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Objective: To evaluate the use of a questionnaire-based decision-making algorithm to triage children with reported antibiotic allergies to proceed directly to an oral provocation challenge., Design: Cohort study., Setting: Children aged 2-16 years attending paediatric emergency department over 1 year (1 June 2018 till 31 May 2019) or identified from four primary care centres in Sheffield with a recorded antibiotic allergy and no previous testing., Participants: 313 children with 325 recorded antibiotic allergies., Exposure: Clinical decision-making algorithm used to either exclude, directly delabel or stratify children to oral antibiotic challenge in outpatient department or primary care practice., Main Outcome Measures: To assess the safety of using the questionnaire-based algorithm for proceeding to a direct oral provocation challenge.The secondary outcomes were to look for associations and predictive factors in positive challenges and to assess parent/carer acceptability of the service by using Likert Scale., Results: Successful contact was made with 200 children, of which 153 children could be evaluated based on inclusion criteria, engagement and availability of medical records.15 children were directly delabelled based on history and records. 138 children underwent challenges in outpatient and primary care. 6% of challenges were reactive with a mild, delayed reaction. Overall, a delabelling rate of 91% was achieved. There were no clear predictors for a positive challenge., Conclusion: Our questionnaire-based algorithm for stratifying children with antibiotic allergies to proceed directly to an oral outpatient or primary care challenge was found to be safe, feasible and acceptable., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2025. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Introduction: The incidence of anal squamous cell carcinoma (SCC) has been increasing over the last decades. Human papillomavirus (HPV) infection accounts for more than 90% of anal cancers, and HIV co-infection increases the risk of invasive cancer. Men who have sex with men (MSM) with HIV are the highest risk group for developing anal high-grade squamous intraepithelial lesions (aHSILs), which can be found in 45%-50% of these patients and are precursor lesions for invasive cancer. Anal cytology is an effective screening tool, but it lacks sensitivity. High-resolution anoscopy (HRA) is the gold standard procedure for diagnosis and treatment of aHSILs. Recent data suggest that early detection and treatment of aHSILs could prevent the development of invasive cancer in this population., Objective: The objective of the study was to describe the implementation of an office-based screening program for anal cancer prevention in a Comprehensive Cancer Center in Brazil., Methods: Training included participation in the International Anal Neoplasia Society (IANS) HRA course at UCSF Medical Center Mount Zion in San Francisco, CA, USA, by three colorectal cancer surgeons. In-person and hands-on training was provided by a specialist through the AIDS Malignancy Consortium (AMC) of the US NIH. Equipment purchased and provided by the AMC included a colposcope with a digital camera, a hands-free mouse pedal, and a photo documentation imaging software program that allows images to be recorded for documentation and training purposes., Results: The program was implemented in 2022 after a delay of more than two years due to the COVID-19 pandemic. An average of 24 exams are performed monthly. Patients with HIV aged 35 years or older who are undergoing antiretroviral therapy were recruited from the metropolitan area of Rio de Janeiro and referred by primary care providers for screening. Patients diagnosed with aHSILs are scheduled for in-office ablative treatment in the clinic. From March 2022 to June 2024, 324 exams were performed, and aHSIL was found in 38.2% of 220 high-risk patients, including 45 of 129 MSMs (34.9%), 6 of 19 transgender women (31.6%), and 33 of 72 women living with HIV (45.8%). A total of 69 treatments for aHSIL were performed in 62 patients. Patients are followed on a regular basis and long-term results are awaited, including the effectiveness of local therapy for aHSIL., Conclusions: The screening and treatment program was successfully implemented in a tertiary comprehensive Cancer Center. Team training and external proctorship were decisive for the achievement of benchmark standards. The program aims to permanently provide screening for the prevention of anal cancer through the detection and treatment of aHSIL within the National Cancer Institute of Brazil for populations considered at-risk for anal cancer., (© 2024 Wiley Periodicals LLC.)

Context: Patients receiving inpatient palliative care often face physical and psychological uncertainties during transitions out of the hospital. Family caregivers often take on responsibilities to ensure patient safety, quality of care, and extend palliative care principles, but often without support or training, potentially compromising their health and well-being., Objectives: This study tested an eight-week intervention using video visits between palliative care nurse interventionists and caregivers to assess changes in caregiver outcomes and patient quality of life., Methods: This randomized controlled trial, conducted from 2018 to 2022, enrolled adult caregivers in rural or medically underserved areas in Minnesota, Wisconsin, and Iowa. Eligible caregivers included those caring for patients who received inpatient palliative care and transitioned out of the hospital. The intervention group received teaching, guidance, and counseling from a palliative care nurse before and for eight weeks after hospital discharge. The control group received monthly phone calls but no intervention. Caregiver outcomes included changes in depression, burden, and quality of life, and patient quality of life, as reported by the caregiver., Results: Of those consented, 183 completed the intervention, and 184 completed the control arm; 158 participants had complete baseline and eight-week data. In unadjusted analyses, the intervention group and their care recipients showed statistically significant improvements in quality of life compared to the control group. Improvements persisted in adjusted analyses, and depression significantly improved. No differences in caregiver burden were observed., Conclusion: Addressing rural caregivers' needs during transitions in care can enhance caregiver outcomes and improve patient quality of life., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Advanced n-type organic electrochemical transistors (OECTs) play an important part in bioelectronics, facilitating the booming of complementary circuits-based biosensors. This necessitates the utilization of both n-type and p-type organic mixed ionic-electronic conductors (OMIECs) exhibiting a balanced performance. However, the observed subpar electron charge transport ability in most n-type OMIECs presents a significant challenge to the overall functionality of the circuits. In response to this issue, we achieve high-performance OMIECs by leveraging a series of fused electron-deficient monodisperse oligomers with mixed alkyl and glycol chains. Through molecular ordering manipulation by optimizing of their alkyl side chains, we attained a record-breaking OECT electron mobility of 0.62 cm 2 /(V s) and μC* of 63.2 F/(cm V s) for bgTNR-3DT with symmetrical alkyl chains. Notably, the bgTNR-3DT film also exhibits the highest structural ordering, smallest energetic disorder, and the lowest trap density among the series, potentially explaining its ideal charge transport property. Additionally, we demonstrate an organic inverter incorporating bgTNR-3DT OECTs with a gain above 30, showcasing the material's potential for constructing organic circuits. Our findings underscore the indispensable role of alkyl chain optimization in the evolution of prospective high performance OMIECs for constructing advanced organic complementary circuits.

This study aimed to describe the prevalence of high-risk human papillomavirus (HR-HPV) types in the anal canal in a cohort of people living with HIV (PLWHIV) with a history of malignancy., Setting: Referral tertiary care hospital for adult patients with cancer., Methods: We reviewed data of patients from the AIDS Cancer Clinic on antiretroviral therapy in chronic control who were consecutively referred for high-resolution anoscopy (HRA), where they underwent anal evaluation, collection of specimens for anal cytology and anal human papillomavirus (HPV) followed by HRA with directed biopsy if needed., Results: A total of 155 patients were included; 149 (96.1%) were men, all of them men who have sex with men (MSM); the median age was 39 (IQR 32-47) years; 105 (67.7%) with Kaposi sarcoma, 40 (25.8%) with non-Hodgkin lymphoma and 10 (6.4%) with other neoplasms; only 7 (4.5%) had active cancer. The prevalence of HR-HPV infection was 89% (n=138) (95% CI 83-93) with at least one HR-HPV infection, and 62% (96) had coinfection with at least two types; the median HR-HPV types of coinfection were 3 (IQR 2-4). The number of patients infected with HPV 16 was 64 (41.3%, 95% CI 33.8-49.3), HPV 18 was 74 (47.7%, 95% CI 39.9-55.7) and with both 35 (22.6%). Some 59 patients (38%) had high-grade squamous intraepithelial lesions (HSIL) and 49 (31.6%) had low-grade squamous intraepithelial lesions (LSIL). The prevalence of HR-HPV and HSIL among patients aged ≤35 and >35 years was the same., Conclusions: In this cohort of PLWHIV with a history of malignancy we found a high prevalence of HR-HPV 16 and 18 and anal HSIL, even in persons aged ≤35 years. These data highlight the importance of anal cancer screening in PLWHIV and history of malignancy., (© 2024 British HIV Association.)

Background: Anal canal squamous cell carcinoma (SCC) is a relatively uncommon neoplasia, and it is mostly a local-regional cancer, of low metastatic potential (only 15%), resulting in cure in most cases treated with definitive chemoradiation. On the other hand, its incidence has been steadily increasing over the last decades, which makes it an important public health problem. In an effort to provide surgeons and oncologists who treat patients with anal cancer with the most updated information based on the best scientific evidence, the Brazilian Society of Surgical Oncology (SBCO) has produced the present guideline for the management of anal canal SCC, focused on the main topics related to daily clinical practice., Objectives: The SBCO developed the present guidelines to provide recommendations on the main topics related to the management of anal canal squamous cell carcinoma (SCC) based on current scientific evidence., Methods: Between October 2022 and January 2023, 14 experts met to develop the guidelines for the management of anal canal cancer. A total of 30 relevant topics were distributed among the participants. The methodological quality of a final list with 121 sources was evaluated, all the evidence was examined and revised, and the management guidelines were formulated by the 14-expert committee. To reach a final consensus, all the topics were reviewed in a meeting that was attended by all the experts., Results: The proposed guidelines contained 30 topics considered to be highly relevant in the management of anal canal cancer, covering subjects related to screening recommendations, preventive measures, tests required for diagnosing and staging, treatment strategies, response assessment after chemoradiotherapy, surgical technique-related aspects, and follow-up recommendations. In addition, screening and response assessment algorithms, and a checklist were proposed to summarize the important information and offer an updated tool to assist surgeons and oncologists who treat anal canal cancer and in providing the best care to their patients., Conclusion: These guidelines summarize recommendations based on the most current scientific evidence on relevant aspects of anal canal cancer management and are a practical guide to help surgeons and oncologists who treat anal canal cancer make the best therapeutic decisions., (© 2023 Wiley Periodicals LLC.)

Introduction: Prior work has demonstrated utility in using operative time to measure surgeon learning for surgical stabilization of rib fractures (SSRF); however, no studies have used operative time to evaluate the benefit of proctoring in subsequent generations of surgeons. We sought to evaluate whether there is a difference in learning between an original series (TOS) of self-taught surgeons versus the next generation (TNG) of proctored surgeons using cumulative summation (CUSUM) analysis. We hypothesized that TNG would have a comparatively accelerated learning curve., Methods: A single-center retrospective review of all SSRF at a level 1 trauma center was performed. Data were collected from the beginning of an operative chest injury program to include at least 2 y of TNG experience. Operative time was used to determine success and misstep based on prior methods. Learning curves using CUSUM analysis were calculated based on an anticipated success rate of 90% and compared between TOS and TNG groups., Results: Over 7 y, 163 patients with a median Injury Severity Score of 24 underwent SSRF. Median operative time was 165 min with a 0.5 plate-to-fracture ratio. All three TOS surgeons experienced a positive slope indicative of early missteps for their first 15-20 cases. By contrast, all three TNG surgeons demonstrated a series of early successes resulting in negative CUSUM slopes which coincided with a period of proctoring. By the end of TNG series, the composite cumulative score was less than half of the TOS surgeon' scores., Conclusions: Operative time continues to be a useful surrogate for observing SSRF learning curves. In a mature institutional program, proctored novice surgeons appear to have an accelerated learning curve compared to novice surgeons developing a new operative rib program., (Published by Elsevier Inc.)

Background: Normally functioning implantable cardioverter-defibrillators (ICDs) with intact lead systems occasionally fail to deliver therapy for ventricular tachycardia/fibrillation (VT/VF) or deliver it only after clinically significant delays (failure-to-treat)., Objective: We aimed to investigate ICD failure-to-treat VT/VF in a large patient cohort., Methods: We searched the US Food and Drug Administration's online Manufacturer and User Facility Device Experience (MAUDE) database from 2019 to 2023 for manufacturer-verified reports in which normally functioning ICDs failed to treat VT/VF., Results: We identified 854 reports classified as deaths (n = 96 [11.2%]), injuries (n = 585 [68.5%]), or malfunctions (n = 173 [20.3%]) for normally functioning ICDs. The most common causes were misclassification as supraventricular tachycardia (SVT) or atrial fibrillation (AF; 54.8%), undersensing (21.1%), and failure to satisfy programmed rate/duration criteria (8.7%). Most events caused by misclassification as SVT/AF (89.5%) and failure to satisfy rate/duration criteria (70.3%) were VT; most caused by undersensing were either VF (54.4%) or not specified as VT or VF (19.4%). Undersensing caused 65.6% of deaths, although it represented only 21.1% of reports. In the United States, the number of reports increased faster than that of ICD patients., Conclusion: In the largest reported series of failure-to-treat VT/VF by normally functioning ICDs, the most common cause was misclassification of VT as SVT/AF; the most common cause of death was undersensing of VF. Although relatively few patients with normally functioning ICDs experience failure-to-treat VT/VF, the absolute number of verified MAUDE reports suggests that more work is needed to quantify the magnitude of the problem, to identify root causes, and to develop solutions., Competing Interests: Disclosures R.G.H.: advisory board (Cardiac Insight). C.D.S.: honoraria, consultant fees, and patent royalties (Medtronic). The other authors have no conflicts of interest to disclose., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Mechanistic Target of Rapamycin Complex 1 (mTORC1) is a master metabolic regulator that is active in nearly all proliferating eukaryotic cells; however, it is unclear whether mTORC1 activity changes throughout the cell cycle. We find that mTORC1 activity oscillates from lowest in mitosis/G1 to highest in S/G2. The interphase oscillation is mediated through the TSC complex but is independent of major known regulatory inputs, including Akt and Mek/Erk signaling. By contrast, suppression of mTORC1 activity in mitosis does not require the TSC complex. mTORC1 has long been known to promote progression through G1. We find that mTORC1 also promotes progression through S and G2 and is important for satisfying the Chk1/Wee1-dependent G2/M checkpoint to allow entry into mitosis. We also find that low mTORC1 activity in G1 sensitizes cells to autophagy induction in response to partial mTORC1 inhibition or reduced nutrient levels. Together, these findings demonstrate that mTORC1 is differentially regulated throughout the cell cycle, with important phase-specific consequences for proliferating cells., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Mitosis and meiosis have two mechanisms for regulating the accuracy of chromosome segregation: error correction and the spindle assembly checkpoint (SAC). We have investigated the function of several checkpoint proteins in meiosis I of Drosophila oocytes. Evidence of a SAC response by several of these proteins is found upon depolymerization of microtubules by colchicine. However, unattached kinetochores or errors in biorientation of homologous chromosomes does not induce a SAC response. Furthermore, the metaphase I arrest does not depend on SAC genes, suggesting the APC is inhibited even if the SAC is silenced. Two SAC proteins, ROD of the ROD-ZW10-Zwilch (RZZ) complex and MPS1, are also required for the biorientation of homologous chromosomes during meiosis I, suggesting an error correction function. Both proteins aid in preventing or correcting erroneous attachments and depend on SPC105R for localization to the kinetochore. We have defined a region of SPC105R, amino acids 123-473, that is required for ROD localization and biorientation of homologous chromosomes at meiosis I. Surprisingly, ROD removal, or "streaming", is independent of the dynein adaptor Spindly and is not linked to the stabilization of end-on attachments. Instead, meiotic RZZ streaming appears to depend on cell cycle stage and may be regulated independently of kinetochore attachment or biorientation status. We also show that dynein adaptor Spindly is also required for biorientation at meiosis I, and surprisingly, the direction of RZZ streaming.

Background: Obesity is associated with resistance to the metabolic (glucose uptake) and vascular (nitric-oxide mediated dilation and microvascular recruitment) actions of insulin. These vascular effects contribute to insulin sensitivity by increasing tissue delivery of glucose. Studies by us and others suggest that sympathetic activation contributes to insulin resistance to glucose uptake. Here we tested the hypothesis that sympathetic activation contributes to impaired insulin-mediated vasodilation in adult subjects with obesity., Methods and Results: In a randomized crossover study, we used a euglycemic hyperinsulinemic clamp in 12 subjects with obesity to induce forearm arterial vasodilation (forearm blood flow) and microvascular recruitment (contrast-enhanced ultrasonography) during an intrabrachial infusion of saline (control) or phentolamine (sympathetic blockade). Insulin increased forearm blood flow on both study days (from 2.21±1.22 to 4.89±4.21 mL/100 mL per min, P =0.003 and from 2.42±0.89 to 7.19±3.35 mL/100 mL per min, P =0.002 for the intact and blocked day, respectively). Sympathetic blockade with phentolamine resulted in a significantly greater increase in microvascular flow velocity (∆microvascular flow velocity: 0.23±0.65 versus 2.51±3.01 arbitrary intensity units (AIU/s) for saline and phentolamine respectively, P =0.005), microvascular blood volume (∆microvascular blood volume: 1.69±2.45 versus 3.76±2.93 AIU, respectively, P =0.05), and microvascular blood flow (∆microvascular blood flow: 0.28±0.653 versus 2.51±3.01 AIU 2 /s, respectively, P =0.0161). To evaluate if this effect was not due to nonspecific vasodilation, we replicated the study in 6 subjects with obesity comparing intrabrachial infusion of phentolamine to sodium nitroprusside. At doses that produced similar increases in forearm blood flow, insulin-induced changes in microvascular flow velocity were greater during phentolamine than sodium nitroprusside (%microvascular flow velocity=58% versus 29%, respectively, P =0.031)., Conclusions: We conclude that sympathetic activation impairs insulin-mediated microvascular recruitment in adult subjects with obesity.

Background: Anal cancer is caused by human papillomavirus (HPV), particularly HPV-16, and is preceded by anal high-grade squamous intraepithelial lesions (HSILs). The incidence of anal cancer is highest among men who have sex with men (MSM) living with HIV (MSMLWH) and increases with age. However, most previous studies of anal HPV infection and anal HSIL were performed on men under 50 years old, and relatively little is known about HSIL among older MSMLWH or MSM not living with HIV (MSM-Not-LWH)., Setting: We enrolled MSM who were aged 50+ during 2018-2022 in San Francisco, CA., Methods: One hundred twenty-nine MSMLWH and 109 MSM-not-LWH participated. All participants had anal HPV DNA testing (Atila Biosystems) and high-resolution anoscopy with a biopsy of visible lesions., Results: Among MSMLWH, 47% had anal HSIL, 19% had HPV-16, and 51% had other oncogenic anal HPV types (excluding HPV-16). Among MSM-not-LWH, 37% had anal HSIL, 22% had HPV-16, and 34% had other oncogenic anal HPV types. Increasing age was not statistically associated with prevalent HSIL, HPV-16, or other oncogenic HPV infections in MSMLWH or MSM-not-LWH. HPV-16 (odds ratio: 45.1, 95% confidence interval: 15.8-129); other oncogenic HPV types (odds ratio: 5.95, 95% confidence interval: 2.74-12.9) were associated with increased odds of anal HSIL, adjusted for age, income, education, and HIV status., Conclusion: The prevalence of oncogenic anal HPV, anal HPV-16, and anal HSIL remains very high in older MSMLWH and MSM-not-LWH. With recent evidence showing that treating anal HSIL prevents anal cancer, MSM aged 50+ should be considered for anal cancer screening., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

The reductional division of meiosis I requires the separation of chromosome pairs towards opposite poles. We have previously implicated the outer kinetochore protein SPC105R/KNL1 in driving meiosis I chromosome segregation through lateral attachments to microtubules and coorientation of sister centromeres. To identify the domains of SPC105R that are critical for meiotic chromosome segregation, an RNAi-resistant gene expression system was developed. We found that the SPC105R C-terminal domain (aa 1284-1960) is necessary and sufficient for recruiting NDC80 to the kinetochore and building the outer kinetochore. Furthermore, the C-terminal domain recruits BUBR1, which in turn recruits the cohesion protection proteins MEI-S332 and PP2A. Of the remaining 1283 amino acids, we found the first 473 are most important for meiosis. The first 123 amino acids of the N-terminal half of SPC105R contain the conserved SLRK and RISF motifs that are targets of PP1 and Aurora B kinase and are most important for regulating the stability of microtubule attachments and maintaining metaphase I arrest. The region between amino acids 124 and 473 are required for lateral microtubule attachments and biorientation of homologues, which are critical for accurate chromosome segregation in meiosis I.

Saphenous vein graft (SVG) pseudoaneurysms are an infrequent, but life-threatening complication of coronary artery bypass grafting (CABG) surgery if left untreated. Here, we discuss the case of a 77-year-old patient, with a prior history of CABG and transcatheter aortic valve implantation (TAVI), who was incidentally found on computed tomography angiography (CTA) to have a pseudoaneurysm of his SVG with an initial chief complaint of dizziness. Despite increasing reports of SVG pseudoaneurysm, there is no consensus on definitive treatment. Due to the high mortality risk of this patient with surgical intervention, a minimally invasive percutaneous coronary intervention was performed. The patient was effectively treated with two overlapping Viabahn-covered stents, which completely excluded the pseudoaneurysm. Follow-up imaging at two months showed two well-positioned overlapping self-expanding stents with total occlusion of the pseudoaneurysm., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Patel et al.)

Background: Although prior research has estimated the overarching cost burden of heart failure (HF), a thorough analysis examining medical expense differences and trends, specifically among commercially insured patients with heart failure, is still lacking. Thus, the study aims to examine historical trends and differences in medical costs for commercially insured heart failure patients in the United States from 2006 to 2021., Methods: A population-based, cross-sectional analysis of medical and pharmacy claims data (IQVIA PharMetrics ® Plus for Academic) from 2006 to 2021 was conducted. The cohort included adult patients (age > = 18) who were enrolled in commercial insurance plans and had healthcare encounters with a primary diagnosis of HF. The primary outcome measures were the average total annual payment per patient and per cost categories encompassing hospitalization, surgery, emergency department (ED) visits, outpatient care, post-discharge care, and medications. The sub-group measures included systolic, diastolic, and systolic combined with diastolic, age, gender, comorbidity, regions, states, insurance payment, and self-payment., Results: The study included 422,289 commercially insured heart failure (HF) patients in the U.S. evaluated from 2006 to 2021. The average total annual cost per patient decreased overall from $9,636.99 to $8,201.89, with an average annual percentage change (AAPC) of -1.11% (95% CI: -2% to -0.26%). Hospitalization and medication costs decreased with an AAPC of -1.99% (95% CI: -3.25% to -0.8%) and - 3.1% (95% CI: -6.86-0.69%). On the other hand, post-discharge, outpatient, ED visit, and surgery costs increased by an AAPC of 0.84% (95% CI: 0.12-1.49%), 4.31% (95% CI: 1.03-7.63%), 7.21% (95% CI: 6.44-8.12%), and 9.36% (95% CI: 8.61-10.19%)., Conclusions: The study's findings reveal a rising trend in average total annual payments per patient from 2006 to 2015, followed by a subsequent decrease from 2016 to 2021. This decrease was attributed to the decline in average patient costs within the Medicare Cost insurance category after 2016, coinciding with the implementation of the Medicare Access and CHIP Reauthorization Act (MACRA) of 2015. Additionally, expenses related to surgical procedures, emergency department (ED) visits, and outpatient care have shown substantial growth over time. Moreover, significant differences across various variables have been identified., (© 2024. The Author(s).)

Competing Interests: Declaration of interests We declare no competing interests.

Background: Atopic eczema is a common childhood skin problem linked with asthma, food allergy and allergic rhinitis that impairs quality of life., Objectives: To determine whether advising parents to apply daily emollients in the first year can prevent eczema and/or other atopic diseases in high-risk children., Design: A United Kingdom, multicentre, pragmatic, two-arm, parallel-group randomised controlled prevention trial with follow-up to 5 years., Setting: Twelve secondary and four primary care centres., Participants: Healthy infants (at least 37 weeks' gestation) at high risk of developing eczema, screened and consented during the third trimester or post delivery., Interventions: Infants were randomised (1 : 1) within 21 days of birth to apply emollient (Doublebase Gel®; Dermal Laboratories Ltd, Hitchin, UK or Diprobase Cream®) daily to the whole body (excluding scalp) for the first year, plus standard skin-care advice (emollient group) or standard skin-care advice only (control group). Families were not blinded to allocation., Main Outcome Measures: Primary outcome was eczema diagnosis in the last year at age 2 years, as defined by the UK Working Party refinement of the Hanifin and Rajka diagnostic criteria, assessed by research nurses blinded to allocation. Secondary outcomes up to age 2 years included other eczema definitions, time to onset and severity of eczema, allergic rhinitis, wheezing, allergic sensitisation, food allergy, safety (skin infections and slippages) and cost-effectiveness., Results: One thousand three hundred and ninety-four newborns were randomised between November 2014 and November 2016; 693 emollient and 701 control. Adherence in the emollient group was 88% (466/532), 82% (427/519) and 74% (375/506) at 3, 6 and 12 months. At 2 years, eczema was present in 139/598 (23%) in the emollient group and 150/612 (25%) in controls (adjusted relative risk 0.95, 95% confidence interval 0.78 to 1.16; p = 0.61 and adjusted risk difference -1.2%, 95% confidence interval -5.9% to 3.6%). Other eczema definitions supported the primary analysis. Food allergy (milk, egg, peanut) was present in 41/547 (7.5%) in the emollient group versus 29/568 (5.1%) in controls (adjusted relative risk 1.47, 95% confidence interval 0.93 to 2.33). Mean number of skin infections per child in the first year was 0.23 (standard deviation 0.68) in the emollient group versus 0.15 (standard deviation 0.46) in controls; adjusted incidence rate ratio 1.55, 95% confidence interval 1.15 to 2.09. The adjusted incremental cost per percentage decrease in risk of eczema at 2 years was £5337 (£7281 unadjusted). No difference between the groups in eczema or other atopic diseases was observed during follow-up to age 5 years via parental questionnaires., Limitations: Two emollient types were used which could have had different effects. The median time for starting emollients was 11 days after birth. Some contamination occurred in the control group (< 20%). Participating families were unblinded and reported on some outcomes., Conclusions: We found no evidence that daily emollient during the first year of life prevents eczema in high-risk children. Emollient use was associated with a higher risk of skin infections and a possible increase in food allergy. Emollient use is unlikely to be considered cost-effective in this context., Future Research: To pool similar studies in an individual patient data meta-analysis., Trial Registration: This trial is registered as ISRCTN21528841., Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 12/67/12) and is published in full in Health Technology Assessment ; Vol. 28, No. 29. See the NIHR Funding and Awards website for further award information.

Background: Cow's milk allergy (CMA) overdiagnosis in young children appears to be increasing and has not been well characterised. We used a clinical trial population to characterise CMA overdiagnosis and identify individual-level and primary care practice-level risk factors., Methods: We analysed data from 1394 children born in England in 2014-2016 (BEEP trial, ISRCTN21528841). Participants underwent formal CMA diagnosis at ≤2 years. CMA overdiagnosis was defined in three separate ways: parent-reported milk reaction; primary care record of milk hypersensitivity symptoms; and primary care record of low-allergy formula prescription., Results: CMA was formally diagnosed in 19 (1.4%) participants. CMA overdiagnosis was common: 16.1% had parent-reported cow's milk hypersensitivity, 11.3% primary care recorded milk hypersensitivity and 8.7% had low-allergy formula prescription. Symptoms attributed to cow's milk hypersensitivity in participants without CMA were commonly gastrointestinal and reported from a median age of 49 days. Low-allergy formula prescriptions in participants without CMA lasted a median of 10 months (interquartile range 1, 16); the estimated volume consumed was a median of 272 litres (26, 448). Risk factors for CMA overdiagnosis were high practice-based low-allergy formula prescribing in the previous year and maternal report of antibiotic prescription during pregnancy. Exclusive formula feeding from birth was associated with increased low-allergy formula prescription. There was no evidence that practice prescribing of paediatric adrenaline auto-injectors or anti-reflux medications, or maternal features such as anxiety, age, parity and socioeconomic status were associated with CMA overdiagnosis., Conclusion: CMA overdiagnosis is common in early infancy. Risk factors include high primary care practice-based low-allergy formula prescribing and maternal report of antibiotic prescription during pregnancy., (© 2024 The Author(s). Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Spore-forming pathogens have a unique capacity to thrive in diverse environments, and with temporal persistence afforded through their ability to sporulate. Their prevalence in diverse ecosystems requires a One Health approach to identify critical reservoirs and outbreak-associated transmission chains, given their capacity to freely move across soils, waterways, foodstuffs and as commensals or infecting pathogens in human and animal populations. Among anaerobic spore-formers, genomic resources for pathogens including C. botulinum, C. difficile, and C. perfringens enable our capacity to identify common and unique factors that support their persistence in diverse reservoirs and capacity to cause disease. Publicly available genomic resources for spore-forming pathogens at NCBI's Pathogen Detection program aid outbreak investigations and longitudinal monitoring in national and international programs in public health and food safety, as well as for local healthcare systems. These tools also enable research to derive new knowledge regarding disease pathogenesis, and to inform strategies in disease prevention and treatment. As global community resources, the continued sharing of strain genomic data and phenotypes further enhances international resources and means to develop impactful applications. We present examples showing use of these resources in surveillance, including capacity to assess linkages among clinical, environmental, and foodborne reservoirs and to further research investigations into factors promoting their persistence and virulence in different settings., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The International Anal Neoplasia Society (IANS) developed consensus guidelines to inform anal cancer screening use among various high-risk groups. Anal cancer incidence estimates by age among risk groups provided the basis to identify risk thresholds to recommend screening. Guided by risk thresholds, screening initiation at age 35 years was recommended for men who have sex with men (MSM) and transgender women (TW) with HIV. For other people with HIV and MSM and TW not with HIV, screening initiation at age 45 years was recommended. For solid organ transplant recipients, screening initiation beginning from 10 years post-transplant was recommended. For persons with a history of vulvar precancer or cancer, screening initiation was recommended starting within 1 year of diagnosis of vulvar precancer or cancer. Persons aged ≥45 years with a history of cervical/vaginal HSIL or cancer, perianal warts, persistent (>1 year) cervical HPV16, or autoimmune conditions could be considered for screening with shared decision-making, provided there is adequate capacity to perform diagnostic procedures (high-resolution anoscopy [HRA]). Anal cytology, high-risk (hr) human papillomavirus (HPV) testing (including genotyping for HPV16), and hrHPV-cytology co-testing are different strategies currently used for anal cancer screening that show acceptable performance. Thresholds for referral for HRA or follow-up screening tests are delineated. These recommendations from IANS provide the basis to inform management of abnormal screening results, considering currently available screening tools. These guidelines provide a pivotal foundation to help generate consensus among providers and inform the introduction and implementation of risk-targeted screening for anal cancer prevention., (© 2024 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Iron redox flow batteries (IRFBs) are cost-efficient RFBs that have the potential to develop low-cost grid energy storage. Electrode kinetics are pivotal in defining the cycle life and energy efficiency of the battery. In this study, graphite felt (GF) is heat-treated at 400, 500 and 600 °C, and its physicochemical and electrochemical properties are studied using XPS, FESEM, Raman and cyclic voltammetry. Surface morphology and structural changes suggest that GF heat-treated at 500 °C for 6 h exhibits acceptable thermal stability while accessing the benefits of heat treatment. Specific capacitance was calculated for assessing the wettability and electrochemical properties of pristine and treated electrodes. The 600 °C GF has the highest specific capacitance of 34.8 Fg -1 at 100 mV s -1 , but the 500 °C GF showed the best battery performance. The good battery performance of the 500 °C GF is attributed to the presence of oxygen functionalities and the absence of thermal degradation during heat treatment. The battery consisting of 500 °C GF electrodes offered the highest voltage efficiency of ~74%, Coulombic efficiency of ~94%, and energy efficiency of ~70% at 20 mA cm -2 . Energy efficiency increased by 7% in a battery consisting of heat-treated GF in comparison to pristine GF. The battery is capable of operating for 100 charge-discharge cycles with an average energy efficiency of ~ 67% for over 100 cycles.

E-selectin, a cytoadhesive glycoprotein, is expressed on venular endothelial cells and mediates leukocyte localization to inflamed endothelium, the first step in inflammatory cell extravasation into tissue. Constitutive marrow endothelial E-selectin expression also supports bone marrow hematopoiesis via NF-κB-mediated signaling. Correspondingly, E-selectin interaction with E-selectin ligand (sialyl Lewis x ) on acute myeloid leukemia (AML) cells leads to chemotherapy resistance in vivo. Uproleselan (GMI-1271) is a carbohydrate analog of sialyl Lewis x that blocks E-selectin binding. A Phase 2 trial of MEC chemotherapy combined with uproleselan for relapsed/refractory AML showed a median overall survival of 8.8 months and low (2%) rates of severe oral mucositis. Clinical trials seek to confirm activity in AML and mitigation of neutrophil-mediated adverse events (mucositis and diarrhea) after intensive chemotherapy. In this review we summarize E-selectin biology and the rationale for uproleselan in combination with other therapies for hematologic malignancies. We also describe uproleselan pharmacology and ongoing clinical trials., Competing Interests: Declaration of competing interest Geoffrey L. Uy: Advisory Board, Jazz Pharmaceuticals. Daniel J. DeAngelo: Consultancy for Amgen, Autolos, Agios, Blueprint, FortySeven, Gilead, Incyte, Jazz Pharmaceuticals, Novartis, Pfizer, Servier and Takeda. Research funding from Abbvie, GlycoMimetics, Novartis, and Blueprint Pharmaceuticals. Data Safety Monitoring Boards for Daiichi-Sankyo, Fibrogen, Mt. Sinai Myeloproliferative Neoplasms Consortium. Jay N. Lozier: Employment and equity position in GlycoMimetics, Inc. Dennis M Fisher: Consultancy for GlycoMimetics, Inc. Brian A Jonas: Consultant/advisor for AbbVie, BMS, Daiichi Sankyo, Genentech, Gilead, GlycoMimetics, Kymera, Pfizer, Rigel, Servier, and Takeda; protocol steering committee for GlycoMimetics; data monitoring committee for Gilead; travel reimbursement/support from Rigel; institutional research funding from AbbVie, Amgen, Aptose, AROG, BMS, Celgene, Daiichi Sankyo, F. Hoffmann-La Roche, Forma, Forty-Seven, Genentech/Roche, Gilead, GlycoMimetics, Hanmi, Immune-Onc, Incyte, Jazz, Loxo Oncology, Pfizer, Pharmacyclics, Sigma Tau, and Treadwell. John L. Magnani: Employment, consultancy, and equity positions in GlycoMimetics, Inc., and Glycotech, Inc. Pamela S. Becker: Research funding from Glycomimetics, Notable Labs, Pfizer and GPCR. Medical Advisor to Accordant Health Services. Hillard M. Lazarus: Consultancy for Actinium Pharmaceuticals, CSL Behring, GlycoMimetics Inc., Jazz Pharmaceuticals, Partner Therapeutics, Pluristem Therapeutics Inc., and Seattle Genetics. Equity position in Partner Therapeutics. Speakers' bureau for AstraZeneca and Bristol-Myers Squibb. Data Safety Monitoring Board for BioSight and Bristol-Myers Squibb. Ingrid G. Winkler: Patents and royalties on GlycoMimetics, Inc. compounds. The authors thank Drew Provan for excellent graphic design and rendering of figures, Ed Rock and Kerry Woodford for careful review of the manuscript, Scott Brittain for help generating Supplemental Figs. 1 and 2, and Shanti Rodriguez for help in preparation of the manuscript., (Copyright © 2024 GlycoMimetics, Inc. Published by Elsevier Ltd.. All rights reserved.)

Background: Detection and treatment of anal histologic high-grade squamous intraepithelial lesions (hHSIL) prevents anal cancer. However, anal hHSIL incidence among women with human immunodeficiency virus (HIV, WHIV) remains unknown. Performance of anal high-risk human papillomavirus ([hr]HPV), anal cytology (anal-cyt), and both for hHSIL detection longitudinally over 2 years also remains undetermined., Methods: We determined 2-year incidence and cumulative risk estimates (2-y-CR) of anal hHSIL among WHIV using prevalence and incidence (per 100 person-years [py]) observations stratified by baseline hrHPV and/or anal-cyt results., Results: In total, 229 WHIV with complete baseline data were included in the analysis; 114 women without prevalent anal hHSIL were followed with 2 annual evaluations. Median age was 51, 63% were Black, and 23% were Hispanic. Anal hrHPV or abnormal anal-cyt was associated with an increased risk of incident anal hHSIL at 2 years (18.9/100py [95% confidence interval {CI} 11.4-31.3] and 13.4/100py [95% CI 8.0-22.7], respectively) compared with no detection of anal HPV or negative cytology (2.8/100py [95% CI 1.1-7.4] and 4.2 [95% CI, 1.8-10.2]) The presence of anal hrHPV with abnormal cytology was associated with 2-y-CR of anal hHSIL of 65.6% (95% CI 55.4%-75%); negative hrHPV with negative cytology was associated with 2-y-CR of anal hHSIL of 9.2% (95% CI 7.0-16.0)., Conclusions: Detection of anal hrHPV or abnormal anal cytology are comparable predictors for 2-y-CR of anal hHSIL. The absence of anal hrHPV combined with negative cytology was predictive of a lower (but measurable) risk of developing anal hHSIL. These findings provide important data to inform anal cancer screening guidelines for WHIV., Competing Interests: Potential conflicts of interest. J. M. P. reports consulting fees from Vir Biotechnologies, Roche Diagnostics, Abbott, Antiva Biosciences, and Merck and Co.; consulting fees and stock options from Virion Therapeutics; travel support from Merck and Co.; an unpaid role with the International Papillomavirus Society; research support to University of California, San Francisco (UCSF) and gifts from Atila Biosystems. M. H. E. reports research support to institution from J&J, Pfizer, Inovio, PDS Biotechnologies, AstraZeneca, Imvax, Iovance, B-D, and Zentalis; consulting fees (paid to institution) from Papivax, Merck, B-D, PDS Biotechnologies, and World Health Organization; travel support for meetings from Merck and Zentalis; and participation on Merck's Advisory Board for HPV research. T. W. reports institutional grants or contracts from Merck; payment or honoraria for speaking engagements from ViiV Healthcare and Merck; travel support and donation of vaccine for trials from Merck. E. A. S. reports travel support from National Cancer Institute and ASCCP; and board membership with ASCCP. R. A. L. reports a role on their institutions data safety monitoring board. H. M. G. reports a contract with the University of Puerto Rico; honoraria for lectures from Salud Integral de la Montana, American College of Physicians, and Infectious Diseases Society of Puerto Rico; payment for expert testimony (21-CV-001169-FAB; CG2020CV01235 (Caguas, 101); C DP2015-0062, Arecibo); travel support from University of Puerto Rico School of Medicine; and unpaid roles as President of Infectious Diseases Society of Puerto Rico and membership on the Puerto Rico Medical Task Force for COVID-19. A. L. F. reports institutional grants from NIH. G. E. reports honoraria from Northeast/Caribbean AIDS Education and Training Center (NECA AETC) and International AIDS Society – USA (IAS-USA). A. A. D. reports consulting fees from Value Analytics Lab unrelated to the current work. LFB reports an unpaid role as President of International Anal Neoplasia Society. N. J. reports Board membership for International Anal Neoplasia Society. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

High-frequency ultrasound (sonolysis) has been shown as a practical approach for mineralizing PFAS in highly concentrated PFAS waste. However, a fluorine mass balance approach showing complete mineralization for ultrasound treatment has not been elucidated. The impact of ultrasonic power density (W/L) and the presence of co-occurring PFAS on the degradation of individual PFAS are not well understood. In this research, the performance of a 10L sonochemical reactor was assessed for treating synthetic high-concentration PFAS waste with carboxylic and sulfonic perfluoroalkyl surfactants ranging in chain length from four to eight carbons at three different initial concentrations: 6, 55, 183 μM. The mass balance for fluorine was performed using three analytical techniques: triple quadrupole liquid chromatography-mass spectrometry, a fluoride ion selective electrode, and 19F nuclear magnetic resonance. The test results showed near complete mineralization of PFAS in the waste without the formation of intermediate fluorinated by-products. The PFAS mineralization efficiency of the sonolysis treatment at two different power densities for similar initial concentrations were almost identical; the G value at 145 W/L was 9.7*10 -3  g/kWh, whereas the G value at 90 W/L was 9.3*10 -3  g/kWh. The results of this study highlight the implications for the scalability of the sonolytic process to treat high-concentration PFAS waste., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: Rheumatoid purpura is the most common vasculitis in children, and its renal involvement determines the prognosis. To date, no national protocol exists for its management. A protocol was drafted for the French Grand Ouest inter-region in 2011 in order to standardize practices., Objectives: The main objective is to evaluate renal sequelae with a median follow-up of 2 years since the implementation of this protocol. The secondary objectives are to evaluate the different therapeutic and diagnostic management., Method: Inclusion of all children from 2006 to 2018 with nephropathy due to rheumatoid purpura followed in the university hospitals of Rennes, Nantes, Tours, Angers and Brest., Results: 169 patients were included, of whom 104 were treated accroding to protocol and 65 differently. Sequels at 2-year follow-up concerned 27.0% of patients with no significant difference according to whether or not the protocol was followed. A significant decrease of 26.1% in the number of renal biopsies was observed in the group that followed the protocol. The latter was performed with a median delay of less than 30 days., Conclusion: The protocol allowed a standardization of practices without deleterious consequences at 2 years of follow-up and a decrease in renal biopsy punctures. It is in agreement with the recommendations of KDIGO (Kidney Disease Improving Global Outcomes) and European experts. On the other hand, in view of recent studies and the physiopathology, immunosuppressive drugs other than corticosteroids could be introduced earlier in severe forms.

High levels of psychological distress present a major public health issue among LGBTQ+ youth and adults; however, research has repeatedly identified community connectedness as an important protective factor for mental health in LGBTQ+ populations. The aim of the present study was to examine whether age moderates the association of community connectedness on psychological distress in a community sample of LGBTQ+ people. In the present exploratory study, we analyzed secondary cross-sectional data from a sample of LGBTQ+ youth and adults ( n = 292) in a semi-rural community in the Western United States. Participants completed a measure of community connectedness, the K6, and the PHQ-4. The results of two moderation models showed that the negative association of community connectedness on psychological distress was strongest among youth, weaker among young adults, and nonsignificant among older middle-aged adults and older adults. These results provide further evidence for the potential buffering role of community connectedness on psychological distress for LGBTQ+ youth and young adults.

Over the past 30 years there have been numerous large-scale and longitudinal psychiatric research efforts to improve our understanding and treatment of mental health conditions. However, despite the huge effort by the research community and considerable funding, we still lack a causal understanding of most mental health disorders. Consequently, the majority of psychiatric diagnosis and treatment still operates at the level of symptomatic experience, rather than measuring or addressing root causes. This results in a trial-and-error approach that is a poor fit to underlying causality with poor clinical outcomes. Here we discuss how a research framework that originates from exploration of causal factors, rather than symptom groupings, applied to large scale multi-dimensional data can help address some of the current challenges facing mental health research and, in turn, clinical outcomes. Firstly, we describe some of the challenges and complexities underpinning the search for causal drivers of mental health conditions, focusing on current approaches to the assessment and diagnosis of psychiatric disorders, the many-to-many mappings between symptoms and causes, the search for biomarkers of heterogeneous symptom groups, and the multiple, dynamically interacting variables that influence our psychology. Secondly, we put forward a causal-orientated framework in the context of two large-scale datasets arising from the Adolescent Brain Cognitive Development (ABCD) study, the largest long-term study of brain development and child health in the United States, and the Global Mind Project which is the largest database in the world of mental health profiles along with life context information from 1.4 million people across the globe. Finally, we describe how analytical and machine learning approaches such as clustering and causal inference can be used on datasets such as these to help elucidate a more causal understanding of mental health conditions to enable diagnostic approaches and preventative solutions that tackle mental health challenges at their root cause., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Newson, Bala, Giedd, Maxwell and Thiagarajan.)

Steroidogenic Factor-1 (SF-1, NR5A1) is a member of the nuclear receptor superfamily of ligand-regulated transcription factors, consisting of a DNA-binding domain (DBD) connected to a transcriptional regulatory ligand binding domain (LBD) via an unstructured hinge domain. SF-1 is a master regulator of development and adult function along the hypothalamic pituitary adrenal and gonadal axes, with strong pathophysiological association with endometriosis and adrenocortical carcinoma. SF-1 was shown to bind and be regulated by phospholipids, one of the most interesting aspects of SF-1 regulation is the manner in which SF-1 interacts with phospholipids: SF-1 buries the phospholipid acyl chains deep in the hydrophobic core of the SF-1 protein, while the lipid headgroups remain solvent-exposed on the exterior of the SF-1 protein surface. Here, we have reviewed several aspects of SF-1 structure, function and physiology, touching on other transcription factors that help regulate SF-1 target genes, non-canonical functions of SF-1, the DNA-binding properties of SF-1, the use of mass spectrometry to identify lipids that associate with SF-1, how protein phosphorylation regulates SF-1 and the structural biology of the phospholipid-ligand binding domain. Together this review summarizes the form and function of Steroidogenic Factor-1 in physiology and in human disease, with particular emphasis on adrenal cancer., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Human Ferredoxin 1, also referred to as Adrenodoxin (Adx), is the sole electron carrier supporting the function of all seven mitochondrial cytochrome P450 (CYP) enzymes. Adx utilizes conserved negatively charged residues along its α-helix3 to interact with either the proximal surface of CYP enzymes or the binding surface of Adrendodoxin Reductase (AdR). However, in the oxidized state, Adx assumes a monomer-homodimer equilibrium that requires the presence of its unstructured C-terminal tail. Crystallographic structures of full-length human Adx dimers indicate that part of the binding surface necessary for its interactions with CYPs or with AdR is partially occluded by the dimer interface. In this study, protein NMR spectroscopy was used to interrogate the interactions between full-length (2-124) or truncated monomeric (2-108) human Adx and human CYP24A1 (with and without its vitamin-D substrate) as well as interactions with AdR. Here, monomeric Adx induced a similar pattern of peak broadening as that induced by addition of CYP24A1 substrate, consistent with a 1:1 Adx:CYP interaction as the functional complex. Additionally, removal of the C-terminal tail appears to enhance the interaction with AdR, despite removal of some of the AdR contacts in the tail region. This finding was also supported by an NMR competition assay. These findings suggest that the Adx dimers do not undergo meaningful interactions with either CYP or AdR, but may instead be responsible for regulating access to monomeric Adx. These conclusions are discussed in the context of a revised model of the Adx electron shuttle mechanism., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: D. Fernando Estrada reports financial support was provided by National Institute of General Medical Sciences., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Component malpositioning and joint malalignment following unicompartmental knee arthroplasty (UKA) increase the risk for revision. This study investigates whether accelerometer-based navigation (NAV) decreases radiographic outliers with respect to component placement and joint alignment in comparison to conventional instrumentation in UKA., Methods: A radiographic review of UKAs was performed by a single surgeon following adoption of an accelerometry-guided navigation system (OrthAlign, Aliso Viejo, CA). This cohort was then compared to previous patients undergoing UKA with conventional instrumentation. Six-week postoperative radiographs were used to compare femoral coronal and sagittal angles, tibial coronal and sagittal angles, the net coronal angle, tibial component rotation, and medial tibial overhang. Outliers in implant positioning were compared between groups. Patient variables including age, gender, body mass index, American Society of Anesthesiology, and surgical time (incision until the start of closure) were also compared between groups., Results: Eighty-eight UKA's were reviewed (49 conventional instrumentation [CI] patients; 39 NAV patients). Using 2-sample t-tests, no significant differences were found in patient demographics, radiographic parameters, and operative times between the CI and NAV cohorts. Using chi-squared tests, no significant difference was found in the number of radiographic outliers between the CI and NAV cohorts., Conclusions: Our study found that a high-volume UKA surgeon achieved a low rate of radiographic outliers in both NAV and CI cohorts. This data suggests that NAV is no different from conventional instrumentation with respect to implant positioning, overall joint alignment, and operative time when used by a high-volume UKA surgeon., (© 2023 The Authors.)

Objectives: Sexual gender minority (SGM) populations are at risk for human papillomavirus (HPV)-related cancers of the anogenital tract and oropharynx and often face barriers to health care. The goals of this document are to clarify language to provide inclusive care for SGM populations and to provide recommendations for screening and prevention of HPV-related cancers in SGM populations., Materials and Methods: An expert committee convened by the American Society for Colposcopy and Cervical Pathology performed a narrative review of the literature through February 2023. A comprehensive MEDLINE database search was performed for relevant studies. The literature review was divided into categories by organ/topic and by SGM population. Given the variability in available data for several of the categories, recommendations were made based on national guidelines where appropriate or expert opinion where there were less data to support risk-based guidelines., Results: Definitions and terminology relevant to SGM populations are presented. The authors advocate the adoption of sexual orientation gender identity data collection and an organ-based screening approach, which is possible with knowledge of patient anatomy, sexual behaviors, and clinical history. This includes screening for cervical cancer per national recommendations, as well as screening for anal, vulvar, vaginal, penile, and oral cancers based on risk factors and shared clinical decision making. The authors recommend consideration of HPV vaccination in all SGM individuals up to age 45 years old who are at risk., Conclusions: An organ-based screening approach is part of a global strategy to create an inclusive care environment and mitigate barriers to screening and prevention of HPV-mediated cancers in SGM populations., Competing Interests: The authors have declared they have no conflicts of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the ASCCP.)

Background: Recent discoveries have led to the suggestion that enhancing skin barrier from birth might prevent eczema and food allergy., Objective: To determine the cost-effectiveness of daily all-over-body application of emollient during the first year of life for preventing atopic eczema in high-risk children at 2 years from a health service perspective. We also considered a 5-year time horizon as a sensitivity analysis., Methods: A within-trial economic evaluation using data on health resource use and quality of life captured as part of the BEEP trial alongside the trial data. Parents/carers of 1394 infants born to families at high risk of atopic disease were randomised 1:1 to the emollient group, which were advised to apply emollient (Doublebase Gel or Diprobase Cream) to their child at least once daily to the whole body during the first year of life or usual care. Both groups received advice on general skin care. The main economic outcomes were incremental cost-effectiveness ratio (ICER), defined as incremental cost per percentage decrease in risk of eczema in the primary cost-effectiveness analysis. Secondary analysis, undertaken as a cost-utility analysis, reports incremental cost per Quality-Adjusted Life Year (QALY) where child utility was elicited using the proxy CHU-9D at 2 years., Results: At 2 years, the adjusted incremental cost was £87.45 (95% CI -54.31, 229.27) per participant, whilst the adjusted proportion without eczema was 0.0164 (95% CI -0.0329, 0.0656). The ICER was £5337 per percentage decrease in risk of eczema. Adjusted incremental QALYs were very slightly improved in the emollient group, 0.0010 (95% CI -0.0069, 0.0089). At 5 years, adjusted incremental costs were lower for the emollient group, -£106.89 (95% CI -354.66, 140.88) and the proportion without eczema was -0.0329 (95% CI -0.0659, 0.0002). The 5-year ICER was £3201 per percentage decrease in risk of eczema. However, when inpatient costs due to wheezing were excluded, incremental costs were lower and incremental effects greater in the usual care group., Conclusions: In line with effectiveness endpoints, advice given in the BEEP trial to apply daily emollient during infancy for eczema prevention in high-risk children does not appear cost-effective., (© 2023 The Authors. Clinical & Experimental Allergy published by John Wiley & Sons Ltd.)

Here we report the thermal properties of weakly stabilized 0.9, 1.6, and 4.1 nm Au nanoparticles (NPs)/nanoclusters (NCs) attached to indium-tin-oxide- or fluorine-doped-tin-oxide-coated glass electrodes (glass/ITO or glass/FTO). The peak oxidation potential ( E p ) for Au measured by anodic stripping voltammetry (ASV) is indicative of the NP/NC size. Heating leads to a positive shift in E p due to an increase in NP/NC size from thermal ripening. The size transition temperature ( T t ) decreases with decreasing NP/NC size following the order of 4.1 nm (509 °C) > 1.6 nm (132 °C) > 0.9 nm (90 °C/109 °C, two transitions) as compared to the bulk melting point ( T m,b ) for Au of 1064 °C. The T t generally agrees with models describing the size-dependent melting point of Au NPs ( T m,NP ) for 4.1 and 1.6 nm diameter Au NPs but is higher than the models for 0.9 nm Au NCs. Scanning electron microscopy (SEM) and UV-vis size analysis confirm the electrochemical results. The thermal stability of electrode-supported metal NPs/NCs is important for their effective use in catalysis, sensing, nanoelectronics, photovoltaics, and other applications.

Background: Depression and cognitive dysfunction (CD) are not routinely screened for in patients before transcatheter aortic valve replacement (TAVR) and their association with postprocedural outcomes is poorly understood. The objectives of this study are to determine the prevalence of depression and CD in patients with aortic stenosis undergoing TAVR and evaluate their association with mortality and quality of life., Methods: We analyzed a prospective, multicenter TAVR registry that systematically screened patients for preexisting depression and CD with the Patient Health Questionnaire-2 and Mini-Cog, respectively. The associations with mortality were assessed with Cox proportional hazard models and quality of life (Kansas City Cardiomyopathy Questionnaire and EuroQol visual analogue scale) were evaluated using multivariable ordinal regression models., Results: A total of 884 patients were included; median follow-up was 2.88 years (interquartile range=1.2-3.7). At baseline, depression was observed in 19.6% and CD in 31.8%. In separate models, after adjustment, depression (HR, 1.45 [95% CI, 1.13-1.86]; P <0.01) and CD (HR, 1.27 [95% CI, 1.02-1.59]; P =0.04) were each associated with increased mortality. Combining depression and CD into a single model, mortality was greatest among those with both depression and CD (n=62; HR, 2.06 [CI, 1.44-2.96]; P <0.01). After adjustment, depression was associated with 6.6 (0.3-13.6) points lower on the Kansas City Cardiomyopathy Questionnaire 1-year post-TAVR and 6.7 (0.5-12.7) points lower on the EuroQol visual analogue scale. CD was only associated with lower EuroQol visual analogue scale., Conclusions: Depression and CD are common in patients that undergo TAVR and are associated with increased mortality and worse quality of life. Depression may be a modifiable therapeutic target to improve outcomes after TAVR., Competing Interests: Disclosures Dr Fearon receives institutional research support from Edwards, Abbott, Boston Scientific, and Medtronic. Dr Elmariah has received research grants from Edwards Lifesciences, Medtronic, and Abbott and consulting fees from Edwards Lifesciences. Dr Gillam is an advisor to Bracco Diagnostics, Philips and Edwards Lifesciences and directs an imaging core laboratory with contracts with Edwards Lifesciences, Medtronic, and Abbott (no direct compensation). Dr Whisenant is a consultant at Edwards Lifescience and Medtronic. Dr Zajarias is a consultant at Edwards Lifescience. Dr Welt formerly sat on the Medtronic Advisory Board. Dr Coylewright received research funding from Edwards LifeSciences and received consulting fees and serves on an executive steering committee for Medtronic. Dr Piana serves on the data safety monitoring boards for Abbott Medical and Baim Cardiovascular Research Institute and Dr Lindman has received research grants from Edwards Lifesciences and Roche Diagnostics. The other authors report no conflicts.

An intermediate-scale reactor with 10L capacity and two transducers operating at 700 and 950 kHz frequencies was developed to study the scalability of the sonolytic destruction of Per and Polyfluoroalkyl substance (PFAS). The impact of frequency, height of liquid or power density, and transducer position on reactor performance was evaluated with the potassium iodide (KI) oxidation and calorimetric power. The dual frequency mode of operation has a synergistic effect based on the triiodide concentration, and calorimetric power. The triiodide concentration, and calorimetric power were higher in this mode compared to the combination of both frequencies operating individually. The sonochemical efficiency for an intermediate-scale reactor (10L) was similar that obtained from a bench-scale reactor (2L), showing the scalability of the sonolytic technology. The placement of the transducer at the bottom or side wall of the reactor had no significant impact on the sonochemical reactivity. The superposition of the ultrasonic field from the dual transducer mode (side and bottom) did not produce a synergistic effect compared to the single transducer mode (bottom or side). This can be attributed to a disturbance due to the interaction of ultrasonic fields of two frequencies from each transducer. With the encouraging results scaling up is in progress for site implementation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Gunshot wounds account for significant morbidity and mortality in the United States. A rare and potentially fatal complication of a gunshot wound is bullet embolus. Potential complications include distal limb ischemia, coronary infarct, renal infarction, stroke, pulmonary embolization, cardiac valvular injury, thrombophlebitis, and dysrhythmias. Overall, surgical embolectomy and endovascular retrieval are the preferred treatments for bullet emboli. We report one case of venous bullet embolus and one case of arterial bullet embolus, both of which were successfully treated with endovascular retrieval. A thorough physical exam and appropriate imaging are vital to prompt identification and treatment of bullet emboli, as the repercussions of missed injuries can be devastating.

Plastic materials that are less than 5 mm in size are defined as Microplastics (MPs). MPs that are intentionally produced are called primary MPs; however, the most abundant type in the environment consists of the remainder created by the fragmentation of large plastic debris through physical, chemical, and oxidative processes, which are called secondary MPs. Due to their abundance in the environment, poor degradability, toxicological properties, and negative impact on aquatic and terrestrial organisms, including humans, MP pollution has become a global environmental issue. Combatting MP pollution requires both remediation and preventive measures. Although remediation is a must, considering where the technology stands today, it may take long time to make it happen. Prevention, on the other hand, can be and should be done now. However, the effectiveness of preventive measures depends heavily on how well MP escape routes are researched and understood. In this research, we argue that such escape routes (rather, loopholes) exist not only due to mismanaged plastic waste, but also due to cracks in the current waste management systems. One known MP loophole is facilitated by wastewater treatment plants (WWTP). The inability of existing WWTP to retain finer MPs, which are finally released to water bodies together with the treated wastewater, along with the return of captured larger MPs back to landfills and their release into the environment through land applications, are a few examples. Organic waste composting and upcycling of waste incineration ash provide other MP escape pathways. In addition, it is important to understand that the plastics that are in current circulation (active use as well as idling) are responsible for producing MPs through regular wear and tear. Closing these loopholes may be best attempted through policy interventions.

Background Studies in mice and small patient subsets implicate metabolic dysfunction in cardiac remodeling in aortic stenosis, but no large comprehensive studies of human metabolism in aortic stenosis with long-term follow-up and characterization currently exist. Methods and Results Within a multicenter prospective cohort study, we used principal components analysis to summarize 12 echocardiographic measures of left ventricular structure and function pre-transcatheter aortic valve implantation in 519 subjects (derivation). We used least absolute shrinkage and selection operator regression across 221 metabolites to define metabolic signatures for each structural pattern and measured their relation to death and multimorbidity in the original cohort and up to 2 validation cohorts (N=543 for overall validation). In the derivation cohort (519 individuals; median age, 84 years, 45% women, 95% White individuals), we identified 3 axes of left ventricular remodeling, broadly specifying systolic function, diastolic function, and chamber volumes. Metabolite signatures of each axis specified both known and novel pathways in hypertrophy and cardiac dysfunction. Over a median of 3.1 years (205 deaths), a metabolite score for diastolic function was independently associated with post-transcatheter aortic valve implantation death (adjusted hazard ratio per 1 SD increase in score, 1.54 [95% CI, 1.25-1.90]; P <0.001), with similar effects in each validation cohort. This metabolite score of diastolic function was simultaneously associated with measures of multimorbidity, suggesting a metabolic link between cardiac and noncardiac state in aortic stenosis. Conclusions Metabolite profiles of cardiac structure identify individuals at high risk for death following transcatheter aortic valve implantation and concurrent multimorbidity. These results call for efforts to address potentially reversible metabolic biology associated with risk to optimize post-transcatheter aortic valve implantation recovery, rehabilitation, and survival.

Background: In the U.S. there are thousands of ballistic firearm injuries to the extremities and subsequent infections, yearly. There is a lack of consensus regarding the ideal duration of antibiotic treatment to prevent infection of these wounds. Our study investigated infection rate among ballistic extremity fracture patients based on antibiotic prophylaxis duration, operative management, wound severity, and fracture location., Materials and Methods: Retrospective chart review of ballistic extremity fracture patients from a single trauma center from 01/01/2010 to 12/31/2020., Results: Of 1611 fracture cases screened, 193 met our inclusion criteria. Infection rate was significantly higher among patients who received antibiotic prophylaxis for ≥48 hours (19.4%) compared to those who received antibiotics for <48 hours (4.4%) (Chi 2 = 9.89, P = .001). This trend continued among patients who underwent operative management ( P < .001), patients with articular ballistic fractures ( P = .014), patients with non-articular ballistic fractures ( P = .03), and patients with ballistic fractures to the lower extremities ( P = .003). There was no difference in the rate of infection between patients who received ≥48 hours or <48 hours of antibiotic prophylaxis among patients with Gustilo-Anderson grade I, grade II, or grade III injuries, patients with ballistic fracture to the upper extremities, and patients who did not undergo operative management., Discussion: Across all analyses in the present study, there was not a single correlation between antibiotic prophylaxis duration for ≥48 hours and lower rates of subsequent infection. For patients with ballistic fractures to the extremities, prophylactic antibiotic administration for ≥48 hours is unwarranted.

Organic thin-film transistors (OTFTs) with ideal behavior are highly desired, because nonideal devices may overestimate the intrinsic property and yield inferior performance in applications. In reality, most polymer OTFTs reported in the literature do not exhibit ideal characteristics. Supported by a structure-property relationship study of several low-disorder conjugated polymers, here, we present an empirical selection rule for polymer candidates for textbook-like OTFTs with high reliability factors (100% for ideal transistors). The successful candidates should have low energetic disorder along their backbones and form thin films with spatially uniform energetic landscapes. We demonstrate that these requirements are satisfied in the semicrystalline polymer PffBT4T-2DT, which exhibits a reliability factor (~100%) that is exceptionally high for polymer devices, rendering it an ideal candidate for OTFT applications. Our findings broaden the selection of polymer semiconductors with textbook-like OTFT characteristics and would shed light upon the molecular design criteria for next-generation polymer semiconductors.

Methicillin-resistant Staphylococcus aureus (MRSA) infections cause substantive morbidity and mortality in neonates. Using publicly available resources from the National Center of Biotechnology Information (NCBI) and Food and Drug Administration's (FDA) GalaxyTrakr pipeline, we illustrate the dynamics of MRSA colonization and infection in neonates. Over 217 days of prospective surveillance, analyses revealed concurrent MRSA transmission chains affecting 11 of 17 MRSA-colonized patients (65%), with two clusters that demonstrated intervals of more than a month among the appearance of isolates. All MRSA infected neonates ( n  = 3) showed previous colonization with the infecting strain. GalaxyTrakr clustering of the NICU strains, in the context of 21,521 international isolates deposited in NCBI's Pathogen Detection Resource, revealed NICU isolates to be distinct from adult MRSA strains seen locally and internationally. Clustering of the NICU strains within an international context enhanced the resolution of strain clusters and supported the rule-out of suspected, local transmission events within the NICU. Analyses also identified sequence type 1535 isolates, emergent in the Middle East, carrying a unique SCC mec with fusC and aac (6')-Ie/ aph (2'')-1a that provided a multidrug-resistant phenotype. NICU genomic pathogen surveillance, leveraging public repositories and outbreak detection tools, supports rapid identification of cryptic MRSA clusters, and can inform infection prevention interventions for this vulnerable patient population. Results demonstrate that sporadic infections in the NICU may be indicative of hidden chains of asymptomatic transmission best identified with sequenced-based approaches., Competing Interests: The authors declare no conflict of interest.

Background: No approved treatment for peanut allergy exists for children younger than 4 years of age, and the efficacy and safety of epicutaneous immunotherapy with a peanut patch in toddlers with peanut allergy are unknown., Methods: We conducted this phase 3, multicenter, double-blind, randomized, placebo-controlled trial involving children 1 to 3 years of age with peanut allergy confirmed by a double-blind, placebo-controlled food challenge. Patients who had an eliciting dose (the dose necessary to elicit an allergic reaction) of 300 mg or less of peanut protein were assigned in a 2:1 ratio to receive epicutaneous immunotherapy delivered by means of a peanut patch (intervention group) or to receive placebo administered daily for 12 months. The primary end point was a treatment response as measured by the eliciting dose of peanut protein at 12 months. Safety was assessed according to the occurrence of adverse events during the use of the peanut patch or placebo., Results: Of the 362 patients who underwent randomization, 84.8% completed the trial. The primary efficacy end point result was observed in 67.0% of children in the intervention group as compared with 33.5% of those in the placebo group (risk difference, 33.4 percentage points; 95% confidence interval, 22.4 to 44.5; P<0.001). Adverse events that occurred during the use of the intervention or placebo, irrespective of relatedness, were observed in 100% of the patients in the intervention group and 99.2% in the placebo group. Serious adverse events occurred in 8.6% of the patients in the intervention group and 2.5% of those in the placebo group; anaphylaxis occurred in 7.8% and 3.4%, respectively. Serious treatment-related adverse events occurred in 0.4% of patients in the intervention group and none in the placebo group. Treatment-related anaphylaxis occurred in 1.6% in the intervention group and none in the placebo group., Conclusions: In this trial involving children 1 to 3 years of age with peanut allergy, epicutaneous immunotherapy for 12 months was superior to placebo in desensitizing children to peanuts and increasing the peanut dose that triggered allergic symptoms. (Funded by DBV Technologies; EPITOPE ClinicalTrials.gov number, NCT03211247.)., (Copyright © 2023 Massachusetts Medical Society.)

Microplastics (MP) are plastic particles less than 5 mm in size. There are two categories of MP: primary and secondary. Primary or microscopic-sized MP are intentionally produced material. Fragmentation of large plastic debris through physical, chemical, and oxidative processes creates secondary MP, the most abundant type in the environment. Microplastic pollution has become a global environmental problem due to their abundance, poor biodegradability, toxicological properties, and negative impact on aquatic and terrestrial organisms including humans. Plastic debris enters the aquatic environment via direct dumping or uncontrolled land-based sources. While plastic debris slowly degrades into MP, wastewater and stormwater outlets discharge a large amount of MP directly into water bodies. Additionally, stormwater carries MP from sources such as tire wear, artificial turf, fertilizers, and land-applied biosolids. To protect the environment and human health, the entry of MP into the environment must be reduced or eliminated. Source control is one of the best methods available. The existing and growing abundance of MP in the environment requires the use of multiple strategies to combat pollution. These strategies include reducing the usage, public outreach to eliminate littering, reevaluation and use of new wastewater treatment and sludge disposal methods, regulations on macro and MP sources, and a wide implementation of appropriate stormwater management practices such as filtration, bioretention, and wetlands.

Background: The effectiveness of emollients for preventing atopic dermatitis/eczema is controversial. The Barrier Enhancement for Eczema Prevention trial evaluated the effects of daily emollients during the first year of life on atopic dermatitis and atopic conditions to age 5 years., Methods: 1394 term infants with a family history of atopic disease were randomized (1:1) to daily emollient plus standard skin-care advice (693 emollient group) or standard skin-care advice alone (701 controls). Long-term follow-up at ages 3, 4 and 5 years was via parental questionnaires. Main outcomes were parental report of a clinical diagnosis of atopic dermatitis and food allergy., Results: Parents reported more frequent moisturizer application in the emollient group through to 5 years. A clinical diagnosis of atopic dermatitis between 12 and 60 months was reported for 188/608 (31%) in the emollient group and 178/631 (28%) in the control group (adjusted relative risk 1.10, 95% confidence interval 0.93 to 1.30). Although more parents in the emollient group reported food reactions in the previous year at 3 and 4 years, cumulative incidence of doctor-diagnosed food allergy by 5 years was similar between groups (92/609 [15%] emollients and 87/632 [14%] controls, adjusted relative risk 1.11, 95% confidence interval 0.84 to 1.45). Findings were similar for cumulative incidence of asthma and hay fever., Conclusions: Daily emollient application during the first year of life does not prevent atopic dermatitis, food allergy, asthma or hay fever., (© 2022 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Arsenic exposure is correlated with atherosclerosis in epidemiological studies and in animal models. We have previously shown that arsenic exposure enhanced the atherosclerotic plaque size, increased the plaque lipid content, and decreased the plaque smooth muscle cell and collagen contents in the apolipoprotein E knockout (apoE-/-) mice. However, the percentage of plaque-resident macrophages, the primary drivers of atherosclerosis remained unchanged. Therefore, we hypothesized that although arsenic does not change the quantity of macrophages, it alters the macrophage transcriptome towards a proatherogenic state. To test this hypothesis, we used bone marrow-derived macrophages, polarized them to either interferon-γ (IFN-ɣ) stimulated, proinflammatory or interleukin-4 (IL-4) stimulated, alternatively activated macrophages in the presence or absence of 0.67 µM (50 ppb) arsenic and performed RNA sequencing. Arsenic exposure altered the gene expression of the macrophages in a subtype-specific manner. Most differentially expressed genes (88%) were altered specifically in either IFN-ɣ- or IL-4-stimulated macrophages, whereas in the remaining 12% of genes that changed in both cell types, did so in opposite directions. In IL-4-stimulated macrophages, arsenic significantly downregulated the genes involved in cholesterol biosynthesis and the chemokines CCL17/CCL22, whereas in IFN-ɣ-stimulated macrophages, the genes associated with the liver X receptor (LXR) pathway were downregulated by arsenic. Using a bone marrow transplant experiment, we validated that the deletion of LXRα from the hematopoietic compartment rescued arsenic-enhanced atherosclerosis in the apoE-/- mouse model. Together, these data suggest that arsenic modulates subtype-specific transcriptomic changes in macrophages and further emphasize the need to define macrophage heterogeneity in atherosclerotic plaques in order to evaluate the proatherogenic role of arsenic., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)