to specific situations, psychological consequences of fatigue, fatigue response to resting/sleeping, depression, number of active/sedentary participants, and the mean time and characteristics of habitual physical activity. Nevertheless, unlike the control sub-group, the physically active MH-susceptible subgroup had a higher fatigue response to resting/sleeping than the sedentary MH susceptible subgroup (respectively, 5.9.ß...ß1.9 vs. 3.9.ß...ß2, t-test unpaired, p.ß

PURPOSE: Several bedside clinical tests have been proposed to predict difficult tracheal intubation. Unfortunately, when used alone, these tests show less than ideal prediction performance. Some multivariate tests have been proposed considering that the combination of some criteria could lead to better prediction performance. The goal of our research was to compare three previously described multivariate models in a group of adult patients undergoing general anesthesia. METHODS: This study included 220 patients scheduled for elective surgery under general anesthesia. A standardized airway evaluation which included modified Mallampati class (MM), thyromental distance (TMD), mouth opening distance (MOD), head and neck movement (HNM), and jaw protrusion capacity was performed before anesthesia. Multivariate models described by El-Ganzouri et al., Naguib et al., and Langeron et al. were calculated using the airway data. After anesthesia induction, an anesthesiologist performed the laryngoscopic classification and tracheal intubation. The sensitivity, specificity, and receiver operating characteristic (ROC) curves of the models were calculated. RESULTS: The overall incidence of difficult laryngoscopic view (DLV) was 12.7%. The area under curve (AUC) for the Langeron, Naguib, and El-Ganzouri models were 0.834, 0.805, and 0.752, respectively, (Langeron...>...El-Ganzouri, p...=...0.004; Langeron...=...Naguib, p...=...0.278; Naguib...=...El-Ganzouri, p...=...0.101). The sensitivities were 85.7%, 67.9%, and 35.7% for the Langeron, Naguib, and El-Ganzouri models, respectively. CONCLUSION: The Langeron model had higher overall prediction performance than that of the El-Ganzouri model. Additionally, the Langeron score had higher sensitivity than the Naguib and El-Ganzouri scores, and therefore yielded a lower incidence of false negatives.

Importance: For primary prevention of atherosclerotic cardiovascular disease (ASCVD), the 2021 European Society of Cardiology (ESC) guidelines on statin use (hereafter European-ESC) recommend a new risk model (Systematic Coronary Risk Evaluation 2 [European-SCORE2]) as well as new age-specific treatment thresholds (≥7.5% 10-year ASCVD risk if aged 40-49 years and ≥10% if aged 50-69 years).Objective: To compare the clinical performance of the 2021 European-ESC, American College of Cardiology/American Heart Association (hereafter US-ACC/AHA), UK National Institute for Health and Care Excellence (UK-NICE), and 2019 ESC/European Atherosclerosis Society (EAS) guidelines in apparently healthy individuals.Design, Setting, and Participants: This population-based contemporary cohort study included 66 909 individuals from the Copenhagen General Population Study. Participants were aged 40 to 69 years and were free of ASCVD, diabetes, chronic kidney disease, and statin use at baseline in 2003 to 2015. Mean follow-up time was 9.2 years. Data were analyzed from November 2021 to April 2022.Exposures: Statin treatment according to guideline criteria.Main Outcomes and Measures: Calibration of risk calculators, statin eligibility, sensitivity, and specificity for ASCVD events according to guideline criteria.Results: During follow-up, a range of 2962 to 4277 nonfatal and fatal ASCVD events was observed, as defined by the 2021 European-SCORE2, US pooled cohort equations (PCE), and UK-QRISK3 models, and 180 fatal ASCVD events were noted as defined by the 2019 European-SCORE1 model. European-SCORE2 was slightly better calibrated with a predicted/observed ASCVD event ratio of 0.8 vs 1.3 for US-PCE, 1.3 for UK-QRISK3, and 5.8 for European-SCORE1. For primary prevention class I recommendations in individuals aged 40 to 69 years, 2862 of 66 909 (4%) qualified for statins according to the 2021 European-ESC guidelines compared with 23 029 (34%) with US-ACC/AHA, 17 659 (26%) with UK-NICE, and 13 496 (20%) with 2019 European-ESC/EAS guidelines, with associated sensitivities for detecting future European-SCORE2-defined ASCVD events of 12%, 60%, 51%, and 36%, respectively. The sensitivity of the European-ESC guidelines was improved considerably by lowering the treatment thresholds, resulting in smaller losses in specificity. To obtain similar clinical performance with the 2021 European-ESC guidelines as in the other guidelines, the threshold with European-SCORE2 should be reduced to 5% overall to match US-ACC/AHA, to 6% to match UK-NICE, and to 7% to match 2019 European-ESC/EAS guidelines.Conclusions and Relevance: Despite an improved European-SCORE2 prediction model, the new treatment thresholds in the 2021 European-ESC guidelines dramatically reduce eligibility for primary prevention with statins in low-risk European countries. Using lower treatment thresholds can improve overall guideline performance.

IMPORTANCE: Uterus transplant is a viable surgical treatment for women affected by absolute uterine-factor infertility, which affects 1 in 500 women. OBJECTIVE: To review transplant and birth outcomes of uterus transplant recipients in the US since the first case in 2016. DESIGN, SETTING, AND PARTICIPANTS: In this cohort study, 5 years of uterus transplant outcome data were collected from the 3 centers performing uterus transplants in the US: Baylor University Medical Center, Dallas, Texas; Cleveland Clinic, Cleveland, Ohio; and University of Pennsylvania, Philadelphia. A total of 33 women with absolute uterine-factor infertility who underwent uterus transplant between February 2016 and September 2021 were included. MAIN OUTCOMES AND MEASURES: Graft survival, live birth, and neonatal outcome. RESULTS: Of the 33 included uterus transplant recipients, 2 (6%) were Asian, 1 (3%) was Black, 1 (3%) was South Asian, and 29 (88%) were White; the mean (SD) age was 31 (4.7) years; and the mean (SD) body mass index (calculated as weight in kilograms divided by height in meters squared) was 24 (3.6). Most uterus transplant recipients (31 of 33 [94%]) had a congenitally absent uterus (Mayer-Rokitansky-Küster-Hauser syndrome), and 21 of 33 (64%) received organs from living donors. Mean (range) follow-up was 36 (1-67) months. There was no donor or recipient mortality. One-year graft survival was 74% (23 of 31 recipients). Through October 2021, 19 of 33 recipients (58%) had delivered 21 live-born children. Among recipients with a viable graft at 1 year, the proportion with a live-born child was 83% (19 of 23). The median (range) gestational age at birth of neonates was 36 weeks 6 days (30 weeks, 1 day to 38 weeks), and the median (range) birth weight was 2860 (1310-3940) g (median [range], 58th [6th-98th] percentile). No congenital malformations were detected. CONCLUSIONS AND RELEVANCE: Uterus transplant is a surgical therapy that enables women with uterine-factor infertility to successfully gestate and deliver children. Aggregate data from US centers demonstrate safety for the recipient, living donor, and child. These data may be used to counsel women with uterine-factor infertility on treatment options.

BACKGROUND: Heart failure is the most common cardiovascular complication of chronic kidney disease (CKD) and foreshadows a high morbidity and mortality rate. Baroreflex impairment likely contributes to cardiovascular mortality. We aimed to study the associations between CKD, heart failure, and baroreflex sensitivity (BRS) and their association with cardiovascular outcomes. METHODS: We retrospectively analyzed data from a cohort of 247 individuals with moderate to severe HF. All subjects underwent BRS measurements after intravenous phenylephrine along with electrocardiography, echocardiography, and laboratory measurements. We used logistic regression models to assess the association of CKD (estimated glomerular filtration rate

BACKGROUND: ACE2 is a key enzyme in the renin-angiotensin system (RAS) capable of balancing the RAS by metabolizing angiotensin II (AngII). First described in cardiac tissue, abundance of ACE2 is highest in the kidney, and it is also expressed in several extrarenal tissues. Previously, we reported an association between enhanced susceptibility to hypertension and elevated renal AngII levels in global ACE2-knockout mice. METHODS: To examine the effect of ACE2 expressed in the kidney, relative to extrarenal expression, on the development of hypertension, we used a kidney crosstransplantation strategy with ACE2-KO and WT mice. In this model, both native kidneys are removed and renal function is provided entirely by the transplanted kidney, such that four experimental groups with restricted ACE2 expression are generated: WT→WT (WT), KO→WT (KidneyKO), WT→KO (SystemicKO), and KO→KO (TotalKO). Additionally, we used nanoscale mass spectrometry–based proteomics to identify ACE2 fragments in early glomerular filtrate of mice. RESULTS: Although significant differences in BP were not detected, a major finding of our study is that shed or soluble ACE2 (sACE2) was present in urine of KidneyKO mice that lack renal ACE2 expression. Detection of sACE2 in the urine of KidneyKO mice during AngII-mediated hypertension suggests that sACE2 originating from extrarenal tissues can reach the kidney and be excreted in urine. To confirm glomerular filtration of ACE2, we used micropuncture and nanoscale proteomics to detect peptides derived from ACE2 in the Bowman’s space. CONCLUSIONS: Our findings suggest that both systemic and renal tissues may contribute to sACE2 in urine, identifying the kidney as a major site for ACE2 actions. Moreover, filtration of sACE2 into the lumen of the nephron may contribute to the pathophysiology of kidney diseases characterized by disruption of the glomerular filtration barrier.

BACKGROUND: Diabetic kidney disease (DKD) is the most common cause of kidney failure in the world, and novel predictive biomarkers and molecular mechanisms of disease are needed. Endothelial cell-specific molecule-1 (Esm-1) is a secreted proteoglycan that attenuates inflammation. We previously identified that a glomerular deficiency of Esm-1 associates with more pronounced albuminuria and glomerular inflammation in DKD-susceptible relative to DKD-resistant mice, but its contribution to DKD remains unexplored. METHODS: Using hydrodynamic tail-vein injection, we overexpress Esm-1 in DKD-susceptible DBA/2 mice and delete Esm-1 in DKD-resistant C57BL/6 mice to study the contribution of Esm-1 to DKD. We analyze clinical indices of DKD, leukocyte infiltration, podocytopenia, and extracellular matrix production. We also study transcriptomic changes to assess potential mechanisms of Esm-1 in glomeruli. RESULTS: In DKD-susceptible mice, Esm-1 inversely correlates with albuminuria and glomerular leukocyte infiltration. We show that overexpression of Esm-1 reduces albuminuria and diabetes-induced podocyte injury, independent of changes in leukocyte infiltration. Using a complementary approach, we find that constitutive deletion of Esm-1 in DKD-resistant mice modestly increases the degree of diabetes-induced albuminuria versus wild-type controls. By glomerular RNAseq, we identify that Esm-1 attenuates expression of kidney disease–promoting and interferon (IFN)-related genes, including Ackr2 and Cxcl11. CONCLUSIONS: We demonstrate that, in DKD-susceptible mice, Esm-1 protects against diabetes-induced albuminuria and podocytopathy, possibly through select IFN signaling. Companion studies in patients with diabetes suggest a role of Esm-1 in human DKD.

BACKGROUND: Reduced 25-hydroxyvitamin D (25[OH]D) metabolism and secondary hyperparathyroidism are common with lower estimated glomerular filtration rate (eGFR) and may contribute to cardiovascular disease and cancer risk. METHODS: We assessed for heterogeneity by baseline eGFR of the effects of vitamin D(3) on cardiovascular and cancer outcomes in the Vitamin D and Omega-3 Trial (VITAL). Participants were randomized to 2000 IU vitamin D(3) and/or 1 g Ω-3 fatty acids daily using a placebo-controlled, two-by-two factorial design (5.3 years follow-up). Primary study end points were incident major cardiovascular events and invasive cancer. Changes in serum 25(OH)D and parathyroid hormone (PTH) were examined. RESULTS: Baseline eGFR was available for 15,917 participants. Participants’ mean age was 68 years, and 51% were women. Vitamin D(3) resulted in higher serum 25(OH)D compared with placebo (difference in change 12.5 ng/ml; 95% CI, 12 to 13.1 ng/ml), without heterogeneity by eGFR (P interaction, continuous eGFR=0.2). Difference in change in PTH between vitamin D(3) and placebo was larger with lower eGFR (P interaction=0.05): –6.9 (95% CI, –10.5 to –3.4), –5.8 (95% CI, –8.3 to –3.4), –4 (95% CI, –5.9 to –2.2), and –3.8 (95% CI, –5.6 to –2) pg/ml for eGFR

BACKGROUND: The benefits of dietary protein restriction in CKD remain unclear, largely due to inadequate adherence in most clinical trials. We examined whether low-protein rice (LPR) previously developed to reduce the protein content of rice, a major staple food, would help improve adherence to dietary protein restriction. METHODS: This open-label, multicenter, randomized, controlled trial evaluated the efficacy of LPR use for reducing dietary protein intake (DPI) in patients with CKD stages G3aA2–G4. Participants were randomly assigned in a 1:1 ratio to an LPR or control group and were followed up for 24 weeks. Both groups received regular counseling by dietitians to help achieve a target DPI of 0.7 g/kg ideal body weight (IBW) per day. The amount of protein in LPR is about 4% of that in ordinary rice, and the participants in the LPR group were instructed to consume LPR with at least two meals per day. The primary outcome was estimated dietary protein intake (eDPI) determined using the Maroni formula. The secondary outcomes included creatinine clearance (CCr) and urinary protein on the basis of 24-hour urine collection. RESULTS: In total, 51 patients were randomized to either the LPR group or the control group. At baseline, mean age was 62.5 years, 70% were men, mean CCr was 52.0 ml/min, and mean eDPI was 0.99 g/kg IBW per day. At 24 weeks, mean eDPI decreased to 0.80 g/kg IBW per day in the LPR group and to 0.91 g/kg IBW per day in the control group, giving a between-group difference of 0.11 g/kg IBW per day (95% confidence interval, 0.03 to 0.19 g/kg IBW per day; P=0.006). There was no significant between-group difference in CCr, but urinary protein was lower at 24 weeks in the LPR group than in the control group. CONCLUSIONS: LPR is a feasible tool for efficiently reducing DPI in patients with CKD. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Randomized, Multicenter, Controlled Study for the Efficacy of Low-Protein Rice Diet in Patients with Chronic Kidney Disease, UMIN000015630

BACKGROUND: Fibrosis progression is a major prognosis factor in kidney transplantation. Its assessment requires an allograft biopsy, which remains an invasive procedure at risk of complications. METHODS: We assessed renal stiffness by magnetic resonance elastography (MRE) as a surrogate marker of fibrosis in a prospective cohort of kidney transplant recipients compared with the histologic gold standard. Interstitial fibrosis was evaluated by three methods: the semi-quantitative Banff ci score, a visual quantitative evaluation by a pathologist, and a computer-assisted quantitative evaluation. MRE-derived stiffness was assessed at the superior, median, and inferior poles of the allograft. RESULTS: We initially enrolled 73 patients, but only 55 had measurements of their allograft stiffness by MRE before an allograft biopsy. There was no significant correlation between MRE-derived stiffness at the biopsy site and the ci score (ρ=–0.25, P=0.06) or with the two quantitative assessments (pathologist: ρ=–0.25, P=0.07; computer assisted: ρ=–0.21, P=0.12). We observed negative correlations between the stiffness of both the biopsy site and the whole allograft, with either the glomerulosclerosis percentage (ρ=–0.32, P=0.02 and ρ=–0.31, P=0.02, respectively) and the overall nephron fibrosis percentage, defined as the mean of the percentages of glomerulosclerosis and interstitial fibrosis (ρ=–0.30, P=0.02 and ρ=–0.28, P=0.04, respectively). At patient level, mean MRE-derived stiffness was similar across the three poles of the allograft (±0.25 kPa). However, a high variability of mean stiffness was found between patients, suggesting a strong influence of confounding factors. Finally, no significant correlation was found between mean MRE-derived stiffness and the slope of eGFR (P=0.08). CONCLUSIONS: MRE-derived stiffness does not directly reflect the extent of fibrosis in kidney transplantation.

BACKGROUND: Bradycardia and asystole events are common among patients treated with maintenance hemodialysis. However, triggers of these events in patients on maintenance hemodialysis (HD), particularly during the long interdialytic period when these events cluster, are uncertain. METHODS: The Monitoring in Dialysis Study (MiD) enrolled 66 patients on maintenance HD who were implanted with loop recorders and followed for 6 months. We analyzed associations of predialysis laboratory values with clinically significant bradyarrhythmia or asystole (CSBA) during the 12 hours before an HD session. Associations with CSBA were analyzed with mixed-effect models. Adjusted negative binomial mixed-effect regression was used to estimate incidence rate ratios (IRR) for CSBA. We additionally evaluated associations of CSBA at any time during follow-up with time-averaged dialytic and laboratory parameters and associations of peridialytic parameters with occurrence of CSBA from the start of one HD session to the beginning of the next. RESULTS: There were 551 CSBA that occurred in the last 12 hours of the interdialytic interval preceding 100 HD sessions in 12% of patients and 1475 CSBA events in 23% of patients overall. We did not identify significant associations between dialytic parameters or serum electrolytes and CSBA in the last 12 hours of the interdialytic interval in adjusted analyses. Median time-averaged ultrafiltration rate was significantly higher in individuals without CSBA (9.8 versus 8, P=0.04). Use of dialysate sodium concentrations ≤135 (versus 140) mEq/L was associated with a reduced risk of CSBA from the start of one session to the beginning of next. CONCLUSIONS: Although a few factors had modest associations with CSBA in some analyses, we did not identify any robust associations of modifiable parameters with CSBA in the MiD Study. Further investigation is needed to understand the high rates of arrhythmia in the hemodialysis population.

BACKGROUND: Abnormalities in calcium, phosphorus, PTH, vitamin D metabolism, bone, and vascular calcification occur in chronic kidney disease mineral bone disorder (CKD-MBD). Calciphylaxis, involving painful, ulcerative skin lesions, is also a major problem associated with CKD-MBD. There are no quality medical interventions to address these clinical issues. Bone ASARM peptides are strong inhibitors of mineralization and induce hypophosphatemia by inhibiting phosphate uptake from the gut. We hypothesize treatment of CKD-MBD rats with ASARM peptides will reverse hyperphosphatemia, reduce soft-tissue calcification, and prevent calciphylaxis. METHODS: To test our hypothesis, we assessed the effects of synthetic ASARM peptide in rats that had undergone a subtotal 5/6th nephrectomy (56NEPHREX), a rodent model of CKD-MBD. All rats were fed a high phosphate diet (2% Pi) to worsen mineral metabolism defects. Changes in serum potassium, phosphate, BUN, creatinine, PTH, FGF23, and calcium were assessed in response to 28 days of ASARM peptide infusion. Also, changes in bone quality, soft-tissue calcification, and expression of gut Npt2b (Slc34a2) were studied following ASARM peptide treatment. RESULTS: Rats that had undergone 56NEPHREX treated with ASARM peptide showed major improvements in hyperphosphatemia, blood urea nitrogen (BUN), and bone quality compared with vehicle controls. Also, ASARM-infused 56NEPHREX rats displayed improved renal, brain, and cardiovascular calcification. Notably, ASARM peptide infusion prevented the genesis of subdermal medial blood vessel calcification and calciphylaxis-like lesions in 56NEPHREX rats compared with vehicle controls. CONCLUSIONS: ASARM peptide infusion corrects hyperphosphatemia and improves vascular calcification, renal calcification, brain calcification, bone quality, renal function, and skin mineralization abnormalities in 56NEPHREX rats. These findings confirm our hypothesis and support the utility of ASARM peptide treatment in patients with CKD-MBD.

BACKGROUND: Diabetic kidney disease (DKD) remains the leading cause of end stage kidney disease worldwide. Despite significant advances in kidney care, there is a need to improve noninvasive techniques to predict the progression of kidney disease better for patients with diabetes. After injury, podocytes are shed in urine and may be used as a biologic tool. We previously reported that SHP-1 is upregulated in the kidney of diabetic mice, leading to podocyte dysfunction and loss. Our objective was to evaluate the expression levels of SHP-1 in urinary podocytes and kidney tissues of patients with diabetes. METHODS: In this prospective study, patients with and without diabetes were recruited for the quantification of SHP-1 in kidney tissues, urinary podocytes, and peripheral blood monocytes. Immunochemistry and mass spectrometry techniques were applied for kidney tissues. Urinary podocytes were counted, and expression of SHP-1 and podocyte markers were measured by quantitative PCR. RESULTS: A total of 66 participants (diabetic n=48, nondiabetic n=18) were included in the analyses. Diabetes was associated with increased SHP-1 expression in kidney tissues (P=0.03). Nephrin and podocin mRNA was not significantly increased in urinary podocytes from patients with diabetes compared with those without diabetes, whereas levels of SHP-1 mRNA expression significantly correlated with HbA1c and estimated glomerular filtration rate (eGFR). Additionally, follow-up (up to 2 years post recruitment) evaluation indicated that SHP-1 mRNA expression continued to increase with eGFR decline. CONCLUSIONS: Levels of SHP-1 in urinary podocytes may serve as an additional marker of glomerular disease progression in this population.

BACKGROUND: Mitochondrial injury occurs in and underlies acute kidney injury (AKI) caused by ischemia-reperfusion and other forms of renal injury. However, to date, a comprehensive analysis of this issue has not been undertaken in heme protein–induced AKI (HP-AKI). We examined key aspects of mitochondrial function, expression of proteins relevant to mitochondrial quality control, and mitochondrial ultrastructure in HP-AKI, along with responses to heme in renal proximal tubule epithelial cells. METHODS: The long-established murine glycerol model of HP-AKI was examined at 8 and 24 hours after HP-AKI. Indices of mitochondrial function (ATP and NAD(+)), expression of proteins relevant to mitochondrial dynamics, mitochondrial ultrastructure, and relevant gene/protein expression in heme-exposed renal proximal tubule epithelial cells in vitro were examined. RESULTS: ATP and NAD(+) content and the NAD(+)/NADH ratio were all reduced in HP-AKI. Expression of relevant proteins indicate that mitochondrial biogenesis (PGC-1α, NRF1, and TFAM) and fusion (MFN2) were impaired, as was expression of key proteins involved in the integrity of outer and inner mitochondrial membranes (VDAC, Tom20, and Tim23). Conversely, marked upregulation of proteins involved in mitochondrial fission (DRP1) occurred. Ultrastructural studies, including novel 3D imaging, indicate profound changes in mitochondrial structure, including mitochondrial fragmentation, mitochondrial swelling, and misshapen mitochondrial cristae; mitophagy was also observed. Exposure of renal proximal tubule epithelial cells to heme in vitro recapitulated suppression of PGC-1α (mitochondrial biogenesis) and upregulation of p-DRP1 (mitochondrial fission). CONCLUSIONS: Modern concepts pertaining to AKI apply to HP-AKI. This study validates the investigation of novel, clinically relevant therapies such as NAD(+)-boosting agents and mitoprotective agents in HP-AKI.

ImportanceSome individuals experience persistent symptoms after initial symptomatic SARS-CoV-2 infection (often referred to as Long COVID).ObjectiveTo estimate the proportion of males and females with COVID-19, younger or older than 20 years of age, who had Long COVID symptoms in 2020 and 2021 and their Long COVID symptom duration.Design, Setting, and ParticipantsBayesian meta-regression and pooling of 54 studies and 2 medical record databases with data for 1.2 million individuals (from 22 countries) who had symptomatic SARS-CoV-2 infection. Of the 54 studies, 44 were published and 10 were collaborating cohorts (conducted in Austria, the Faroe Islands, Germany, Iran, Italy, the Netherlands, Russia, Sweden, Switzerland, and the US). The participant data were derived from the 44 published studies (10 501 hospitalized individuals and 42 891 nonhospitalized individuals), the 10 collaborating cohort studies (10 526 and 1906), and the 2 US electronic medical record databases (250 928 and 846 046). Data collection spanned March 2020 to January 2022.ExposuresSymptomatic SARS-CoV-2 infection.Main Outcomes and MeasuresProportion of individuals with at least 1 of the 3 self-reported Long COVID symptom clusters (persistent fatigue with bodily pain or mood swings; cognitive problems; or ongoing respiratory problems) 3 months after SARS-CoV-2 infection in 2020 and 2021, estimated separately for hospitalized and nonhospitalized individuals aged 20 years or older by sex and for both sexes of nonhospitalized individuals younger than 20 years of age.ResultsA total of 1.2 million individuals who had symptomatic SARS-CoV-2 infection were included (mean age, 4-66 years; males, 26%-88%). In the modeled estimates, 6.2% (95% uncertainty interval [UI], 2.4%-13.3%) of individuals who had symptomatic SARS-CoV-2 infection experienced at least 1 of the 3 Long COVID symptom clusters in 2020 and 2021, including 3.2% (95% UI, 0.6%-10.0%) for persistent fatigue with bodily pain or mood swings, 3.7% (95% UI, 0.9%-9.6%) for ongoing respiratory problems, and 2.2% (95% UI, 0.3%-7.6%) for cognitive problems after adjusting for health status before COVID-19, comprising an estimated 51.0% (95% UI, 16.9%-92.4%), 60.4% (95% UI, 18.9%-89.1%), and 35.4% (95% UI, 9.4%-75.1%), respectively, of Long COVID cases. The Long COVID symptom clusters were more common in women aged 20 years or older (10.6% [95% UI, 4.3%-22.2%]) 3 months after symptomatic SARS-CoV-2 infection than in men aged 20 years or older (5.4% [95% UI, 2.2%-11.7%]). Both sexes younger than 20 years of age were estimated to be affected in 2.8% (95% UI, 0.9%-7.0%) of symptomatic SARS-CoV-2 infections. The estimated mean Long COVID symptom cluster duration was 9.0 months (95% UI, 7.0-12.0 months) among hospitalized individuals and 4.0 months (95% UI, 3.6-4.6 months) among nonhospitalized individuals. Among individuals with Long COVID symptoms 3 months after symptomatic SARS-CoV-2 infection, an estimated 15.1% (95% UI, 10.3%-21.1%) continued to experience symptoms at 12 months.Conclusions and RelevanceThis study presents modeled estimates of the proportion of individuals with at least 1 of 3 self-reported Long COVID symptom clusters (persistent fatigue with bodily pain or mood swings; cognitive problems; or ongoing respiratory problems) 3 months after symptomatic SARS-CoV-2 infection.

ImportanceBirth in the periviable period between 22 weeks 0 days and 25 weeks 6 days’ gestation is a major source of neonatal morbidity and mortality, and the decision to initiate active life-saving treatment is challenging.ObjectiveTo assess whether the frequency of active treatment among live-born neonates in the periviable period has changed over time and whether active treatment differed by gestational age at birth and race and ethnicity.Design, Setting, and ParticipantsSerial cross-sectional descriptive study using National Center for Health Statistics natality data from 2014 to 2020 for 61 908 singleton live births without clinical anomalies between 22 weeks 0 days and 25 weeks 6 days in the US.ExposuresYear of delivery, gestational age at birth, and race and ethnicity of the pregnant individual, stratified as non-Hispanic Asian/Pacific Islander, non-Hispanic Black, Hispanic/Latina, and non-Hispanic White.Main Outcomes and MeasuresActive treatment, determined by whether there was an attempt to treat the neonate and defined as a composite of surfactant therapy, immediate assisted ventilation at birth, assisted ventilation more than 6 hours in duration, and/or antibiotic therapy. Frequencies, mean annual percent change (APC), and adjusted risk ratios (aRRs) were estimated.ResultsOf 26 986 716 live births, 61 908 (0.2%) were periviable live births included in this study: 5% were Asian/Pacific Islander, 37% Black, 24% Hispanic, and 34% White; and 14% were born at 22 weeks, 21% at 23 weeks, 30% at 24 weeks, and 34% at 25 weeks. Fifty-two percent of neonates received active treatment. From 2014 to 2020, the overall frequency (mean APC per year) of active treatment increased significantly (3.9% [95% CI, 3.0% to 4.9%]), as well as among all racial and ethnic subgroups (Asian/Pacific Islander: 3.4% [95% CI, 0.8% to 6.0%]); Black: 4.7% [95% CI, 3.4% to 5.9%]; Hispanic: 4.7% [95% CI, 3.4% to 5.9%]; and White: 3.1% [95% CI, 1.1% to 4.4%]) and among each gestational age range (22 weeks: 14.4% [95% CI, 11.1% to 17.7%] and 25 weeks: 2.9% [95% CI, 1.5% to 4.2%]). Compared with neonates born to White individuals (57.0%), neonates born to Asian/Pacific Islander (46.2%; risk difference [RD], −10.81 [95% CI, −12.75 to −8.88]; aRR, 0.82 [95% CI, [0.79-0.86]), Black (51.6%; RD, −5.42 [95% CI, −6.36 to −4.50]; aRR, 0.90 [95% CI, 0.89 to 0.92]), and Hispanic (48.0%; RD, −9.03 [95% CI, −10.07 to −7.99]; aRR, 0.83 [95% CI, 0.81 to 0.85]) individuals were significantly less likely to receive active treatment.Conclusions and RelevanceFrom 2014 to 2020 in the US, the frequency of active treatment among neonates born alive between 22 weeks 0 days and 25 weeks 6 days significantly increased, and there were differences in rates of active treatment by race and ethnicity.

BACKGROUND: Fibroblast growth factor 23 (FGF23) is a bone-derived phosphatonin that is elevated in chronic kidney disease (CKD) and has been implicated in the development of cardiovascular disease. It is unknown whether elevated FGF23 in CKD is associated with impaired cardiovascular functional capacity, as assessed by maximum exercise oxygen consumption (VO(2)Max). We sought to determine whether FGF23 is associated with cardiovascular functional capacity in patients with advanced CKD and after improvement of VO(2)Max by kidney transplantation. METHODS: We performed secondary analysis of 235 patients from the Cardiopulmonary Exercise Testing in Renal Failure and After Kidney Transplantation (CAPER) cohort, which recruited patients with stage 5 CKD who underwent kidney transplantation or were waitlisted and hypertensive controls. All patients underwent cardiopulmonary exercise testing (CPET) and echocardiography and were followed longitudinally for 1 year after study enrollment. RESULTS: Patients across FGF23 quartiles differed in BMI (P=0.004) and mean arterial pressure (P

BACKGROUND: Frailty is present in ≥50% of older adults receiving dialysis. Our objective was to a develop an administrative data–based frailty index and assess the frailty index’s predictive validity for mortality and future hospitalizations. METHODS: We used United States Renal Data System data to establish two cohorts of adults aged ≥65 years, initiating dialysis in 2013 and in 2017. Using the 2013 cohort (development dataset), we applied the deficit accumulation index approach to develop a frailty index. Adjusting for age and sex, we assessed the extent to which the frailty index predicts the hazard of time until death and time until first hospitalization over 12 months. We assessed the Harrell’s C-statistic of the frailty index, a comorbidity index, and jointly. The 2017 cohort was used as a validation dataset. RESULTS: Using the 2013 cohort (n=20,974), we identified 53 deficits for the frailty index across seven domains: disabilities, diseases, equipment, procedures, signs, tests, and unclassified. Among those with ≥1 deficit, the mean (SD) frailty index was 0.30 (0.13), range 0.02–0.72. Over 12 months, 18% (n=3842) died, and 55% (n=11,493) experienced a hospitalization. Adjusted hazard ratios for each 0.1-point increase in frailty index in models of time to death and time to first hospitalization were 1.41 (95% confidence interval, 1.37 to 1.44) and 1.33 (95% confidence interval, 1.31 to 1.35), respectively. For mortality, C-statistics for frailty index, comorbidity index, and both indices were 0.65, 0.65, and 0.66, respectively. For hospitalization, C-statistics for frailty index, comorbidity index, and both indices were 0.61, 0.60, and 0.61, respectively. Data from the 2017 cohort were similar. CONCLUSIONS: We developed a novel frailty index for older adults receiving dialysis. Further studies are needed to improve on this frailty index and validate its use for clinical and research applications.

BACKGROUND: Acute kidney injury (AKI) is most commonly caused by tubular injury and is associated with a wide variety of critical illnesses. It is well known that urinary biomarkers can lead to the early identification of AKI. However, the ability of urinary biomarkers to distinguish between different types of critical illness has been less studied. METHODS: In this prospective cohort study, urinary neutrophil gelatinase–associated lipocalin (uNGAL) was measured in 107 patients consecutively admitted to the ICUs in our tertiary medical center. uNGAL samples were collected within 3–6 hours of admission to an ICU and measured by ELISA. All data were analyzed using R statistical software, and univariate analysis was used to determine the correlations of uNGAL levels with AKI stage, admission diagnoses, and ICU course. RESULTS: uNGAL level increased by a mean of 24-fold (SD 10–59) in ICU patients with AKI and demonstrated a significant correlation with the different AKI stages. uNGAL predicted the need for RRT, with values increased by more than 15-fold (P

BACKGROUND: Physical inactivity is common in patients receiving hemodialysis, but activity patterns throughout the day and in relation to dialysis are largely unknown. This knowledge gap can be addressed by long-term continuous activity monitoring, but this has not been attempted and may not be acceptable to patients receiving dialysis. METHODS: Ambulatory patients with end-stage kidney disease receiving thrice-weekly hemodialysis wore commercially available wrist-worn activity monitors for 6 months. Step counts were collected every 15 minutes and were linked to dialysis treatments. Physical function was assessed using the Short Physical Performance Battery (SPPB). Fast time to recovery from dialysis was defined as ≤2 hours. Mixed effects models were created to estimate step counts over time. RESULTS: Of 52 patients enrolled, 48 were included in the final cohort. The mean age was 60 years, and 75% were Black or Hispanic. Comorbidity burden was high, 38% were transported to and from dialysis by paratransit, and 79% had SPPB

BACKGROUND: The availability of dialysis facilities and distance traveled to receive care can impact health outcomes for patients with newly onset kidney failure. We examined recent changes in county-level number of dialysis facilities between 2012 and 2019 and assessed the association between county-level dialysis facility supply and the distance incident kidney failure patients travel to receive care. METHODS: We conducted a cross-sectional study of 828,427 adult patients initiating in-center hemodialysis for incident kidney failure between January 1, 2012, and December 31, 2019. We calculated the annual county-level number of dialysis facilities, and counties were categorized as having zero, one, two, or three or more dialysis facilities at the time of treatment initiation. We then measured the distance traveled between a patient’s home address and dialysis facility at treatment initiation (in miles) and evaluated the association between county-level number of dialysis facilities and distance traveled to initiate treatment. RESULTS: The average annual county-level number of facilities increased from 1.8 to 2.3 between 2012 and 2019. In our study period, 5% of incident adult kidney failure patients resided in a county that had zero dialysis facilities between 2012 and 2019. Compared with counties with three or more dialysis facilities, patients living in counties with no facilities in our study period traveled 14.3 miles (95% CI, 13.4 to 15.2) further for treatment. CONCLUSIONS: Kidney failure patients in counties that had no dialysis facilities traveled further, limiting their access to dialysis. Counties with no dialysis facilities at the end of the study period were more rural and had higher poverty than other counties.

BACKGROUND: Persistent hyperkalemia (hyperK) and hyperphosphatemia (hyperP) despite renal replacement therapy (RRT) was anecdotally reported in COVID-19 and acute kidney injury (AKI) requiring RRT (CoV-AKI-RRT). However, observation bias could have accounted for the reports. Thus, we systematically examined the rate and severity of hyperK and hyperP in patients with CoV-AKI-RRT in comparison with the pre-COVID-19 era. METHODS: We identified patients with CoV-AKI-RRT treated with sustained low-efficiency dialysis (SLED) for ≥2 days in March–April 2020. As pre-COVID-19 control, we included patients with AKI treated with SLED in December 2019. We examined the rates of hyperK (serum potassium [sK] ≥5.5 mEq/L), severe hyperK (sK ≥6.5 mEq/L), hyperP (serum phosphate [sP] ≥4.5 mg/dl), and moderate or severe hyperP (sP ≥7–10 and >10 mg/dl, respectively) as %SLED-days with an event. RESULTS: Along the duration of SLED, the incidence of hyperK was greater in CoV-AKI-RRT (n=64; mean 19%±2% versus 14%±3% SLED-days, P=0.002) compared with control (n=60). The proportion of patients with one or more event of severe hyperK was greater in CoV-AKI (33% versus 7%, P

Reherniation and reoperation rates of 4.5%-36% are reported in canine patients treated for intervertebral disc herniation (IVDH). Decision-making for surgical reintervention can prove challenging, especially since common postoperative changes are poorly described on MRI. The purpose of this single-center, retrospective, descriptive study was to describe the MRI characteristics of the surgical site in dogs treated for thoracolumbar IVDH and presenting for ongoing or recurrent neurological signs. Twenty-one patients were included for a total of 42 MRI studies. Chondrodystrophic breeds, specifically Dachshunds, were overrepresented. Mean number of days between surgery and second MRI was 335 (range 2-1367). Metallic susceptibility artifacts were seen in seven of 21 cases (33%), but these were limited in extent, spanning on average 1.3 vertebral bodies. In 11 cases, spinal cord compression suspected to be clinically significant was found at the surgical site; the extradural compressive material consisted of intervertebral disc material only, or a combination of intervertebral disc material and hematoma or inflammatory changes in 10 cases, and a displaced articular process and fibrous tissue in one case. The latter is a newly described complication of mini-hemilaminectomies. Paravertebral soft tissue changes and vertebral new bone formation varied according to the postoperative stage at which the patients were imaged. The results of this study supported the use of MRI as a diagnostic modality for spinal imaging following IVDH surgery, and showed that the presence of extradural disc material at a spinal surgical site is common along with various vertebral and paravertebral changes., No source of funding

BACKGROUND: The consequences of low levels of environmental heavy metal exposure, as found widely in the United States, in those with impaired renal function remain underexplored. METHODS: We examined the cross-sectional association of indices of renal function with lead and cadmium levels in blood and urine among National Health and Nutrition Examination Survey (NHANES) participants. We used the 1999–2002 cycle, which included measures of cystatin C, in order to quantify renal function most precisely and defined chronic kidney disease (CKD) as an estimated glomerular filtration rate (eGFR)

BACKGROUND: Of the more than 550,000 patients receiving maintenance hemodialysis (HD) in the United States, each has an average of 1.6 admissions annually (>880,000 inpatient HD sessions). Little is known about the temporal changes in laboratory values, ECGs, and intravascular and extravascular volume during inpatient HD sessions. METHODS: In this prospective cohort study of hospitalized HD patients, we assessed intradialytic laboratory values (metabolic panels, blood gases, ionized calcium levels), ECGs, and sonographic measures of volume status. RESULTS: Among 30 participants undergoing HD (mean age 62 years; 53% men, 43% Black) laboratory values had the largest changes in the first hour of HD. There was no significant change in ionized calcium levels pre- to post-HD (change: –0.01±0.07, P=0.24); 12 of 30 and 17 of 30 patients had levels below the lower reference limit at the beginning and end of HD, respectively. The mean pH increased pre- to post-HD (change: 0.06±0.04, P

BACKGROUND: Although those with kidney disease may have heightened susceptibility to heavy metal toxicity, whether low levels of drinking water lead contamination have clinical consequence is unknown. METHODS: Given that lead toxicity is known to associate with iron deficiency, we merged data from the Environmental Protection Agency (EPA) Safe Drinking Water Information and United States Renal Data Systems to examine whether municipal 90th percentile drinking water lead levels associate with iron deficiency among incident dialysis patients. Iron deficiency was defined across thresholds of transferrin saturation (

ImportancePatient-reported symptom burden was recently found to be associated with emergency department use and unplanned hospitalization (ED/Hosp) in patients with head and neck cancer. It was hypothesized that symptom scores could be combined with administrative health data to accurately risk stratify patients.ObjectiveTo develop and validate a machine learning approach to predict future ED/Hosp in patients with head and neck cancer.Design, Setting, and ParticipantsThis was a population-based predictive modeling study of patients in Ontario, Canada, diagnosed with head and neck cancer from January 2007 through March 2018. All outpatient clinical encounters were identified. Edmonton Symptom Assessment System (ESAS) scores and clinical and demographic factors were abstracted. Training and test cohorts were randomly generated in a 4:1 ratio. Various machine learning algorithms were explored, including (1) logistic regression using a least absolute shrinkage and selection operator, (2) random forest, (3) gradient boosting machine, (4) k-nearest neighbors, and (5) an artificial neural network. Data analysis was performed from September 2021 to January 2022.Main Outcomes and MeasuresThe main outcome was any 14-day ED/Hosp event following symptom assessment. The performance of each model was assessed on the test cohort using the area under the receiver operator characteristic (AUROC) curve and calibration plots. Shapley values were used to identify the variables with greatest contribution to the model.ResultsThe training cohort consisted of 9409 patients (mean [SD] age, 63.3 [10.9] years) undergoing 59 089 symptom assessments (80%). The remaining 2352 patients (mean [SD] age, 63.3 [11] years) and 14 193 symptom assessments were set aside as the test cohort (20%). Several models had high predictive accuracy, particularly the gradient boosting machine (validation AUROC, 0.80 [95% CI, 0.78-0.81]). A Youden-based cutoff corresponded to a validation sensitivity of 0.77 and specificity of 0.66. Patient-reported symptom scores were consistently identified as being the most predictive features within models. A second model built only with symptom severity data had an AUROC of 0.72 (95% CI, 0.70-0.74).Conclusions and RelevanceIn this study, machine learning approaches predicted with a high degree of accuracy ED/Hosp in patients with head and neck cancer. These tools could be used to accurately risk stratify patients and may help direct targeted intervention.

IMPORTANCE: Post–cardiopulmonary bypass (CPB) coagulopathy and bleeding are among the most common reasons for blood product transfusion in surgical practices. Current retrospective data suggest lower transfusion rates and blood loss in patients receiving prothrombin complex concentrate (PCC) compared with plasma after cardiac surgery. OBJECTIVE: To analyze perioperative bleeding and transfusion outcomes in patients undergoing cardiac surgery who develop microvascular bleeding and receive treatment with either PCC or plasma. DESIGN, SETTING, AND PARTICIPANTS: A single-institution, prospective, randomized clinical trial performed at a high-volume cardiac surgical center. Patients were aged 18 years or older and undergoing cardiac surgery with CPB. Patients undergoing complex cardiac surgical procedures (eg, aortic replacement surgery, multiple procedures, or repeated sternotomy) were preferentially targeted for enrollment. During the study period, 756 patients were approached for enrollment, and 553 patients were randomized. Of the 553 randomized patients, 100 patients met criteria for study intervention. INTERVENTIONS: Patients with excessive microvascular bleeding, a prothombin time (PT) greater than 16.6 seconds, and an international normalized ratio (INR) greater than 1.6 were randomized to receive treatment with either PCC or plasma. The PCC dose was 15 IU/kg or closest standardized dose; the plasma dose was a suggested volume of 10 to 15 mL/kg rounded to the nearest unit. MAIN OUTCOMES AND MEASURES: The primary outcome was postoperative bleeding (chest tube output) from the initial postsurgical intensive care unit admission through midnight on postoperative day 1. Secondary outcomes were PT/INR, rates of intraoperative red blood cell (RBC) transfusion after treatment, avoidance of allogeneic transfusion from the intraoperative period to the end of postoperative day 1, postoperative bleeding, and adverse events. RESULTS: One hundred patients (mean [SD] age, 66.8 [13.7] years; 61 [61.0%] male; and 1 [1.0%] Black, 1 [1.0%] Hispanic, and 98 [98.0%] White) received the study intervention (49 plasma and 51 PCC). There was no significant difference in chest tube output between the plasma and PCC groups (median [IQR], 1022 [799-1575] mL vs 937 [708-1443] mL). After treatment, patients in the PCC arm had a greater improvement in PT (effect estimate, −1.37 seconds [95% CI, −1.91 to −0.84]; P

IMPORTANCE: The administration of a fourth BNT162b2 COVID-19 vaccine dose was approved in Israel in December 2021 for individuals 60 years or older who were vaccinated with a third dose 4 months previously or earlier to control the substantial surge of the SARS-CoV-2 Omicron variant. Nonetheless, the association between receipt of the fourth dose and protection against infection remains elusive. OBJECTIVE: To determine the association of the fourth BNT162b2 dose with protection against SARS-CoV-2–related infections, hospitalizations, and deaths during the Omicron surge in long-term care facility (LTCF) residents. DESIGN, SETTING, AND PARTICIPANTS: This prospective cohort study was conducted in Israel between January 10 and March 31, 2022 and included LTCF residents 60 years or older. EXPOSURES: Vaccination with the fourth dose of BNT162b2 vs 3 doses that were administered 4 months previously or earlier. MAIN OUTCOMES AND MEASURES: Cumulative incidences of SARS-CoV-2 infections, hospitalizations, and deaths during the Omicron surge. The follow-up was initiated more than 7 days after receipt of the fourth dose, which was matched to the follow-up initiation date of those who had received 3 doses of vaccine in each facility. We obtained hazard ratios and 95% confidence intervals from multivariable Cox regression models. RESULTS: The data of 43 775 residents (mean [SD] age, 80.1 [9.4] years; 29 679 women [67.8%]) were analyzed, of whom 24 088 (55.0%) and 19 687 (45.0%) received the fourth and third dose (4 months previously or earlier), respectively. The median follow-up time was 73 days (4-dose group: IQR, 6 days; 3-dose group: IQR, 56 days). More than 7 days postvaccination with the fourth dose, SARS-CoV-2 infection was detected among 4058 fourth-dose vs 4370 third-dose recipients (cumulative incidence, 17.6% vs 24.9%). The corresponding incidences of hospitalizations for mild-to-moderate COVID-19, severe illness, and mortality were 0.9% and 2.8%, 0.5% and 1.5%, and 0.2% and 0.5%, respectively. The adjusted protections were 34% (95% CI, 30%-37%), 64% (95% CI, 56%-71%), and 67% (95% CI, 57%-75%) against overall infection, hospitalizations for mild-to-moderate illness, and severe illness, respectively, and 72% (95% CI, 57%-83%) against related deaths. CONCLUSIONS AND RELEVANCE: The results of this cohort study suggest that receipt of a fourth BNT162b2 dose conferred high protection against COVID-19 hospitalizations and deaths among LTCF residents during a substantial Omicron variant surge, but protection was modest against infection. These findings are relevant to the control of COVID-19 pandemic globally, especially among the population of LTCFs.

IMPORTANCE: The clinical relevance of antirituximab antibodies (ARAs) in patients with pemphigus who are treated with rituximab (RTX) is currently unknown. OBJECTIVE: To determine the prevalence of ARAs in patients with pemphigus who are treated with RTX and their association with complete remission (CR) and relapse. DESIGN, SETTING, AND PARTICIPANTS: This post hoc analysis of the Ritux3 trial was conducted from January 2010 to December 2015 in 25 dermatology departments in France and included 42 patients with moderate-to-severe pemphigus who were randomized to receive treatment with RTX. Five additional patients were recruited for an ancillary study. The proportions of patients who achieved CR or relapsed after an initial treatment cycle of RTX were compared depending on whether patients had ARAs. EXPOSURES: Patients were treated with 1000 mg of RTX on days 1 and 15 and 2 maintenance infusions of 500 mg at months 12 and 18. MAIN OUTCOMES AND MEASURES: Rates of relapse and sustained CR at month 36. Levels of ARAs, antidesmoglein 1/3 antibodies, RTX serum concentrations, and peripheral blood CD19(+) B-cell frequency were measured. RESULTS: Of 42 participants with vs without ARAs, the mean (SD) age was 55 (17) years and 56 (17) years, respectively; 25 (59.5%) were women. Antirituximab antibodies were detected in the serum samples of 13 of 42 patients (31%) during the first year. Nine patients who experienced relapse before month 12 were excluded because they received additional infusions and could not be further analyzed. Among the 33 remaining patients, 2 patients (6.1%) experienced relapse after month 12, and 31 (95.9%) maintained a sustained CR until month 36. The rate of sustained CR was not different whether patients had ARAs (11 of 13 [85%]) or not (20 of 20 [100%]) (P = .15). Both groups (ARA(+) vs ARA(−)) also had similar CD19(+) B-cell depletion and RTX levels, but patients with ARAs had higher anti–desmoglein 3 antibody (DSG3 Abs) levels compared with those without ARAs (mean [SD], 30.1 [50.9] AU/mL vs 4.0 [4.3] AU/mL; P = .03). The 2 patients with ARAs who experienced relapse after month 12 had an undetectable RTX level, incomplete B-cell depletion, and higher anti-DSG3 Abs level than the 11 patients who maintained a sustained CR with ARAs (RTX mean [SD] concentration, 0 ug/mL vs 12.5 [2.2] ug/mL; P = .03; incomplete B-cell depletion, 2 of 2 vs 4 of 11; P = .19; mean [SD] anti-DSG3 Abs levels, 103.5 [61.5] AU/mL vs 19.5 [11.0] AU/mL; P = .001) or patients without ARAs (mean [SD] RTX concentration, 0 ug/mL vs 13.5 [1.8] ug/mL; P = .02; incomplete B-cell depletion, 2 of 2 vs 5 of 20; P = .09; mean [SD] anti-DSG3 Abs level, 103.5 [61.5] AU/mL vs 4.0 [1.0] AU/mL; P

IMPORTANCE: The study team investigated costs associated with the ranibizumab port delivery system (PDS) for neovascular age-related macular (nAMD), an alternative to conventional intravitreal anti–vascular endothelial growth factor (VEGF) injections. OBJECTIVE: To investigate costs of intravitreal anti-VEGF injections vs ranibizumab PDS for patients with neovascular AMD (nAMD). DESIGN, SETTING, AND PARTICIPANTS: This cost analysis used trial data and Medicare reimbursement rates and included patients with nAMD who were receiving ranibizumab, aflibercept, bevacizumab injections, or ranibizumab PDS. MAIN OUTCOMES AND MEASURES: The number of intravitreal ranibizumab, aflibercept, and bevacizumab injections to break even with costs of ranibizumab PDS. Total direct medical costs over 1 year and 5 years for the ranibizumab PDS arm with refills at fixed 6-month intervals compared with monthly or bimonthly injections were calculated using Medicare rates. Scenario and sensitivity analyses accounted for uncertainty and variation. RESULTS: The mean (SD) number of ranibizumab, aflibercept, and bevacizumab injections to break even with the cost of ranibizumab PDS with 1 refill was 10.8 (1.3), 9.3 (1.1), and 34.5 (4.2), respectively. Ranibizumab PDS with fixed 6-month refills over 1 year cost $21 016 ($2102). Comparatively, monthly intravitreal ranibizumab cost $1943 (95% CI, −$3047 to $6932; P = .34) more, aflibercept cost $5702 (95% CI, $253-$11 151; P = .04) more, and bevacizumab cost $16 732 (95% CI, −$20 170 to −$13 294, P

IMPORTANCE: Patients with language barriers have a higher risk of experiencing hospital safety events. This study hypothesized that language barriers would be associated with poorer perceptions of hospital safety climate relating to communication openness. OBJECTIVE: To examine disparities in reported hospital safety climate by language proficiency in a cohort of hospitalized children and their families. DESIGN, SETTING, AND PARTICIPANTS: This cohort study conducted from April 29, 2019, through March 1, 2020, included pediatric patients and parents or caregivers of hospitalized children at general and subspecialty units at 21 US hospitals. Randomly selected Arabic-, Chinese-, English-, and Spanish-speaking hospitalized patients and families were approached before hospital discharge and were included in the analysis if they provided both language proficiency and health literacy data. Participants self-rated language proficiency via surveys. Limited English proficiency was defined as an answer of anything other than “very well” to the question “how well do you speak English?” MAIN OUTCOMES AND MEASURES: Primary outcomes were top-box (top most; eg, strongly agree) 5-point Likert scale ratings for 3 Children’s Hospital Safety Climate Questionnaire communication openness items: (1) freely speaking up if you see something that may negatively affect care (top-box response: strongly agree), (2) questioning decisions or actions of health care providers (top-box response: strongly agree), and (3) being afraid to ask questions when something does not seem right (top-box response: strongly disagree [reverse-coded item]). Covariates included health literacy and sociodemographic characteristics. Logistic regression was used with generalized estimating equations to control for clustering by site to model associations between openness items and language proficiency, adjusting for health literacy and sociodemographic characteristics. RESULTS: Of 813 patients, parents, and caregivers who were approached to participate in the study, 608 completed surveys (74.8% response rate). A total of 87.7% (533 of 608) of participants (434 [82.0%] female individuals) completed language proficiency and health literacy items and were included in the analyses; of these, 14.1% (75) had limited English proficiency. Participants with limited English proficiency had lower odds of freely speaking up if they see something that may negatively affect care (adjusted odds ratio [aOR], 0.26; 95% CI, 0.15-0.43), questioning decisions or actions of health care providers (aOR, 0.19; 95% CI, 0.09-0.41), and being unafraid to ask questions when something does not seem right (aOR, 0.44; 95% CI, 0.27-0.71). Individuals with limited health literacy (aOR, 0.66; 95% CI, 0.48-0.91) and a lower level of educational attainment (aOR, 0.59; 95% CI, 0.36-0.95) were also less likely to question decisions or actions. CONCLUSIONS AND RELEVANCE: This cohort study found that limited English proficiency was associated with lower odds of speaking up, questioning decisions or actions of providers, and being unafraid to ask questions when something does not seem right. This disparity may contribute to higher hospital safety risk for patients with limited English proficiency. Dedicated efforts to improve communication with patients and families with limited English proficiency are necessary to improve hospital safety and reduce disparities.

IMPORTANCE: The effectiveness and safety of intravenous alteplase given before or concurrently with endovascular thrombectomy (EVT) is uncertain. Randomized clinical trials suggest there is little difference in outcomes but with only modest precision and insufficient power to analyze uncommon outcomes including symptomatic intracranial hemorrhage (sICH). OBJECTIVE: To determine whether 8 prespecified outcomes are different in patients with acute ischemic stroke treated in routine clinical practice with EVT with alteplase compared with patients treated with EVT alone without alteplase. It was hypothesized that alteplase would be associated with higher risk of sICH. DESIGN, SETTING, AND PARTICIPANTS: This was an observational cohort study conducted from February 1, 2019, to June 30, 2020, that included adult patients with acute ischemic stroke treated with EVT within 6 hours of time last known well, after excluding patients without information on discharge destination and patients with in-hospital stroke. Participants were recruited from Get With The Guidelines–Stroke, a large nationwide registry of patients with acute ischemic stroke from 555 hospitals in the US. EXPOSURES: Intravenous alteplase or no alteplase. MAIN OUTCOMES AND MEASURES: Prespecified outcomes were discharge destination, independent ambulation at discharge, modified Rankin score at discharge, discharge mortality, cerebral reperfusion according to modified Thrombolysis in Cerebral Infarction grade, and sICH. RESULTS: There were 15 832 patients treated with EVT (median [IQR] age, 72.0 [61.0-82.0] years; 7932 women [50.1%]); 10 548 (66.7%) received alteplase and 5284 (33.4%) did not. Patients treated with alteplase were younger, arrived via Emergency Medical Services sooner, were less likely to have certain comorbidities, including atrial fibrillation, hypertension, and diabetes, but had similar National Institutes of Health Stroke Severity (NIHSS) scores. Compared with patients who did not receive alteplase treatment, patients treated with alteplase were less likely to die (11.1% [1173 of 10 548 patients] vs 13.9% [734 of 5284 patients]; adjusted odds ratio [aOR] 0.83; 95% CI, 0.77-0.89; P

IMPORTANCE: Postthyroidectomy hemorrhage is a potentially life-threatening complication with no reliable noninvasive method of early detection. OBJECTIVE: To evaluate the diagnostic accuracy of neck circumference measurement for early detection of postoperative hemorrhage after thyroidectomy. DESIGN, SETTING, AND PARTICIPANTS: This diagnostic accuracy study at an academic teaching hospital used a prospective cohort of patients undergoing thyroid surgery from November 1, 2015, to January 31, 2018 (group 1), and a retrospective cohort of patients undergoing the same surgery from January 1, 2020, to September 30, 2021 (group 2). We performed repeated perioperative neck circumference measurements to evaluate the association of increased neck circumference with postthyroidectomy hemorrhage among patients at risk for hemorrhage. MAIN OUTCOMES AND MEASURES: The primary end point was the diagnostic value of neck circumference measurement for detection of postthyroidectomy hemorrhage. Additionally, data on demographic information and risk factors for postthyroidectomy hemorrhage were examined. Data analyses were performed from November 1, 2021, to January 5, 2022. RESULTS: The prospective cohort (group 1) comprised 60 patients (45 [75%] women) with a mean (SD) age of 52.2 (13.5) years; those who experienced a postthyroidectomy hemorrhage had a mean (SD) age of 57.4 (9.0) years. The retrospective cohort (group 2) comprised 353 patients (258 [73%] women) with a mean (SD) age of 55.3 (14.1) years; patients who experienced a postthyroidectomy hemorrhage had a mean (SD) age of 62.2 (10.0) years. In group 1, postoperative neck circumference increased by a median (range) of 5.0 (4.0 to 7.0) cm in patients with hemorrhage, and only 1.0 (−2.5 to 4.0) cm in patients with no postoperative bleeding (difference in the medians, 4.0 cm [95% CI, 3.0 to 5.5 cm]; effect size, 3.74 [95% CI, 2.6 to 4.9]). Defining a 7% or greater increase in neck circumference as the cutoff value for detecting postthyroidectomy hemorrhage showed a diagnostic sensitivity and specificity of 1.0 (95% CI, 0.48 to 1.0) and 0.86 (95% CI, 0.71 to 0.92), respectively. The retrospective validation also showed a difference in median (range) increase of postoperative neck circumference between patients with hemorrhage and those without—3.0 (0 to 6.0) cm vs 0.0 (−6.0 to 5.0) cm (difference in medians, 3.8 cm [95% CI, 3.0 to 4.9]; effect size, 1.63 [95% CI, 0.96 to 2.3]). Considering 12 false-positive and 332 correct-negative results, the diagnostic tool showed a sensitivity of 0.89 (95% CI, 0.51 to 0.99) and a specificity of 0.97 (95% CI, 0.94 to 0.98). CONCLUSIONS AND RELEVANCE: The findings of this diagnostic accuracy study suggest that neck circumference measurement is a feasible and easy-to-use diagnostic tool for routine clinical care to detect postthyroidectomy hemorrhage. A 7% or greater increase over the postoperative baseline neck circumference seems to be a reliable threshold for detecting postthyroidectomy hemorrhage. Neck circumference measurement should be used in combination with surveillance of clinical signs and symptoms.

ImportanceOptimal postoperative pain management is challenging. Virtual reality (VR) provides immersive, 3-dimensional experiences that may improve pain control and reduce reliance on pharmacologic pain management.ObjectiveTo evaluate use of VR on postoperative pain management after head and neck surgery.Design, Setting, and ParticipantsThis prospective, pilot randomized clinical trial was conducted at Oregon Health & Science University from July 2020 to October 2021 and included patients hospitalized after major head and neck surgery.InterventionsSimilar 15-minute interactive gaming experiences (Angry Birds) using an Oculus Quest VR headset (VR intervention) or a handheld smartphone device (control).Main Outcomes and MeasuresThe primary outcome was postintervention pain reduction. Pain scores were obtained preintervention, immediately after intervention, and then hourly for 4 hours. Secondary outcomes included changes in opioid use, measured as milligram morphine equivalents (MMEs), and patient experiences with their intervention using 5-point Likert scales.ResultsOf the 30 patients randomized for inclusion, the final population included 14 patients in the VR cohort and 15 patients in the control cohort; the majority of patients were male (26 of 29 [90%]), and the mean (SD) age was 58.3 (13.8) years. After outlier removal, there were clinically meaningful reductions in postintervention pain among patients in the VR group immediately after intervention (mean difference, −1.42; 95% CI, −2.15 to −0.70; d = 1.50), at 1 hour (mean difference, −0.86; 95% CI, −1.90 to 0.14; d = 0.67), 2 hours (mean difference, −1.07; 95% CI, −2.30 to 0.14; d = 0.69), and 3 hours (mean difference, −1.36; 95% CI, −2.80 to 0.13; d = 0.71) compared with patients in the control group. Patients in the VR group also demonstrated reductions in 4-hour postintervention opioid use compared with 4-hour preintervention opioid use (mean difference, −9.10 MME; 95% CI, −15.00 to −1.27 MME; d = 0.90) and 8-hour postintervention opioid use compared with 8-hour preintervention opioid use (mean difference, −14.00 MME; 95% CI, −25.60 to −2.40 MME; d = 0.94). There were no meaningful differences in subjective patient experiences with their respective interventions.Conclusions and RelevanceIn this randomized clinical trial, VR reduced pain scores and opioid use compared with a control intervention. Virtual reality may be a useful adjunct for postoperative pain management after head and neck surgery.Trial RegistrationClinicalTrials.gov Identifier: NCT04464304

IMPORTANCE: Topical formulations of tretinoin precursors (retinol and its ester derivatives) are widely available over the counter and may offer similar clinical benefits to those of tretinoin for treatment of photoaging. However, which of the many purported molecular effects of retinoids most strongly drives clinical improvements in tretinoin-treated skin remains unclear. OBJECTIVES: To evaluate the clinical efficacy of topical tretinoin precursors (TTP) vs tretinoin (RA) in treating moderate to severe facial photodamage and to identify potential biomarkers that correlate with clinical efficacy. DESIGN, SETTING, AND PARTICIPANTS: This randomized, double-blind, single-center, parallel-arm study of 24 patients with moderate to severe facial photodamage was conducted at an academic referral center from November 2010 to December 2011, with data analysis performed from January 2012 to December 2021. INTERVENTIONS: Daily topical application of 0.02% RA or 1.1% TTP formulation containing retinol, retinyl acetate, and retinyl palmitate for 24 weeks. MAIN OUTCOMES AND MEASURES: Photoaging and tolerability were assessed by dermatologist evaluations and patient-reported outcomes. Target gene expression was assessed by real-time quantitative polymerase chain reaction of biopsied tissue from treated areas. RESULTS: A total of 20 White women were ultimately analyzed (9 randomized to TTP, 11 randomized to RA). At week 24, there was no significant difference in Griffiths photoaging scores among patients receiving TTP vs RA (median, 4 vs 5) (TTP − RA difference: −1; 95% CI, −2 to 1; P = .27). Treatment with TTP was associated with erythema 6 times less frequently than RA (11% vs 64%) (TTP − RA difference: −0.53; 95% CI, −0.88 to −0.17; P = .01). Target gene analysis showed significant CRABP2 messenger RNA (mRNA) induction (confirming retinoic acid receptor signaling) but no significant changes in procollagen I or MMP1/3/9 mRNA in TTP-treated samples. Instead, MMP2 mRNA, which encodes a type IV collagenase, was significantly reduced in TTP-treated samples (week 24 − baseline mRNA difference: −5; 96% CI, −33 to 1.6; P = .02), and changes in MMP2 were strongly correlated with changes in fine wrinkles (r = 0.54; 95% CI, 0.12 to 0.80; P = .01). Interestingly, patients with severe baseline wrinkles exhibited greater improvements (r = −0.74; 95% CI, −0.89 to −0.43; P

IMPORTANCE: Preterm infants are at risk for poor visual acuity (VA) outcomes, even without retinal problems on ophthalmoscopy. Infant retinal microanatomy may provide insight as to potential causes. OBJECTIVE: To evaluate the association between preterm infant retinal microanatomy and VA at 9 months’ corrected age. DESIGN, SETTING, AND PARTICIPANTS: This prospective observational study took place from November 2016 and December 2019 at a single academic medical center and included preterm infants enrolled in Study of Eye Imaging in Preterm Infants (BabySTEPS). Infants were eligible for enrollment in BabySTEPS if they met criteria for retinopathy of prematurity (ROP) screening, were 35 weeks’ postmenstrual age or older at the time of first OCT imaging, and a parent or guardian provided written informed consent. Of 118 infants enrolled in BabySTEPS, 61 were included in this analysis. Data were analyzed from March to April 2021. EXPOSURES: Bedside optical coherence tomography (OCT) imaging at a mean (SD) 39.85 (0.79) weeks’ postmenstrual age and monocular grating VA measurement at 9 months’ corrected age. MAIN OUTCOMES AND MEASURES: Presence and severity of macular edema and presence of ellipsoid zone at the fovea measured by extracting semiautomated thicknesses of inner nuclear layer, inner retina, and total retina at the foveal center; choroid across foveal 1 mm; and retinal nerve fiber layer (RNFL) across the papillomacular bundle (PMB). Pearson correlation coefficients were calculated and 95% CIs were bootstrapped for the association between retinal layer thicknesses and continuous logMAR VA. Associations were analyzed between retinal microanatomy and normal (3.70 cycles/degree or greater) vs subnormal grating VA at 9 months’ corrected age using logistic regression and with logMAR VA using linear regression, adjusting for birth weight, gestational age, and ROP severity at the time of OCT imaging and accounting for intereye correlation using generalized estimating equations. RESULTS: The mean (SD; range) gestational age of included infants was 27.6 (2.8; 23.0-34.6) weeks, and mean (SD; range) birth weight was 958.2 (293.7; 480-1580) g. In 122 eyes of 61 infants, the correlations between retinal layer thicknesses and logMAR VA were as follows: r, 0.01 (95% CI, −0.07 to −0.27) for inner nuclear layer; r, 0.19 (95% CI, 0.01 to 0.35) for inner retina; r, 0.15 (95% CI, −0.02 to 0.31) for total retina; r, −0.22 (95% CI, −0.38 to −0.03) for choroid; and r, −0.27 (95% CI, −0.45 to 0.10) for RNFL across the PMB. In multivariable analysis, thinner RNFL across the PMB (regression coefficient, −0.05 per 10-μm increase in RNFL thickness; 95% CI, −0.10 to −0.01; P = .046) and prior ROP treatment (regression coefficient, 0.33 for ROP treatment; 95% CI, 0.11 to 0.56; P = .003) were independently associated with poorer 9-month logMAR VA. CONCLUSIONS AND RELEVANCE: In preterm infants, RNFL thinning across the PMB was associated with poorer 9-month VA, independent of birth weight, gestational age, need for ROP treatment, and macular microanatomy. Evaluation of RNFL thickness using OCT may help identify preterm infants at risk for poor vision outcomes.

IMPORTANCE: The clinical significance of gangrenous, suppurative, or exudative (GSE) findings is poorly characterized in children with nonperforated appendicitis. OBJECTIVE: To evaluate whether GSE findings in children with nonperforated appendicitis are associated with increased risk of surgical site infections and resource utilization. DESIGN, SETTING, AND PARTICIPANTS: This multicenter cohort study used data from the Appendectomy Targeted Database of the American College of Surgeons Pediatric National Surgical Quality Improvement Program, which were augmented with operative report data obtained by supplemental medical record review. Data were obtained from 15 hospitals participating in the Eastern Pediatric Surgery Network (EPSN) research consortium. The study cohort comprised children (aged ≤18 years) with nonperforated appendicitis who underwent appendectomy from July 1, 2015, to June 30, 2020. EXPOSURES: The presence of GSE findings was established through standardized, keyword-based audits of operative reports by EPSN surgeons. Interrater agreement for the presence or absence of GSE findings was evaluated in a random sample of 900 operative reports. MAIN OUTCOMES AND MEASURES: The primary outcome was 30-day postoperative surgical site infections (incisional and organ space infections). Secondary outcomes included rates of hospital revisits, postoperative abdominal imaging, and postoperative length of stay. Multivariable mixed-effects regression was used to adjust measures of association for patient characteristics and clustering within hospitals. RESULTS: Among 6133 children with nonperforated appendicitis, 867 (14.1%) had GSE findings identified from operative report review (hospital range, 4.2%-30.2%; P

IMPORTANCE: The use of neoadjuvant therapy (NAT) in resectable pancreatic ductal adenocarcinoma (PDAC) remains controversial. A favorable pathologic response (complete or marked tumor regression) to NAT is associated with better outcomes in patients with resected PDAC. The role of NAT for early systemic control compared with immediate surgical resection for PDAC is under investigation. In the era of precision medicine, biomarkers for patient selection and prediction of therapy response are crucial. OBJECTIVE: To evaluate the use of assessment for protein expression on fine-needle aspiration (FNA) biopsy specimens in predicting pathologic response to NAT in treatment-naive patients. DESIGN, SETTING, AND PARTICIPANTS: This was a single-institution prognostic study from a high-volume center for pancreatic cancer. All specimens were obtained between January 1, 2009, and December 31, 2018, with a median (SE) follow-up of 20.2 (1.4) months. Analysis of the data was performed from October 1, 2019, to April 30, 2021. Targeted RNA sequencing of frozen FNA biopsy specimens from a discovery cohort of 23 patients was performed to identify genes with aberrant expression that was associated with patients’ pathologic response to NAT. Immunohistochemical staining was performed on an additional 80 FNA biopsy specimens to assess expression of matrix metalloproteinase 7 (MMP-7) and its association with pathologic response. Receiver operating characteristic curves for prediction of favorable pathologic response were determined. RESULTS: In the discovery cohort (12 [52.1%] male; 3 [13.0%] Black and 20 [86.9%] White), RNA sequencing showed that lower MMP-7 expression was associated with favorable pathologic response (College of American Pathologists system scores of 0 [complete response] and 1 [marked response]). In the validation cohort (40 [50.0%] female; 9 [11.3%] Black and 71 [88.7%] White), patients with negative MMP-7 expression were significantly more likely to have a favorable pathologic response (odds ratio, 21.25; 95% CI, 6.19-72.95; P = .001). Receiver operating characteristic curves for prediction of favorable pathologic response from multivariable Cox proportional hazards regression modeling showed that MMP-7 expression increased the area under the curve from 0.726 to 0.906 (P

IMPORTANCE: Considerably less is known about self-injurious thoughts and behaviors (SITBs) in preadolescence than older age groups, owing partly to the common view that young children are incapable of suicidal thoughts. Yet, preadolescent suicide has increased in recent years and is now the fifth leading cause of death in this age group, leading the National Institute of Mental Health to identify it as a priority for research and intervention. OBJECTIVE: To assess prevalence estimates of preadolescent SITBs, identify correlates of these outcomes, and conduct head-to-head comparisons of preadolescent and adolescent SITBs in terms of associated characteristics. DATA SOURCES: MEDLINE, PsycINFO, and Embase were systematically searched from inception through December 23, 2021, for studies on the prevalence and correlates of preadolescent SITBs. The search was restricted to English language publications and peer-reviewed journals. STUDY SELECTION: Two reviewers independently identified studies providing data on prevalence and correlates of preadolescent SITBs. DATA EXTRACTION AND SYNTHESIS: Two reviewers independently extracted data from each study, and the Joanna Briggs Institute Checklist for Prevalence Studies was used to assess study quality. Pooled prevalence and Cohen d were derived from random-effects meta-analyses. Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline was followed. MAIN OUTCOMES AND MEASURES: Prevalence and correlates of suicidal ideation, suicide attempts, suicide deaths, and nonsuicidal self-injury among preadolescents. RESULTS: Fifty-eight studies with 626 486 590 individuals were included. Lifetime prevalence of suicide in the general population was 0.79 per 1 million children. Prevalence for lifetime suicidal thoughts, suicide attempts, and nonsuicidal self-injury among preadolescents were 15.1%, 2.6%, and 6.2%, respectively, in community samples. These data suggest that approximately 17.0% of preadolescents with suicidal ideation transition to attempting suicide. Across several analyses, male individuals appear more likely to have SITBs in preadolescence than adolescence. Correlate data were modest for SITBs other than suicidal ideation, but among specific disorders, attention-deficit/hyperactivity disorder (suicidal ideation: d = 0.54 [95% CI, 0.34-0.75]) and depression (suicidal ideation: d = 0.90 [95% CI, 0.71-1.09]; suicide attempts: d = 0.47 [95% CI, 0.26-0.68]) emerged as the strongest correlates. Among interpersonal factors, child maltreatment (suicidal ideation: d = 2.62 [95% CI, 1.56-3.67]) and parental support (suicidal ideation: d = −0.34 [95% CI, −0.46 to −0.22]) yielded the largest effect sizes. CONCLUSIONS AND RELEVANCE: In this systematic review anda meta-analysis, although preadolescent suicide deaths were rare, other SITB types occur with concerning frequency. Male individuals were at greater risk for SITBs in preadolescence relative to adolescence. Attention-deficit/hyperactivity disorder, child maltreatment, and parental support were especially relevant to suicidal ideation, as well as depression for suicidal thoughts and behaviors, in this age group. Further study, especially of SITBs other than suicidal ideation, is needed.

IMPORTANCE: The association between physician fatigue and patient outcomes is important to understand but has been difficult to examine given methodological and data limitations. Surgeons frequently perform urgent procedures overnight and perform additional procedures the following day, which could adversely affect outcomes for those daytime operations. OBJECTIVE: To examine the association between an attending surgeon operating overnight and outcomes for operations performed by that surgeon the next day. DESIGN, SETTING, AND PARTICIPANTS: In this cross-sectional study, a retrospective analysis of a large multicenter registry of surgical procedures was done using a within-surgeon analysis to address confounding, with data from 20 high-volume US institutions. This study included 498 234 patients who underwent a surgical procedure during the day (between 7 am and 5 pm) between January 1, 2010, and August 30, 2020. EXPOSURES: Whether the attending surgeon for the current day’s procedures operated between 11 pm and 7 am the previous night. Two exposure measures were examined: whether the surgeon operated at all the previous night and the number of hours spent operating the previous night (including having performed no work at all). MAIN OUTCOMES AND MEASURES: The primary composite outcome was in-hospital death or major complication (sepsis, pneumonia, myocardial infarction, thromboembolic event, or stroke). Secondary outcomes included operation length and individual outcomes of death, major complications, and minor complications (surgical site infection or urinary tract infection). RESULTS: Among 498 234 daytime operations performed by 1131 surgeons, 13 098 (2.6%) involved an attending surgeon who operated the night before. The mean (SD) age of the patients who underwent an operation was 55.3 (16.4) years, and 264 740 (53.1%) were female. After adjusting for operation type, surgeon fixed effects, and observable patient characteristics (ie, age and comorbidities), the adjusted incidence of in-hospital death or major complications was 5.89% (95% CI, 5.41%-6.36%) among daytime operations when the attending surgeon operated the night before compared with 5.87% (95% CI, 5.85%-5.89%) among daytime operations when the same surgeon did not (absolute adjusted difference, 0.02%; 95% CI, −0.47% to 0.51%; P = .93). No significant associations were found between overnight work and secondary outcomes except for operation length. Operating the previous night was associated with a statistically significant decrease in length of daytime operations (adjusted length, 112.7 vs 117.4 minutes; adjusted difference, −4.7 minutes; 95% CI, −8.7 to −0.8, P = .02), although this difference is unlikely to be meaningful. CONCLUSIONS AND RELEVANCE: The findings of this cross-sectional study suggest that operating overnight was not associated with worse outcomes for operations performed by surgeons the subsequent day. These results provide reassurance concerning the practice of having attending surgeons take overnight call and still perform operations the following morning.

Item does not contain fulltext IMPORTANCE: Recent studies suggest that the diabetes drug metformin has a protective effect on open-angle glaucoma (OAG) and age-related macular degeneration (AMD). However, studies have not addressed the critical issue of confounding by indication, and associations have not been evaluated in a large prospective cohort. OBJECTIVE: To determine the association between diabetes medication and the common eye diseases OAG, AMD, and cataract and to evaluate their cumulative lifetime risks in a large cohort study. DESIGN, SETTING, AND PARTICIPANTS: This cohort study included participants from 3 independent cohorts from the prospective, population-based Rotterdam Study between April 23, 1990, and June 25, 2014. Participants were monitored for incident eye diseases (OAG, AMD, cataract) and had baseline measurements of serum glucose. Data on diabetes medication use and data from ophthalmologic examinations were gathered. EXPOSURES: Type 2 diabetes (T2D) and the diabetes medications metformin, insulin, and sulfonylurea derivatives. MAIN OUTCOMES AND MEASURES: Diagnosis and cumulative lifetime risk of OAG, AMD, and cataract. RESULTS: This study included 11 260 participants (mean [SD] age, 65.1 [9.8]; 6610 women [58.7%]). T2D was diagnosed in 2406 participants (28.4%), OAG was diagnosed in 324 of 7394 participants (4.4%), AMD was diagnosed in 1935 of 10 993 participants (17.6%), and cataract was diagnosed in 4203 of 11 260 participants (37.3%). Untreated T2D was associated with a higher risk of OAG (odds ratio [OR], 1.50; 95% CI, 1.06-2.13; P = .02), AMD (OR, 1.35; 95% CI, 1.11-1.64; P = .003), and cataract (OR, 1.63; 95% CI, 1.39-1.92; P

IMPORTANCE: Otitis media with effusion (OME) is one of the most common causes of acquired conductive hearing loss (CHL). Persistent hearing loss is associated with poor childhood speech and language development and other adverse consequence. However, to obtain accurate and reliable hearing thresholds largely requires a high degree of cooperation from the patients. OBJECTIVE: To predict CHL from otoscopic images using deep learning (DL) techniques and a logistic regression model based on tympanic membrane features. DESIGN, SETTING, AND PARTICIPANTS: A retrospective diagnostic/prognostic study was conducted using 2790 otoscopic images obtained from multiple centers between January 2015 and November 2020. Participants were aged between 4 and 89 years. Of 1239 participants, there were 209 ears from children and adolescents (aged 4-18 years [16.87%]), 804 ears from adults (aged 18-60 years [64.89%]), and 226 ears from older people (aged >60 years, [18.24%]). Overall, 679 ears (54.8%) were from men. The 2790 otoscopic images were randomly assigned into a training set (2232 [80%]), and validation set (558 [20%]). The DL model was developed to predict an average air-bone gap greater than 10 dB. A logistic regression model was also developed based on otoscopic features. MAIN OUTCOMES AND MEASURES: The performance of the DL model in predicting CHL was measured using the area under the receiver operating curve (AUC), accuracy, and F1 score (a measure of the quality of a classifier, which is the harmonic mean of precision and recall; a higher F1 score means better performance). In addition, these evaluation parameters were compared to results obtained from the logistic regression model and predictions made by three otologists. RESULTS: The performance of the DL model in predicting CHL showed the AUC of 0.74, accuracy of 81%, and F1 score of 0.89. This was better than the results from the logistic regression model (ie, AUC of 0.60, accuracy of 76%, and F1 score of 0.82), and much improved on the performance of the 3 otologists; accuracy of 16%, 30%, 39%, and F1 scores of 0.09, 0.18, and 0.25, respectively. Furthermore, the DL model took 2.5 seconds to predict from 205 otoscopic images, whereas the 3 otologists spent 633 seconds, 645 seconds, and 692 seconds, respectively. CONCLUSIONS AND RELEVANCE: The model in this diagnostic/prognostic study provided greater accuracy in prediction of CHL in ears with OME than those obtained from the logistic regression model and otologists. This indicates great potential for the use of artificial intelligence tools to facilitate CHL evaluation when CHL is unable to be measured.

IMPORTANCE: Adjuvant denosumab might improve disease-free survival in hormone receptor (HR)–positive primary breast cancer (BC). The optimal neoadjuvant nab-paclitaxel schedule in terms of efficacy and safety is unclear. OBJECTIVE: To determine whether adding denosumab to anthracycline/taxane-containing neoadjuvant chemotherapy (NACT) increases the pathological complete response (pCR) rate and which nab-paclitaxel schedule is more effective in the NACT setting. DESIGN, SETTING, AND PARTICIPANTS: The GeparX was a multicenter, prospective, open-label, phase 2b, 2 × 2 randomized clinical trial conducted by GBG and AGO-B at 38 German sites between February 2017 and March 2019. The analysis data set was locked September 4, 2020; analysis was completed November 13, 2020. Patients had unilateral or bilateral primary BC, stage cT2-cT4a-d or cT1c, with either clinically node-positive or pathologically node-positive or HR-negative disease, or Ki-67 proliferation index greater than 20%, or ERBB2 (formerly HER2)–positive BC. INTERVENTIONS: Patients were randomized to receive or not receive denosumab, 120 mg subcutaneously every 4 weeks for 6 cycles, and either nab-paclitaxel, 125 mg/m(2) weekly for 12 weeks or days 1 and 8 every 3 weeks for 4 cycles (8 doses), followed by 4 cycles of epirubicin/cyclophosphamide, 90/600 mg/m(2) (every 2 weeks or every 3 weeks). Carboplatin was given in triple-negative BC (TNBC), and trastuzumab biosimilar ABP980 plus pertuzumab was given in ERBB2-positive BC (ERBB2-positive substudy). MAIN OUTCOMES AND MEASURES: The primary outcome was pCR rates between arms for each randomization. RESULTS: A total of 780 female (n = 779) and male (n = 1) patients (median [range] age, 49.0 [22-80] years) were randomized to the 4 treatment groups. The pCR (ypT0 ypN0) rate was 41.0% (90% CI, 37%-45%) with denosumab vs 42.8% (90% CI, 39%-47%) (P = .58) without denosumab, irrespective of BC subtype. Nab-paclitaxel weekly resulted in a significantly (significance level of α = .10) higher pCR rate of 44.9% (90% CI, 41%-49%) vs 39.0% (90% CI, 35%-43%) (P = .06) with nab-paclitaxel days 1 and 8 every 3 weeks. The pCR rates for nab-paclitaxel schedules in subgroups were only significantly different for TNBC (60.4% vs 50.0%; P = .06). Grade 3 to 4 toxic effects did not differ with or without denosumab. Nonhematologic toxic effects of grade 3 to 4 were higher with nab-paclitaxel weekly (33.7% vs 24.1%; P = .004). CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, denosumab added to anthracycline/taxane-based NACT did not improve pCR rates. Nab-paclitaxel at a dosage of 125 mg/m(2) weekly significantly increased the pCR rate compared with the days 1 and 8, every-3-weeks schedule overall and in TNBC, but generated higher toxicity. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02682693

Key Points Question Are alcohol-induced loss of consciousness and heavy weekly alcohol consumption associated with increased risk of future dementia? Findings In this multicohort study of 131 415 adults, a 1.2-fold excess risk of dementia was associated with heavy vs moderate alcohol consumption. Those who reported having lost consciousness due to alcohol consumption, regardless of their overall weekly consumption, had a 2-fold increased risk of dementia compared with people who had not lost consciousness and were moderate drinkers. Meaning The findings of this study suggest that alcohol-induced loss of consciousness is a long-term risk factor for dementia among both heavy and moderate drinkers., Importance Evidence on alcohol consumption as a risk factor for dementia usually relates to overall consumption. The role of alcohol-induced loss of consciousness is uncertain. Objective To examine the risk of future dementia associated with overall alcohol consumption and alcohol-induced loss of consciousness in a population of current drinkers. Design, Setting, and Participants Seven cohort studies from the UK, France, Sweden, and Finland (IPD-Work consortium) including 131 415 participants were examined. At baseline (1986-2012), participants were aged 18 to 77 years, reported alcohol consumption, and were free of diagnosed dementia. Dementia was examined during a mean follow-up of 14.4 years (range, 12.3-30.1). Data analysis was conducted from November 17, 2019, to May 23, 2020. Exposures Self-reported overall consumption and loss of consciousness due to alcohol consumption were assessed at baseline. Two thresholds were used to define heavy overall consumption: greater than 14 units (U) (UK definition) and greater than 21 U (US definition) per week. Main Outcomes and Measures Dementia and alcohol-related disorders to 2016 were ascertained from linked electronic health records. Results Of the 131 415 participants (mean [SD] age, 43.0 [10.4] years; 80 344 [61.1%] women), 1081 individuals (0.8%) developed dementia. After adjustment for potential confounders, the hazard ratio (HR) was 1.16 (95% CI, 0.98-1.37) for consuming greater than 14 vs 1 to 14 U of alcohol per week and 1.22 (95% CI, 1.01-1.48) for greater than 21 vs 1 to 21 U/wk. Of the 96 591 participants with data on loss of consciousness, 10 004 individuals (10.4%) reported having lost consciousness due to alcohol consumption in the past 12 months. The association between loss of consciousness and dementia was observed in men (HR, 2.86; 95% CI, 1.77-4.63) and women (HR, 2.09; 95% CI, 1.34-3.25) during the first 10 years of follow-up (HR, 2.72; 95% CI, 1.78-4.15), after excluding the first 10 years of follow-up (HR, 1.86; 95% CI, 1.16-2.99), and for early-onset (, This cohort study examines the association of overall consumption of alcohol and resultant loss of consciousness with risk for dementia.

IMPORTANCE: Psychiatric care following somatic treatment for deliberate self-harm (DSH) is pivotal in patients’ lives both in the short and long term, but evidence to guide such care is limited. OBJECTIVE: To examine follow-up psychiatric care for patients treated for DSH (ie, intentional self-injury or self-poisoning, irrespective of motivation) at hospital emergency departments and to assess the association of psychiatric referral and treatment attendance with risk of subsequent mortality in these patients. DESIGN, SETTING, AND PARTICIPANTS: Retrospective data from several Norwegian registries were interlinked to follow up a national cohort of all patients with hospital-treated DSH for up to 11 years from 2008 through 2018. Data were analyzed from March to October 2021. EXPOSURES: Socioeconomic characteristics, psychiatric history, and clinical features of DSH. MAIN OUTCOMES AND MEASURES: Referral to psychiatric services, attendance in psychiatric treatment, and prospective mortality were the 3-stage outcomes during follow-up. Logistic regression with odds ratios and cause-specific survival analysis with hazard ratios were used to examine associations between exposures and outcomes. RESULTS: The study identified 43 153 patients (24 286 [56.3%] female; median [IQR] age at index DSH, 39.0 [23.0-56.0] years) involving 69 569 DSH episodes. Of these patients, 6762 (15.7%) were referred to psychiatric services after somatic treatment for DSH, and 22 008 patients (51.0%) attended psychiatric treatment within 3 months of discharge following somatic treatment for DSH. Prior psychiatric history and psychiatric disorders comorbid with DSH were associated with both referral to and attendance in psychiatric care. During follow-up, 7041 patients died by suicide (n = 911) or other causes (n = 6130). While suicide risk was associated with male sex, age 35 to 64 years, and particularly prior and coexisting psychopathologies, other-cause mortality was associated with age 65 years and older and socioeconomic disadvantage. Patients with psychiatric referrals generally had an increased risk of suicide, but the risk was particularly high among patients who received a referral but did not subsequently attend psychiatric treatment (adjusted hazard ratio, 3.07; 95% CI, 2.28-4.12). The observed association was more pronounced during the first years of follow-up and in patients aged 10 to 34 years or 35 to 64 years and those with a clear intent of self-harm. CONCLUSIONS AND RELEVANCE: This national cohort study found an association between psychiatric care attendance following treatment for DSH and prospective mortality, highlighting the importance of patient engagement in psychiatric treatment.

IMPORTANCE: Pediatric sepsis definitions have evolved, and some have proposed using the measure used in adults to quantify organ dysfunction, a Sequential Organ Failure Assessment (SOFA) score of 2 or more in the setting of suspected infection. A pediatric adaptation of SOFA (pSOFA) showed excellent discrimination for mortality in critically ill children but has not been evaluated in an emergency department (ED) population. OBJECTIVE: To delineate test characteristics of the pSOFA score for predicting in-hospital mortality among (1) all patients and (2) patients with suspected infection treated in pediatric EDs. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study took place from January 1, 2012, to January 31, 2020 in 9 US children’s hospitals included in the Pediatric Emergency Care Applied Research Network (PECARN) Registry. The data was analyzed from February 1, 2020, to April 18, 2022. All ED visits for patients younger than 18 years were included. EXPOSURES: ED pSOFA score was assigned by summing maximum pSOFA organ dysfunction components during ED stay (each 0-4 points). In the subset with suspected infection, visit meeting criteria for sepsis (suspected infection with a pSOFA score of 2 or more) and septic shock (suspected infection with vasoactive infusion and serum lactate level >18.0 mg/dL) were identified. MAIN OUTCOMES AND MEASURES: Test characteristics of pSOFA scores of 2 or more during the ED stay for hospital mortality. RESULTS: A total of 3 999 528 (female, 47.3%) ED visits were included. pSOFA scores ranged from 0 to 16, with 126 250 visits (3.2%) having a pSOFA score of 2 or more. pSOFA scores of 2 or more had sensitivity of 0.65 (95% CI, 0.62-0.67) and specificity of 0.97 (95% CI, 0.97-0.97), with negative predictive value of 1.0 (95% CI, 1.00-1.00) in predicting hospital mortality. Of 642 868 patients with suspected infection (16.1%), 42 992 (6.7%) met criteria for sepsis, and 374 (0.1%) met criteria for septic shock. Hospital mortality rates for suspected infection (599 502), sepsis (42 992), and septic shock (374) were 0.0%, 0.9%, and 8.0%, respectively. The pSOFA score had similar discrimination for hospital mortality in all ED visits (area under receiver operating characteristic curve, 0.81; 95% CI, 0.79-0.82) and the subset with suspected infection (area under receiver operating characteristic curve, 0.82; 95% CI, 0.80-0.84). CONCLUSIONS AND RELEVANCE: In a large, multicenter study of pediatric ED visits, a pSOFA score of 2 or more was uncommon and associated with increased hospital mortality yet had poor sensitivity as a screening tool for hospital mortality. Conversely, children with a pSOFA score of 2 or less were at very low risk of death, with high specificity and negative predictive value. Among patients with suspected infection, patients with pSOFA-defined septic shock demonstrated the highest mortality.

IMPORTANCE: Previous estimates suggested that 1 in 3 cases of Alzheimer disease and related dementia (ADRDs) in the US are associated with modifiable risk factors, the most prominent being physical inactivity, depression, and smoking. However, these estimates do not account for changes in risk factor prevalence over the past decade and do not consider potential differences by sex or race and ethnicity. OBJECTIVE: To update estimates of the proportion of ADRDs in the US that are associated with modifiable risk factors and to assess for differences by sex and race and ethnicity. DESIGN, SETTING, AND PARTICIPANTS: For this cross-sectional study, risk factor prevalence and communality were obtained from the nationally representative US Behavioral Risk Factor Surveillance Survey data from January 2018 to December 2018, and relative risks for each risk factor were extracted from meta-analyses. Data were analyzed from December 2020 to August 2021. Respondents included 378 615 noninstitutionalized adults older than 18 years. The number before exclusion was 402 410. Approximately 23 795 (~6%) had missing values on at least 1 of the variables of interest. EXPOSURES: Physical inactivity, current smoking, depression, low education, diabetes, midlife obesity, midlife hypertension, and hearing loss. MAIN OUTCOMES AND MEASURES: Individual and combined population-attributable risks (PARs) associated with ADRDs, accounting for nonindependence between risk factors. RESULTS: Among 378 615 individuals, 171 161 (weighted 48.7%) were male, and 134 693 (weighted 21.1%) were 65 years and older. Race and ethnicity data were self-reported and defined by the US Behavioral Risk Factor Surveillance System Data; 6671 participants (weighted 0.9%) were American Indian and Alaska Native, 8043 (weighted 5.1%) were Asian, 29 956 (weighted 11.7%) were Black, 28 042 (weighted 16.0%) were Hispanic (any race), and 294 394 (weighted 64.3%) were White. Approximately 1 in 3 of ADRD cases (36.9%) in the US were associated with 8 modifiable risk factors, the most prominent of which were midlife obesity (17.7%; 95% CI, 17.5-18.0), physical inactivity (11.8%; 95% CI, 11.7-11.9), and low educational attainment (11.7%; 95% CI, 11.5-12.0). Combined PARs were higher in men (35.9%) than women (30.1%) and differed by race and ethnicity: American Indian and Alaska Native individuals, 39%; Asian individuals, 16%; Black individuals, 40%; Hispanic individuals (any race), 34%; and White individuals, 29%. The most prominent modifiable risk factors regardless of sex were midlife obesity for American Indian and Alaska Native individuals, Black individuals, and White individuals; low education for Hispanic individuals; and physical inactivity for Asian individuals. CONCLUSIONS AND RELEVANCE: The findings suggest that risk factors associated with ADRDs have changed over the past decade and differ based on sex and race and ethnicity. Alzheimer risk reduction strategies may be more effective if they target higher-risk groups and consider current risk factor profiles.