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In addition to its role as cellular energy currency, adenosine triphosphate (ATP) serves as an extracellular messenger that mediates diverse cell-to-cell communication. Compelling evidence supports that ATP is released from cells through pannexins, a family of membrane proteins that form heptameric large-pore channels. However, the activation mechanisms that trigger ATP release by pannexins remain poorly understood. Here, we discover lysophospholipids as endogenous pannexin activators, using activity-guided fractionation of mouse tissue extracts combined with untargeted metabolomics and electrophysiology. We show that lysophospholipids directly and reversibly activate pannexins in the absence of other proteins. Secretomics experiments reveal that lysophospholipid-activated pannexin 1 leads to the release of not only ATP but also other signaling metabolites, such as 5'-methylthioadenosine, which is important for immunomodulation. We also demonstrate that lysophospholipids activate endogenous pannexin 1 in human monocytes, leading to the release of IL-1β through inflammasome activation. Our results provide a connection between lipid metabolism and purinergic signaling, both of which play major roles in immune responses.

Purpose: Axillary lymph node staging techniques after primary systemic therapy (PST) show low false negative rates, stimulating the omission of axillary lymph node dissection (ALND). Breast cancer patients with extensive nodal disease are underreported in studies on response-guided axillary treatment. In this study, we present the oncologic outcome of breast cancer patients with ≥4 involved axillary lymph nodes treated according to the MARI-protocol., Methods: This prospective single arm registration study included breast cancer patients with extensive nodal disease defined as ≥4 involved axillary lymph nodes on FDG-PET/CT pre-PST between July 2014 and December 2021. After PST, the marked (MARI) lymph node was excised. Patients with a pathologic complete response (pCR) of the MARI node (ypN0) received locoregional radiation treatment (RT). In patients with residual disease of the MARI node (ypN+), ALND was performed followed by RT. Primary endpoint was axillary recurrence rate. Secondary endpoints were invasive disease-free survival (DFS) and overall survival (OS)., Results: In total, 218 patients were registered of which 39 % of patients also had extra-axillary nodal disease. Median (IQR) age was 50 (42-57) years. After PST 47 % of patients (103/218) had ypN0, whereas 53 % of patients (115/218) had ypN+. After a median follow up of 44 (26-62) months, axillary recurrence rate was 2.9 % (n = 3) in the ypN0 group and 3.5 % (n = 4) in the ypN + group. Five-year invasive DFS and OS were respectively 89 % (95 % CI 83 %-96 %) and 95 % (95 % CI 91 %-99 %) in ypN0 patients., Conclusion: Omission of ALND after PST in breast cancer patients with extensive nodal involvement who achieve pCR of the MARI node is associated with excellent five-year oncologic outcome., (Copyright © 2025 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Midbrain dopamine cells encode differences in predictive and expected value to support learning through reward prediction error. Recent findings have questioned whether reward prediction error can fully account for dopamine function and suggest a more complex role for dopamine in encoding detailed features of the reward environment. In this series of studies, we describe a novel role for dopamine in devaluing sensory features of reward. Mesencephalic dopamine cells activated during a mediated devaluation phase were later chemogenetically reactivated. This retrieval of the devalued reward memory elicited a reduction in the hedonic evaluation of sucrose reward. Through optogenetic and chemogenetic manipulations, we confirm dopamine cells are both sufficient and necessary for mediated devaluation, and retrieval of these memories reflected dopamine release in the nucleus accumbens. Consistent with our computational modeling data, our findings indicate a critical role for dopamine in encoding predictive representations of the sensory features of reinforcement. Overall, we elucidate a novel role for dopamine function in mediated devaluation and illuminate a more elaborate framework through which dopamine encodes reinforcement signals., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Background: Prior studies examined the relationship between physician sex and electronic health records (EHR) utilization patterns to assess for provider gender equity, although this has not been explored among pediatric surgical subspecialists. We hypothesized that female surgeons received more inbox messages and had longer message lengths compared to male surgeons., Methods: Surgeons who performed at least five surgical procedures at a free-standing children's hospital between January 2021 and December 2022 were stratified based on sex. EHR utilization data were retrospectively extracted. Message types were restricted to those from patients, health care team members, or results, opting to omit other automated messages from the EHR that were not initiated by a person. Primary outcomes were number of inbox messages received adjusting for the volume of surgical cases performed and message length. Univariate and multivariate analyses were performed to identify outcome predictors., Results: 41 female and 79 male surgeons were included in the final analysis. There was a median of 693 messages received by surgeons over the study period (median of 1.8 messages per surgeon per case). Male surgeons tended to be further out from training but there were no significant differences in terms of surgical case count or characteristics. Surgeon sex was a significant predictor of inbox message count in univariate analysis (incidence rate ratio 1.58 favoring female surgeons, p = 0.03), but not in multivariate analysis, after correcting for case complexity. Surgeon sex was not a significant predictor of message length in either univariate or multivariate analysis., Conclusion: Surgeon sex was not a significant predictor of inbox message count or message length among a cohort of pediatric surgical subspecialists. Ensuring gender equity with respect to EHR activities reaffirms our commitment to avoiding bias., Level of Evidence: III., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to disclose., (Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.)

Abstract: Treatment outcomes for acute promyelocytic leukemia (APL) have improved with the widespread use of targeted therapy with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). Our study aimed to validate these data in a large patient cohort, and to redefine prognostic factors. Leveraging the HARMONY Platform, we analyzed 1438 newly diagnosed patients with APL, diagnosed between 1999 and 2022. Patient data derived from the 2 international multicenter Gruppo Italiano Malattie EMatologiche dell'Adulto (GIMEMA)-APL0406 and National Cancer Research Institute (NCRI)-AML17 trials and 4 European registries: the Haemato Oncology Foundation for Adults in the Netherlands, Belgium and Luxembourg (HOVON), AML Study Group (AMLSG), Swedish AML Registry, and Study Alliance Leukemia (SAL). The study cohort included 721 males and 717 females, with a median age of 50.5 years (range, 16-94 years). Of 1309 patients starting therapy, 562 received ATRA-ATO, and 747 idarubicin-based chemotherapy (AIDA-like CHT). Early death (ED) occurred in 85 of 1438 patients (5.9%) at a median of 9 days after APL diagnosis and was independently associated with increasing age and high Sanz risk score (odds ratio [OR], 1.06; 95% confidence interval [CI], 1.04-1.08; and OR, 4.65; 95% CI, 2.55-8.51, respectively). The median follow-up was 5.5 years (interquartile range, 3.2-7.5 years). ATRA-ATO regimen was associated with the best outcome, reaching 91% 7-year overall survival (vs 81% for AIDA-like CHT; hazard ratio [HR], 2.14; 95% CI, 1.51-3.05), 89% event-free survival (vs 71% for AIDA-like CHT; HR, 2.72; 95% CI, 2.01-3.69), and 3% relapse (vs 13% for AIDA-like CHT; HR, 4.19; 95% CI, 2.38-7.39; P < .001 for all outcomes). The survival advantage of ATRA/ATO was independent of patients' age, Sanz risk score, and treatment scenario. Our study confirms the superiority of ATRA-ATO over ATRA-chemotherapy in patients with APL. Reducing the risk of ED still represents an unmet medical need, in particular in older patients and in high-risk APL., (© 2025 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Many highly competitive academic general surgery residency programs share the mission of training the next generation of academic surgeons. There is a widely held belief that encouraging publications throughout residency will promote sustained research productivity and facilitate a pathway into an academic career. Consequently, the total number of publications is one of the strongest predictors for resident selection among top ranked general surgery programs. However, there is currently a lack of evidence supporting the assumptions that preresidency productivity will be sustained or predictive of an academic career. With an increasingly competitive applicant pool and recent paradigm shifts in the evaluation of applicants, it is becoming increasingly important for program directors to identify meaningful metrics to predict sustained academic success and successful academic surgeons. We discuss current trends in the evaluation of applicants' research, limitations of these methods, potential implications, and alternatives., (Copyright © 2024 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)

BACKGROUNDCurrent clinical sequencing methods cannot effectively detect DNA methylation and allele-specific variation to provide parent-of-origin information from the proband alone. Parent-of-origin effects can lead to differential disease, and the inability to assign parent of origin in de novo cases limits prognostication in the majority of affected individuals with retinoblastoma, a hereditary cancer with suspected parent-of-origin effects.METHODSTo directly assign parent of origin in patients with retinoblastoma, we extracted genomic DNA from blood samples for sequencing using a programmable, targeted, single-molecule, long-read DNA genomic and epigenomic approach. This allowed germline variant calling and simultaneous haplotype-resolved CpG methylation in participants with familial (n = 7) and de novo (n = 9) retinoblastoma.RESULTSTargeted long-read sequencing allowed phasing genomic variation with a differentially methylated region in intron 2 of the retinoblastoma gene to confirm parent of origin in known familial samples. This approach allowed us to directly assign parent of origin in simple and complex de novo cases from the proband alone. The ability to assign parent of origin in all retinoblastoma cases showed that harboring disease-causing variants on the paternally inherited allele, whether arising familially or de novo, was associated with more advanced cancer staging at presentation and significantly greater risk of chemotherapy failure (P = 0.002).CONCLUSIONThis study demonstrates the diagnostic potential of multiomic long-read profiling to unveil the parent-of-origin effect in hereditary cancer. The approach in this work will be instrumental in assigning parent of origin to other genetic diseases using local and distant imprinting signals in the genome.FUNDINGNational Eye Institute, NIH; Gerber Foundation; Research to Prevent Blindness; Angie Karalis Johnson Fund; Dawn's Light Foundation; and Mark J. Daily, MD Research Fund.

Purpose: AML is a genetically heterogeneous disease, particularly in older patients. In patients older than 60 years, survival rates are variable after the most important curative approach, intensive chemotherapy followed by allogeneic hematopoietic cell transplantation (allo-HCT). Thus, there is an urgent need in clinical practice for a prognostic model to identify older patients with AML who benefit from curative treatment., Methods: We studied 1,910 intensively treated patients older than 60 years with AML and high-risk myelodysplastic syndrome (HR-MDS) from two cohorts (NCRI-AML18 and HOVON-SAKK). The median patient age was 67 years. Using a random survival forest, clinical, molecular, and cytogenetic variables were evaluated in an AML development cohort (n = 1,204) for association with overall survival (OS). Relative weights of selected variables determined the prognostic model, which was validated in AML (n = 491) and HR-MDS cohorts (n = 215)., Results: The complete cohort had a high frequency of poor-risk features, including 2022 European LeukemiaNet adverse-risk (57.3%), mutated TP53 (14.4%), and myelodysplasia-related genetic features (65.1%). Nine variables were used to construct four groups with highly distinct 4-year OS in the (1) AML development, (2) AML validation, and (3) HR-MDS test cohorts ([1] favorable: 54% ± 4%, intermediate: 38% ± 2%, poor: 21% ± 2%, very poor: 4% ± 1%; [2] 54% ± 9%, 43% ± 4%, 27% ± 4%, 4% ± 3%; and [3] 54% ± 10%, 33% ± 6%, 14% ± 5%, 0% ± 3%, respectively). This new AML60+ classification improves current prognostic classifications. Importantly, patients within the AML60+ intermediate- and very poor-risk group significantly benefited from allo-HCT, whereas the poor-risk patients showed an indication, albeit nonsignificant, for improved outcome after allo-HCT., Conclusion: The new AML60+ classification provides prognostic information for intensively treated patients 60 years and older with AML and HR-MDS and identifies patients who benefit from intensive chemotherapy and allo-HCT.

The choroid is the thin, vasculature-filled layer of the eye situated between the sclera and the retina, where it serves the metabolic needs of the light-sensing photoreceptors in the retina. Illumination of the interior surface of the back of the eye (fundus) is a critical regulator of subretinal fluid homeostasis, which determines the overall shape of the eye, but it is also important for choroidal perfusion. Noted for having some of the highest blood flow rates in the body, the choroidal vasculature has been reported to lack intrinsic, intravascular pressure-induced (myogenic) autoregulatory mechanisms. Here, we ask how light directly regulates choroid perfusion and ocular fluid homeostasis, testing the hypothesis that light facilitates ocular fluid absorption by directly increasing choroid endothelial permeability and decreasing choroid perfusion. Utilizing ex vivo pressurized whole-choroid and whole-eye preparations from mice expressing cell-specific Ca 2+ indicators, we found that the choroidal vasculature has two intrinsically light-sensitive Ca 2+ -signaling mechanisms: One increases Ca 2+ -dependent production of nitric oxide in choroidal endothelial cells; the other promotes vasoconstriction through Ca 2+ elevation in vascular smooth muscle cells. In addition, we found that choroidal flow, or pressure, modulates endothelial and smooth muscle photosensitivity and trans-retinal absorption of fluid into the choroid. These results collectively suggest that the choroid vasculature exhibits an inverted form of autoregulatory control, where pressure- and light-induced mechanisms work in opposition to regulate blood flow and maintain fluid balance in response to changes in light and dark, aligning with the metabolic needs of photoreceptors., Competing Interests: Competing interests statement:The authors declare no competing interest.

Molecular measurable residual disease (MRD, eg, by real-time quantitative polymerase chain reaction, RT-qPCR), is an integral part of response assessment in acute myeloid leukemia (AML) with established prognostic and evolving therapeutic significance. MRD failure can occur through several pathways (namely MRD persistence at the end of treatment at a high level, MRD progression from a low level or MRD re-emergence during follow up; the latter two constitute MRD relapse as defined by the European Leukemia Net) and is clinically actionable, with survival benefit reported in AML subgroups. Selection of pre-emptive therapy at MRD failure relies upon an integrated clinico-molecular assessment and is subset-specific. In acute promyelocytic leukemia, arsenic trioxide-based regimen for MRD failure following frontline treatment with all-trans-retinoic acid plus chemotherapy represents standard of care, while hypomethylating agents (eg, azacitidine), salvage chemotherapy (eg, FLAG-IDA) and venetoclax-based regimens are effective in NPM1-mutated AML. Specific inhibitors of FLT3 have emerging use in FLT3-mutated AML and are associated with minimal toxicity. Furthermore, immunotherapeutic approaches such as donor lymphocyte infusions and interferon-⍺ are efficacious options in the post-allogeneic-HSCT settings. Enrollment into clinical trials with genomic-guided assignment of pre-emptive therapy at MRD failure should be prioritized. Finally, with the emergence of novel agents (eg, menin inhibitors) and approaches (eg, adoptive cellular and immunological therapy), an exciting future lies ahead where a broad array of highly active pre-emptive therapeutic options will likely be clinically applicable to a wide range of AML subsets., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

According to GNSS/INSAR measurements, the Konya Basin in Central Anatolia is undergoing rapid subsidence within an uplifting orogenic plateau. Further, geophysical studies reveal thickened crust under the basin and a fast seismic wave speed anomaly in the underlying mantle, in addition to a localised depression in calculated residual topography (down to 280 m) over the Konya Basin, based on gravity-topography considerations. Using scaled laboratory (analogue) experiments we show that the active formation of the Konya Basin may be accounted for by the descent of a mantle lithospheric drip causing local circular-shaped surface subsidence. We interpret that the Konya Basin is developing through a secondary drip pulse that is contemporaneous with broad plateau uplift caused by a larger-scale lithospheric drip since the Miocene. The research reveals that basin evolution and plateau uplift may be linked in a multistage process of lithospheric removal during episodic development of orogenic systems., (© 2024. The Author(s).)

Despite advances in sequencing technologies, a molecular diagnosis remains elusive in many patients with Mendelian disease. Current short-read clinical sequencing approaches cannot provide chromosomal phase information or epigenetic information without further sample processing, which is not routinely done and can result in an incomplete molecular diagnosis in patients. The ability to provide phased genetic and epigenetic information from a single sequencing run would improve the diagnostic rate of Mendelian conditions. Here, we describe targeted long-read sequencing of Mendelian disease genes (TaLon-SeqMD) using a real-time adaptive sequencing approach. Optimization of bioinformatic targeting enabled selective enrichment of multiple disease-causing regions of the human genome. Haplotype-resolved variant calling and simultaneous resolution of epigenetic base modification could be achieved in a single sequencing run. The TaLon-SeqMD approach was validated in a cohort of 18 individuals with previous genetic testing targeting 373 inherited retinal disease (IRD) genes, yielding the complete molecular diagnosis in each case. This approach was then applied in 2 IRD cases with inconclusive testing, which uncovered noncoding and structural variants that were difficult to characterize by standard short-read sequencing. Overall, these results demonstrate TaLon-SeqMD as an approach to provide rapid phased-variant calling to provide the molecular basis of Mendelian diseases.

Introduction: Whole blood (WB) resuscitation has reemerged as a resuscitation strategy for injured patients. However, the effect of WB-based resuscitation on outcomes has not been established. The primary objective of this guideline was to develop evidence-based recommendations on whether WB should be considered in civilian trauma patients receiving blood transfusions., Methods: An Eastern Association for the Surgery of Trauma working group performed a systematic review and meta-analysis using the Grading of Recommendations Assessment, Development and Evaluation methodology. One Population, Intervention, Comparison, and Outcomes question was developed to analyze the effect of WB resuscitation in the acute phase on mortality, transfusion requirements, infectious complications, and intensive care unit length of stay. English language studies including adult civilian trauma patients comparing in-hospital WB to component therapy were included. Medline, Embase, Cochrane CENTRAL, CINAHL Plus, and Web of Science were queried. GRADEpro (McMaster University; Evidence Prime, Inc.; Ontario) was used to assess quality of evidence and risk of bias. The study was registered on International Prospective Register of Systematic Reviews (CRD42023451143)., Results: A total of 21 studies were included. Most patients were severely injured and required blood transfusion, massive transfusion protocol activation, and/or a hemorrhage control procedure in the early phase of resuscitation. Mortality was assessed separately at the following intervals: early (i.e., emergency department, 3 hours, or 6 hours), 24 hours, late (i.e., 28 days or 30 days), and in-hospital. On meta-analysis, WB was not associated with decreased mortality. Whole blood was associated with decreased 4-hour red blood cell (mean difference, -1.82; 95% confidence interval [CI], -3.12 to -0.52), 4-hour plasma (mean difference, -1.47; 95% CI, -2.94 to 0), and 24-hour red blood cell transfusions (mean difference, -1.22; 95% CI, -2.24 to -0.19) compared with component therapy. There were no differences in infectious complications or intensive care unit length of stay between groups., Conclusion: We conditionally recommend WB resuscitation in adult civilian trauma patients receiving blood transfusions, recognizing that data are limited for certain populations, including women of childbearing age, and therefore this guideline may not apply to these populations., Level of Evidence: Systematic Review/Meta-Analysis; Level III., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Ballistic embolism (BE) is a rare complication of firearm injuries notoriously associated with a vexing clinical picture in the trauma bay. Unless considered early, the associated confusion can lead to needless delay in the management of the patient with a gunshot wound. Despite this known entity, there is a relative paucity of high-grade evidence regarding complications, management, and follow-up in these patients., Methods: An electronic database literature search was conducted to identify cases of acute intravascular BE in pediatric and adult civilians occurring during index hospitalization, filtered to publications during the past 10 years. Exclusion criteria included non-vascular embolization, injuries occurring in the military setting, and delayed migration defined as occurring after discharge from the index hospitalization., Results: A total of 136 cases were analyzed. Nearly all cases of BE occurred within 48 hours of presentation. Compared with venous emboli, arterial emboli were significantly more likely to be symptomatic (71% vs. 7%, p<0.001), and 43% of patients developed symptoms attributable to BE in the trauma bay. In addition, arterial emboli were significantly less likely to be managed non-invasively (19% vs. 49%, p<0.001). Open retrieval was significantly more likely to be successful compared with endovascular attempts (91% vs. 29%, p<0.001). Patients with arterial emboli were more likely to receive follow-up (52% vs. 39%) and any attempt at retrieval during the hospitalization was significantly associated with outpatient follow-up (p=0.034). All but one patient remained stable or had clinically improved symptoms after discharge., Conclusion: Consideration for BE is reasonable in any patient with new or persistent unexplained signs or symptoms, especially during the first 48 hours after a penetrating firearm injury. Although venous BE can often be safely observed, arterial BE generally necessitates urgent retrieval. Patients who are managed non-invasively may benefit from follow-up in the first year after injury., Competing Interests: None declared., (Copyright © Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Nipple preservation contributes to aesthetic outcome and quality of life in women undergoing Skin-Sparing Mastectomy (SSM) with immediate breast reconstruction for the treatment of breast cancer. Intraoperative Frozen Section (IFS) has been advocated to facilitate conversion from Nipple-Sparing Mastectomy (NSM) to SSM in cases with positive subareolar margins. This study investigated the application of IFS at our comprehensive cancer centre., Methods: In this single-centre retrospective study, for all patients who underwent therapeutic NSM with IFS from 2000 to 2021 pathological reports, patient- and tumour characteristics were retrieved., Results: In total 640 women were included in whom 662 intended NSMs with IFS had been performed. Sensitivity and specificity of frozen section compared with definitive histopathology were 75.2% and 98.5% respectively. In six women with a false positive result, the nipple had been removed. In 16 out of 32 women with a false negative result, the nipple was excised in a second procedure. In total 115 nipples were resected. In 40% of these nipples, no residual disease was detected., Discussion: IFS is a moderately sensitive and highly specific diagnostic tool to detect positive subareolar margins. An alternative approach is to omit frozen section but take intraoperative biopsies of the sub areolar margin, which are postoperatively analysed with definitive formalin-fixed paraffin-embedded histopathology. This allows for shared decision making regarding nipple excision in cases where minimal disease is found in subareolar tissue or cases with an indication for post-mastectomy radiotherapy., 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., (© 2024 Elsevier Ltd, BASO ∼ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Objectives: Food insecurity (FI) remains a major public health problem globally. However, there is limited information about adolescents' experiences. The current study explored FI experiences of pregnant adolescents and adolescent mothers in Cape Coast, Ghana using a Photovoice method. Methods: This study recruited 34 pregnant adolescents and adolescent mothers from communities in Cape Coast, Ghana. Each participated in a training session then was provided prompts to take photos that portrayed food access barriers, facilitators and coping strategies. In a debrief session, each participant selected two pictures they took and explained the image, followed by a group discussion of the selected photos. Debrief sessions were audio recorded and transcribed verbatim to develop themes using a theory-driven approach. Results: Most participants reported several or many experiences with FI (64.7%) in the previous month. Participants discussed money, unwanted pregnancy, and unstable work as barriers to obtaining food and working, selling goods, and family support as facilitators to obtaining food. Coping strategies mentioned include providing services to others, borrowing food and goods, meal stretching, pawning personal items and trading. Conclusion: The FI experience of this population is complex; interventions, including trade training or school retention, should be multifaceted., Competing Interests: The authors declare that they do not have any conflicts of interest., (Copyright © 2024 Posey, Nsiah-Asamoah, Fergusson Russell, Darkwa Entwi and Okronipa.)

Gram-negative bacteria (GNB) are a major cause of neonatal sepsis in low- and middle-income countries (LMICs). Although the World Health Organization (WHO) reports that over 80% of these sepsis deaths could be prevented through improved treatment, the efficacy of the currently recommended first- and second-line treatment regimens for this condition is increasingly affected by high rates of drug resistance. Here we assess three well known antibiotics, fosfomycin, flomoxef and amikacin, in combination as potential antibiotic treatment regimens by investigating the drug resistance and genetic profiles of commonly isolated GNB causing neonatal sepsis in LMICs. The five most prevalent bacterial isolates in the NeoOBS study (NCT03721302) are Klebsiella pneumoniae, Acinetobacter baumannii, E. coli, Serratia marcescens and Enterobacter cloacae complex. Among these isolates, high levels of ESBL and carbapenemase encoding genes are detected along with resistance to ampicillin, gentamicin and cefotaxime, the current WHO recommended empiric regimens. The three new combinations show excellent in vitro activity against ESBL-producing K. pneumoniae and E. coli isolates. Our data should further inform and support the clinical evaluation of these three antibiotic combinations for the treatment of neonatal sepsis in areas with high rates of multidrug-resistant Gram-negative bacteria., (© 2024. The Author(s).)

Despite decades of research, the influence of climate on the export of dissolved organic carbon (DOC) from soil remains poorly constrained, adding uncertainty to global carbon models. The limited temporal range of contemporary monitoring data, ongoing climate reorganisation and confounding anthropogenic activities muddy the waters further. Here, we reconstruct DOC leaching over the last ~14,000 years using alpine environmental archives (two speleothems and one lake sediment core) across 4° of latitude from Te Waipounamu/South Island of Aotearoa New Zealand. We selected broadly comparable palaeoenvironmental archives in mountainous catchments, free of anthropogenically-induced landscape changes prior to ~1200 C.E. We show that warmer temperatures resulted in increased allochthonous DOC export through the Holocene, most notably during the Holocene Climatic Optimum (HCO), which was some 1.5-2.5 °C warmer than the late pre-industrial period-then decreased during the cooler mid-Holocene. We propose that temperature exerted the key control on the observed doubling to tripling of soil DOC export during the HCO, presumably via temperature-mediated changes in vegetative soil C inputs and microbial degradation rates. Future warming may accelerate DOC export from mountainous catchments, with implications for the global carbon cycle and water quality., (© 2024. The Author(s).)

Fibromuscular dysplasia is the most common cause of renovascular hypertension in young adults under 40 years old. It is potentially amenable to renal artery angioplasty, which frequently normalizes blood pressure. However, limited options exist if angioplasty is not technically possible, or restenosis occurs. Here, we describe 2 patients who presented with hypertension secondary to renal artery stenosis. In the first case, a young adult with hypertension secondary to renal artery stenosis (fibromuscular dysplasia), developed restenosis 11 weeks after an initially successful renal artery angioplasty. In the second case, a patient with neurofibromatosis type 1 was diagnosed with hypertension secondary to renal artery stenosis. Angioplasty was not possible due to multiple branch occlusions. Both individuals went on to have successful renal autotransplantations, which ultimately cured their hypertension. In this article, we review the background, indications, and blood pressure outcomes in relation to renal autotransplantation in nonatherosclerotic renal artery stenosis., Competing Interests: During the clinical management of case 1, V. Selvarajah was employed by the Department of Clinical Pharmacology and Therapeutics, Cambridge University Hospitals NHS Foundation Trust, United Kingdom. V. Selvarajah is currently employed by Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom. Informed consent was obtained from both patients for the publication of their case histories and accompanying images in this article. The other authors report no conflicts.

Objective: To determine the effectiveness of active, upper-room, germicidal ultraviolet (GUV) devices in reducing bacterial contamination in patient rooms in air and on surfaces as a supplement to the central heating, ventilation, and air conditioning (HVAC) air handling unit (AHU) with MERV 14 filters and UV-C disinfection., Methods: This study was conducted in an academic medical center, burn intensive care unit (BICU), for 4 months in 2022. Room occupancy was monitored and recorded. In total, 402 preinstallation and postinstallation bacterial air and non-high-touch surface samples were obtained from 10 BICU patient rooms. Airborne particle counts were measured in the rooms, and bacterial air samples were obtained from the patient-room supply air vents and outdoor air, before and after the intervention. After preintervention samples were obtained, an active, upper-room, GUV air disinfection system was deployed in each of the patient rooms in the BICU., Results: The average levels of airborne bacteria of 395 CFU/m 3 before GUV device installation and 37 CFU/m 3 after installation indicated an 89% overall decrease ( P < .0001). Levels of surface-borne bacteria were associated with a 69% decrease ( P < .0001) after GUV device installation. Outdoor levels of airborne bacteria averaged 341 CFU/m 3 in March before installation and 676 CFU/m 3 in June after installation, but this increase was not significant ( P = .517)., Conclusions: Significant reductions in air and surface contamination occurred in all rooms and areas and were not associated with variations in outdoor air concentrations of bacteria. The significant decrease of surface bacteria is an unexpected benefit associated with in-room GUV air disinfection, which can potentially reduce overall bioburden.

Improving outcomes for older patients with acute myeloid leukaemia remains an unmet need. As part of the LI-1 trial, we evaluated lenalidomide (LEN) in combination with low-dose cytosine arabinoside (LDAC) in patients aged >60 years unfit for intensive therapy and compared this to LDAC alone. Two hundred and two patients, randomised 1:1, were evaluable. Overall response rate (CR + CRi) was higher for LDAC + LEN versus LDAC (26% and 13.7% respectively p = 0.031). However, there was no difference in overall survival between the arms (14% and 11.5% at 2 years for LDAC + LEN and LDAC respectively). The addition of LEN was associated with increased toxicity and supportive care requirements., (© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Competing Interests: Competing interests: None declared.

Background: Healthcare-associated infections account for substantial neonatal in-hospital mortality. Chlorhexidine gluconate (CHG) whole body skin application could reduce sepsis by lowering bacterial colonisation density, although safety and optimal application regimen is unclear. Emollients, including sunflower oil, may independently improve skin condition, thereby reducing sepsis. We aimed to inform which concentration and frequency of CHG, with or without emollient, would best balance safety and the surrogate marker of efficacy of reduction in bacterial colonisation, to be taken forward in a future pragmatic trial evaluating clinical outcomes of sepsis and mortality., Methods: In this multicentre, randomised, open-label, factorial pilot trial, neonates in two hospital sites (South Africa, Bangladesh) aged 1-6 days with gestational age ≥ 28 weeks and birthweight 1000-1999 g were randomly assigned in a factorial design stratified by site to three different concentrations of CHG (0.5%, 1%, and 2%), with or without emollient (sunflower oil) applied on working days vs alternate working days. A control arm received neither product. Caregivers were unblinded although laboratory staff were blinded to randomisation Co-primary outcomes were safety (change in neonatal skin condition score incorporating dryness, erythema, and skin breakdown) and efficacy in reducing bacterial colonisation density (change in total skin bacterial log 10  CFU from randomisation to day-3 and day-8). The trial is registered at the ISRCTN registry, ISRCTN 69836999., Findings: Between Apr 12 2021 and Jan 18 2022, 208 infants were randomised and 198 were included in the final analysis. Skin condition scores were low with mean 0.1 (sd = 0.3; N = 208) at baseline, 0.1 (sd = 0.3; N = 199) at day 3 and 0.1 (sd = 0.3; N = 189) at day 8, with no evidence of differences between concentration (1% CHG vs 0.5% estimate = -0.3, 95% CI = (-1.2, 0.6), p = 0.55. 2% CHG vs 0.5% CHG estimate = 0.5 (-0.4, 1.4), p = 0.30), increasing frequency (estimate = -0.4; 95% CI = (-1.1, 0.4), p = 0.33), emollient (estimate = -0.5, (-1.2, 0.3), p = 0.23) or with control (estimate = -0.9, (-2.3, 0.4), p = 0.18). Mean log 10  CFU was 4.9 (sd = 3.0; N = 208) at baseline, 6.3 (sd = 3.1; N = 198) at day 3 and 8.4 (sd = 2.6; N = 183) with no evidence of differences between concentration (1% CHG vs 0.5% estimate = -0.4; 95% CI = (-1.1, 0.23); p = 0.23. 2% CHG vs 0.5% CHG estimate = 0.0 (-0.6, 0.6), p = 0.96), with increasing frequency (estimate = -0.4; 95% CI = (-0.9, 0.2); p = 0.17), with emollient (estimate = 0.4, 95% CI = (-0.2, 0.9); p = 0.18) or with control (estimate = -0.2, 95% CI = (-1.3, 0.9); p = 0.73). By day-8, overall 158/183 (86%) of neonates were colonised with Enterobacterales , and 72/183 (39%) and 69/183 (9%) with Klebsiella spp resistant to third-generation cephalosporin and carbapenems, respectively. There were no CHG-related SAEs, emollient-related SAEs, grade 3 or 4 skin scores or grade 3 or 4 hypothermias., Interpretation: In this pilot trial of CHG with or without sunflower oil, no safety issues were identified, and further trials examining clinical outcomes are warranted. The relatively late start application of emollient, at a mean of 3.8 days of life, may have reduced the impact of the intervention although no subgroup effects were detected. There was no clear evidence in favour of a specific concentration of chlorhexidine, and there was rapid colonisation with Enterobacterales with frequent antimicrobial resistance, regardless of skin application regimen., Funding: The MRC Joint Applied Global Health award, the Global Antibiotic Research and Development Partnership (GARDP), MRC Clinical Trials Unit core funding (UKRI) and St. George's, University of London., Competing Interests: AD reports grants paid to their institution from The European Commission, Gates Foundation, Science for Africa and a NIH K43 Emerging Global Leader Award. AD is a member of the GARD-P Scientific Advisory Committee. ASW reports grants paid to their institution from The Medical Research Council and National Institutes of Health Research. JAB reports grants paid to their institution from EDCTP, Horizon 2020, SNSF, SPHN (SERI), Innosuisse, EDCTP, JPIAMR, Novartis Foundation, and BMGF; consulting fees paid to their institution from Shionogi and GARDP; honoraria for development of educational content paid to their institution from Pfizer, Sandoz, Bayer, and Biomerieux; participating on IDMCs for the Avenir trial, Lakana trial, and Basilea, and the TSC of the CURLY trial; being a Vice President of SwissPedNet; a Working Group leadership role at the Penta Foundation., (© 2024 The Authors.)

Fatty acid desaturation is central to metazoan lipid metabolism and provides building blocks of membrane lipids and precursors of diverse signaling molecules. Nutritional conditions and associated microbiota regulate desaturase expression, but the underlying mechanisms have remained unclear. Here, we show that endogenous and microbiota-dependent small molecule signals promote lipid desaturation via the nuclear receptor NHR-49/PPARα in C. elegans. Untargeted metabolomics of a β-oxidation mutant, acdh-11, in which expression of the stearoyl-CoA desaturase FAT-7/SCD1 is constitutively increased, revealed accumulation of a β-cyclopropyl fatty acid, becyp#1, that potently activates fat-7 expression via NHR-49. Biosynthesis of becyp#1 is strictly dependent on expression of cyclopropane synthase by associated bacteria, e.g., E. coli. Screening for structurally related endogenous metabolites revealed a β-methyl fatty acid, bemeth#1, which mimics the activity of microbiota-dependent becyp#1 but is derived from a methyltransferase, fcmt-1, that is conserved across Nematoda and likely originates from bacterial cyclopropane synthase via ancient horizontal gene transfer. Activation of fat-7 expression by these structurally similar metabolites is controlled by distinct mechanisms, as microbiota-dependent becyp#1 is metabolized by a dedicated β-oxidation pathway, while the endogenous bemeth#1 is metabolized via α-oxidation. Collectively, we demonstrate that evolutionarily related biosynthetic pathways in metazoan host and associated microbiota converge on NHR-49/PPARα to regulate fat desaturation., (© 2024. The Author(s).)

We investigated the effect of estradiol add-back therapy (EAT) on brain activation related to cognitive function and affect in addition to putative changes in gray and white matter volume in testosterone depleted participants with prostate cancer. We conducted a randomized controlled, double-blinded trial in which 40 patients received 0.9 mg of transdermal estradiol per day for 6 months or matched placebo. Anatomical MRI and three functional MRI (fMRI) scans were obtained for the emotion recognition task, verbal memory task, and visuospatial memory task. Activation in corresponding cognitive and affective brain networks was demonstrated for all tasks. Longitudinally, there was no difference in brain activation, reaction time, or accuracy in response to the fMRI tasks between the EAT group and placebo group at 6 months. In addition, there was no detectable change in whole-brain gray or white matter volume or in hippocampal volume between the two groups after 6 months. This study supports earlier findings that EAT does not improve verbal memory or affect and has no immediate effect on hippocampal volume in testosterone depleted patients with prostate cancer.

The PRIME-NP (Professional-Reporter-Interpreter-Manager-Educator/Evaluation-Nurse Practitioner) Model is adapted from the RIME (Reporter-Interpreter-Manager-Educator) model used in medical education to guide medical student and resident education. The Delphi technique was used to validate the PRIME-NP Model. After two rounds of review by a group of experts in NP curriculum, the model was determined to be valid based on expert consensus. Agreement percent increase from the first round to the second round in all categories. Interrater reliability (IRR) was assessed using interclass correlation after instrument validation was completed for each of the five levels of the PRIME-NP model. Overall, the IRR of the instrument was found to be acceptable with some notable exceptions. No variance was noted in professional behaviors at any level. Variance was increased in management and educator/evaluator behaviors in higher/later course levels. The PRIME-NP Model and PRIME-NP OSCE Rubric is a valid and reliable instrument to assess NP student progression in objective structured clinical examinations. This instrument has the potential for adaptation for use in other types of health sciences education and settings., (© 2024. The Author(s).)

Late Pleistocene ice-age climates are routinely characterized as having imposed moisture stress on low- to mid-latitude ecosystems 1-5 . This idea is largely based on fossil pollen evidence for widespread, low-biomass glacial vegetation, interpreted as indicating climatic dryness 6 . However, woody plant growth is inhibited under low atmospheric CO 2  (refs. 7,8 ), so understanding glacial environments requires the development of new palaeoclimate indicators that are independent of vegetation 9 . Here we show that, contrary to expectations, during the past 350 kyr, peaks in southern Australian climatic moisture availability were largely confined to glacial periods, including the Last Glacial Maximum, whereas warm interglacials were relatively dry. By measuring the timing of speleothem growth in the Southern Hemisphere subtropics, which today has a predominantly negative annual moisture balance, we developed a record of climatic moisture availability that is independent of vegetation and extends through multiple glacial-interglacial cycles. Our results demonstrate that a cool-moist response is consistent across the austral subtropics and, in part, may result from reduced evaporation under cool glacial temperatures. Insofar as cold glacial environments in the Southern Hemisphere subtropics have been portrayed as uniformly arid 3,10,11 , our findings suggest that their characterization as evolutionary or physiological obstacles to movement and expansion of animal, plant and, potentially, human populations 10 should be reconsidered., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Collegiate athletes must satisfy the academic obligations common to all undergraduates, but they have the additional structural and social stressors of extensive practice time, competition schedules, and frequent travel away from their home campus. Clearly such stressors can have negative impacts on both their academic and athletic performances as well as on their health. These concerns are made more acute by recent proposals and decisions to reorganize major collegiate athletic conferences. These rearrangements will require more multi-day travel that interferes with the academic work and personal schedules of athletes. Of particular concern is additional east-west travel that results in circadian rhythm disruptions commonly called jet lag that contribute to the loss of amount as well as quality of sleep. Circadian misalignment and sleep deprivation and/or sleep disturbances have profound effects on physical and mental health and performance. We, as concerned scientists and physicians with relevant expertise, developed this white paper to raise awareness of these challenges to the wellbeing of our student-athletes and their co-travelers. We also offer practical steps to mitigate the negative consequences of collegiate travel schedules. We discuss the importance of bedtime protocols, the availability of early afternoon naps, and adherence to scheduled lighting exposure protocols before, during, and after travel, with support from wearables and apps. We call upon departments of athletics to engage with sleep and circadian experts to advise and help design tailored implementation of these mitigating practices that could contribute to the current and long-term health and wellbeing of their students and their staff members., Competing Interests: Conflict of interest statementThe authors have no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Abstract: Molecular failure in NPM1-mutated acute myeloid leukemia (AML) inevitably progresses to frank relapse if untreated. Recently published small case series show that venetoclax combined with low-dose cytarabine or azacitidine can reduce or eliminate measurable residual disease (MRD). Here, we report on an international multicenter cohort of 79 patients treated for molecular failure with venetoclax combinations and report an overall molecular response (≥1-log reduction in MRD) in 66 patients (84%) and MRD negativity in 56 (71%). Eighteen of 79 patients (23%) required hospitalization, and no deaths were reported during treatment. Forty-one patients were bridged to allogeneic transplant with no further therapy, and 25 of 41 were MRD negative assessed by reverse transcription quantitative polymerase chain reaction before transplant. Overall survival (OS) for the whole cohort at 2 years was 67%, event-free survival (EFS) was 45%, and in responding patients, there was no difference in survival in those who received a transplant using time-dependent analysis. Presence of FLT3-ITD mutation was associated with a lower response rate (64 vs 91%; P < .01), worse OS (hazard ratio [HR], 2.50; 95% confidence interval [CI], 1.06-5.86; P = .036), and EFS (HR, 1.87; 95% CI, 1.06-3.28; P = .03). Eighteen of 35 patients who did not undergo transplant became MRD negative and stopped treatment after a median of 10 months, with 2-year molecular relapse free survival of 62% from the end of treatment. Venetoclax-based low intensive chemotherapy is a potentially effective treatment for molecular relapse in NPM1-mutated AML, either as a bridge to transplant or as definitive therapy., (© 2024 by The American Society of Hematology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).)

Background: Desmoid tumors are fibroblastic lesions which often have an unpredictable and variable clinical course. In the context of familial adenomatous polyposis (FAP), these frequently occur intra-abdominally, especially in the small-bowel mesentery resulting in sepsis, fistulation, and invasion of the abdominal wall and retroperitoneum. In selected cases where other modalities have failed, the most radical option is to perform a total enterectomy and intestinal transplantation (ITx). In this study, we present our center's experience of ITx for desmoid in patients with FAP., Methods: We performed a retrospective review of our prospectively collected database between 2007 and 2022. All patients undergoing ITx for FAP-related desmoid were included., Results: Between October 2007 and September 2023, 144 ITx were performed on 130 patients at our center. Of these, 15 patients (9%) were for desmoid associated with FAP (7 modified multivisceral transplants, 6 isolated ITx, and 2 liver-containing grafts). The median follow-up was 57 mo (8-119); 5-y patient survival was 82%, all with functioning grafts without local desmoid recurrence. These patients presented us with several complex surgical issues, such as loss of abdominal domain, retroperitoneal/abdominal wall involvement, ileoanal pouch-related issues, and the need for foregut resection because of adenomatous disease., Conclusions: ITx is a viable treatment in selected patients with FAP and extensive desmoid disease. The decision to refer for ITx can be challenging, particularly the timing and sequence of treatment (simultaneous versus sequential exenteration). Delays can result in additional disease burden, such as secondary liver disease or invasion of adjacent structures., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2024 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)

Skin substitutes including allografts remain a standard therapeutic approach to promote healing of both acute and chronic large wounds. However, none have resulted in the regrowth of lost and damaged tissues and scarless wound healing. Here, we demonstrate skin allograft chimerism and repair through the mobilization of endogenous bone marrow-derived stem and immune cells in rats and swine. We show that pharmacological mobilization of bone marrow stem cells and immune cells into the circulation promotes host repopulation of skin allografts and restoration of the skin's normal architecture without scarring and minimal contracture. When skin allografts from DA rats are transplanted into GFP transgenic Lewis recipients with a combination of AMD3100 and low-dose FK506 (AF) therapy, host-derived GFP-positive cells repopulate and/or regenerate cellular components of skin grafts including epidermis and hair follicles and the grafts become donor-host chimeric skin. Using AF combination therapy, burn wounds with skin allografts were healed by newly regenerated chimeric skin with epidermal appendages and pigmentation and without contracture in swine., (© The Author(s) 2023. Published by Oxford University Press on behalf of the American Burn Association. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Despite recent advances, 40-85% of patients with acute myeloid leukaemia (AML) achieve complete remission after intensive chemotherapy. However, without optimal treatment after remission, the risk of relapse remains high., Summary: A variable number of consolidation cycles consisting of intermediate doses of cytarabine are the most commonly used regimens in low-intermediate-risk AML, while patients at higher risk of relapse should consolidate response by proceeding to HSCT. Different post-consolidation (maintenance therapies) have demonstrated their benefit in prolonging relapse-free survival, and others are still under investigation. Careful consideration should be given to which patients benefit most from each of these interventions, considering that the risk of relapse is dynamic., Key Messages: Patients consolidated with chemotherapy should receive either 2 courses of HDAC or no more than 3-4 cycles of IDAC with dose reduction in patients over 60 years. Patients with mutated FLT3 AML benefit from post-consolidation maintenance with FLT3 inhibitors, and selected patients not fit for adequate consolidation may benefit from CC-468 maintenance. Patients at higher risk of relapse should proceed to allogeneic SCT as soon as possible, opting for a more intensive conditioning in patients younger than 55 years. However, autologous HSCT may still have role in favourable-risk MRD-negative AML. Multiple treatment options targeting MRD are emerging, either as definitive treatment or as a bridge to allogeneic transplantation, and are likely to become increasingly relevant., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

There are currently several validated HPV tests. However, longitudinal data which spans appropriate age ranges, as well as evaluation of potential screening algorithms are necessary for screening programmes choice of test. The objective of our study was to evaluate the performance of HPV mRNA and HPV DNA testing, including partial genotyping, in routine cervical screening. As part of the CERVIVA HPV Primary Screening Study, ThinPrep samples from 10 150 women were tested for HPV mRNA using the Aptima HPV assay and HPV DNA using the Cobas 4800 HPV test. HPV mRNA-positive women were further assessed with the Aptima genotyping assay for HPV 16/18/45. Baseline cytology and prospective follow-up data were collected. The performance of the two tests was examined over 42 months (to date). HPV mRNA demonstrated equivalent sensitivity to HPV DNA testing for detection of CIN2+ (93.2% [92.4-93.9] vs 92.8% [92.0-93.6], respectively) and CIN3+ (94.6% [93.8-95.3] vs 94.6% [93.8-95.3]). HPV mRNA testing had significantly higher specificity compared to HPV DNA for detection of CIN2+ (84.0% [83.5-84.5] vs 80.8% [80.2-81.4], respectively) and CIN3+ (88.44% [88.2-88.6] vs 85.62 [85.4-85.9]). The proportion of CIN2+ and CIN3+, over 3 years (42 months), in HPV-negative women was comparable for both RNA (0.20% and 0.10%) and DNA (0.22% and 0.11%). Genotyping data was comparable across both assay platforms. In the context of HPV primary screening HPV mRNA testing has potential to reduce triage tests and follow-up tests at 12 months compared to DNA testing, with no significant difference in detection of CIN2+ and CIN3+., (© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Two-thirds of small-bowel transplantation (SBT) recipients develop bacteremia, with the majority of infections occurring within 3 months post-transplant. Sepsis-related mortality occurs in 31% of patients and is commonly caused by bacteria of gut origin, which are thought to translocate across the implanted organ. Serial post-transplant surveillance endoscopies provide an opportunity to study whether the composition of the ileal and colonic microbiota can predict the emergence as well as the pathogen of subsequent clinical infections in the SBT patient population. Five participants serially underwent aspiration of ileal and colonic bowel effluents at transplantation and during follow-up endoscopy either until death or for up to 3 months post-SBT. We performed whole-metagenome sequencing (WMS) of 40 bowel effluent samples and compared the results with clinical infection episodes. Microbiome composition was concordant between participants and timepoint-matched ileal and colonic samples. Four out of five (4/5) participants had clinically significant infections thought to be of gut origin. Bacterial translocation from the gut was observed in 3/5 patients with bacterial infectious etiologies. In all three cases, the pathogens had demonstrably colonized the gut between 1-10 days prior to invasive clinical infection. Recipients with better outcomes received donor grafts with higher alpha diversity. There was an increase in the number of antimicrobial resistance genes associated with longer hospital stay for all participants. This metagenomic study provides preliminary evidence to support the pathogen translocation hypothesis of gut-origin sepsis in the SBT cohort. Ileal and colonic microbiome compositions were concordant; therefore, fecal metagenomic analysis could be a useful surveillance tool for impeding infection with specific gut-residing pathogens.

Background: Neonatal sepsis is traditionally classified as early-onset sepsis (EOS) and late-onset sepsis (LOS) disease categories. This paradigm was based on observed epidemiological data from high income settings. However, increasing availability of microbiology results from diverse settings challenges these assumptions, necessitating re-examination of neonatal sepsis classifications., Objectives: To review the literature describing the aetiology of EOS and LOS in hospitalized neonates with stratification of pathogen spectrum by low- (LIC), middle- (MIC) and high-income (HIC) country settings, to critically re-examine the continued appropriateness of the 'EOS vs. LOS' sepsis paradigm in all settings., Sources: PubMed was searched for peer-reviewed English full-text articles published from inception up until 8 August 2022., Content: Studies often report on either EOS or LOS, rather than both. We identified only 49 original articles reporting on pathogen distribution of both EOS and LOS in the same hospital setting. Clear differences in sepsis aetiology were shown between LIC, MIC and HIC settings, with increasing importance of Klebsiella pneumoniae and decreasing importance of Group B Streptococcus in the first 72 hours of life in LIC and MIC., Implications: The concept of 'EOS vs. LOS' may be less useful for predicting the pathogen spectrum of neonatal sepsis in LIC and MIC, but the paradigm has shaped reporting of neonatal sepsis, and our understanding. Future neonatal sepsis reporting should utilize strengthening the reporting of observational studies in epidemiology for newborn infection (STROBE-NI) reporting guidelines and clearly describe timing of infection by day, and variation in pathogen spectrum across the neonatal period. Data identified in this review challenge the generalizability of the prevailing EOS/LOS paradigm in LIC and MIC., (Copyright © 2023. Published by Elsevier Ltd.)

Competing Interests: Authors’ disclosure of potential conflicts of interest Jeffrey Meyer receives royalties from Springer, UpToDate, and sponsored research support from Boston Scientific. The other authors have nothing to disclose.

The pathogenesis of antibodies in severe alcoholic hepatitis (SAH) remains unknown. We analyzed immunoglobulins (Ig) in explanted livers from SAH patients (n=45) undergoing liver transplantation and tissues from corresponding healthy donors (HD, n=10) and found massive deposition of IgG and IgA isotype antibodies associated with complement fragment C3d and C4d staining in ballooned hepatocytes in SAH livers. Ig extracted from SAH livers, but not patient serum exhibited hepatocyte killing efficacy. Employing human and Escherichia coli K12 proteome arrays, we profiled the antibodies extracted from explanted SAH, livers with other diseases, and HD livers. Compared with their counterparts extracted from livers with other diseases and HD, antibodies of IgG and IgA isotypes were highly accumulated in SAH and recognized a unique set of human proteins and E. coli antigens. Further, both Ig- and E. coli -captured Ig from SAH livers recognized common autoantigens enriched in several cellular components including cytosol and cytoplasm (IgG and IgA), nucleus, mitochondrion, and focal adhesion (IgG). Except IgM from primary biliary cholangitis livers, no common autoantigen was recognized by Ig- and E. coli -captured Ig from livers with other diseases. These findings demonstrate the presence of cross-reacting anti-bacterial IgG and IgA autoantibodies in SAH livers., Competing Interests: AA, GS, TG, JM, XH, MH, AC, RW, BP, SO, EK, AG, LQ, BP, JB, RA, ZZ, HL, DF, CC, JQ, BG, HZ, ZS No competing interests declared

Objective: We aimed to evaluate the effects of a multidisciplinary pulmonary embolism (PE) response team (PERT) on the management and outcomes of patients with acute PE., Methods: We retrospectively reviewed all patients presenting to our institution with a diagnosis of PE from July 2020 to April 2022. The primary outcome measures were in-hospital mortality, major bleeding events defined by the International Society on Thrombosis and Haemostasis, and use of catheter-directed interventions (CDIs). The secondary outcome measures included 30-day and 12-month mortality, hospital and intensive care unit (ICU) lengths of stay, vasopressor requirement, and cardiac arrest. Continuous variables were assessed using the Mann-Whitney U test and categorical variables using the χ 2 or Fisher exact test, as appropriate., Results: A total of 279 patients with acute PE were identified, of whom 79 (28%), 173 (62%), and 27 (10%) were considered to have low risk, intermediate risk, and high risk, respectively. The PERT was activated for 133 patients (47.7%). Saddle and main pulmonary artery embolisms (P < .001), right ventricular strain (P= .001), right ventricular dysfunction (P < .001), coexisting deep vein thrombosis (P < .001), and dyspnea as a presenting symptom (P = .008) were significantly associated with PERT activation. Patients evaluated by the PERT were more likely to undergo CDI (49% vs 27%; P < .001) across all risk groups and less likely to have an inferior vena cava filter placed (1% vs 5%; P = .04). PERT consultation showed numerical, but nonstatistically significant, trends toward reduced in-hospital (2% vs 5%; P = .2) and 30-day (2% vs 8%; P = .06) mortality but similar rates of 12-month mortality (7% vs 8%; P = .7). PERT activation was also associated with a trend toward reduced rates of major bleeding (2% vs 7%), cardiac arrest (2% vs 7%), and vasopressor requirement (9% vs 18%). PERT consultations decreased the median number of ICU days by one half; however, we did not observe any differences in the total hospital length of stay between the groups., Conclusions: At our institution, PERT consultations were associated with significantly higher usage of CDIs and improved clinical outcomes, including reduced mortality and a lower rate of major bleeding events. PERT consultations were also associated with fewer ICU days, suggesting a possible economic benefit for implementing PERTs, although further research is needed to confirm that conclusion., (Copyright © 2023 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Study Aim: To describe how socioecological influences of housing instability affect pregnancy health among birthing and postpartum people., Design: We used the socioecological framework to guide this exploratory descriptive study using semi-structured, in-depth interviews., Methods: We purposively recruited birthing people in the southern mid-Atlantic region. Seventeen one-time, semi-structured interviews were conducted between February 2020 and December 2021 with English-speaking unstably housed participants ≥18 years old, currently pregnant, or recently postpartum. Qualitative and quantitative content approaches were used to analyse transcribed interviews. Dedoose software was used to identify code patterns and refine the codebook until group consensus. The team examined code patterns, explored meaning in text and codified code-generated categories to describe experiences., Results: Majority (82.4%) of participants were African Americans between 22 and 41 years, and most were postpartum (76.5%). Participants described multiple forms of housing instability, reasons for losing housing, challenges with finding housing and strategies for finding housing. Participants did not describe housing instability as a barrier to receiving prenatal care. Building and sustaining individual relationships and social support were prominent factors affecting their housing challenges. Participants also reported a lack of obstetric provider inquiry about housing status during pregnancy. Many reported that challenges with housing triggered mental health issues, especially depression., Conclusion: Nurses and other obstetric providers are key points of contact in the prenatal care setting for assessing housing stability. Additionally, refining social structures and funding support services within communities and prenatal health systems should be a strategy for future programme and policy planning improvement., Impact: This study highlights critical areas for consideration when addressing social determinants for birthing people and reinforces the need for more comprehensive assessment in the prenatal setting., Patient or Public Contribution: Members of the public participated in this study as key informants for study interviews., (© 2023 The Authors. Journal of Advanced Nursing published by John Wiley & Sons Ltd.)

Purpose: The purpose of this study was to identify modifiable medical comorbidities, laboratory markers and flaws in perioperative management that increase the risk of acute dislocation in total hip arthroplasty (THA) patients., Methods: All THA with primary indications of osteoarthritis from 2007 to 2020 were queried from the National Surgical Quality Improvement Program (NSQIP) database. Demographic data, preoperative laboratory values, recorded past medical history, operative details as well as outcome and complication information were collected. The study population was divided into two cohorts: non-dislocation and dislocation patients. Statistics were performed to compare the characteristics of both cohorts and to identify risk factors for prosthetic dislocation (α < 0.05)., Results: 275,107 patients underwent primary THA in 2007 to 2020, of which 1,258 (0.5%) patients experienced a prosthetic hip dislocation. Demographics between non-dislocation and dislocation cohorts varied significantly in that dislocation patients were more likely to be female, older, with lower body mass index and a more extensive past medical history (all p < 0.05). Moreover, hypoalbuminemia and moderate/severe anemia were associated with increased risk of dislocation in a multivariate model (all p < 0.05). Finally, use of general anesthesia, longer operative time, and longer length of hospital stay correlated with greater risk of prosthetic dislocation (all p < 0.05)., Conclusions: Elderly female patients and patients with certain abnormal preoperative laboratory values are at risk for sustaining acute dislocations after index THA. Careful interdisciplinary planning and medical optimization should be considered in high-risk patients as dislocations significantly increase the risk of sepsis, cerebral vascular accident, and blood transfusions on readmission., (© 2023. European Society of Sports Traumatology, Knee Surgery, Arthroscopy (ESSKA).)

The ocular surface microbiome, unlike that of the skin or gut, has not been well characterized. Culture experiments historically suggested a nearly sterile ocular surface, but initial application of molecular methods such as 16S ribosomal RNA and high-throughput sequencing demonstrated a surprisingly rich ocular surface microbiome. However, a major limitation in studying such a low-biomass niche is the potential for artifactual results when amplification-based techniques such as ribosomal polymerase chain reaction and shotgun sequencing are used. It will be essential to establish standards across the field for sample collection, positive and negative controls, and limitation of contamination in both the laboratory setting and computational analysis. New developments in ocular microbiome research, including the generation of reference reagents and fluoroscopic imaging techniques, provide improved means to validate sequencing results and to visualize complex interactions between host cells and bacteria. Through more thorough characterization of the ocular surface microbiome, the connections between a dysregulated surface and ophthalmic disease may be better understood., Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Background: Patients with anorexia nervosa (AN) may experience life-threatening malnutrition-related complications requiring inpatient medical stabilisation. Several management guidelines have been developed but discrepancies exist because of limited high-level evidence., Aims: To review the evidence base for recommendations contained in Victorian health services guidelines for the nutritional management of inpatients with AN., Methods: MEDLINE and Embase databases were searched for published studies on the nutritional management of inpatients with AN, combined with a manual search through citations. Studies including patients with AN aged 16 years and older were included. Case reports, small case series of <10 patients, studies of nonmedical management and studies with an exclusive paediatric population were excluded. The search results were compared with AN inpatient medical management guidelines sourced from large tertiary health services across Victoria, Australia., Results: The search yielded 584 studies, subsequently reduced to nine studies using the inclusion and exclusion criteria. The results suggest that commencing refeeding at a higher caloric value allows faster weight gain and shorter hospitalisation. Enteral tube feeding is preferential to parenteral nutrition because of infrequent and milder complications. Zinc supplementation showed a doubled rate of body mass index increase compared with placebo. Comparison with Victorian health services guidelines revealed inconsistent recommendations for high-calorie refeeding and micronutrient supplementation., Conclusion: The evidence supports high-calorie refeeding of 2000 kcal/day in AN inpatient medical management and zinc supplementation in improving the rate of weight restoration. This is inconsistently reflected in different Victorian health services guidelines. Updated national consensus guidelines could assist in improving consistency of evidence-based health care., (© 2022 The Authors. Internal Medicine Journal published by John Wiley & Sons Australia, Ltd on behalf of Royal Australasian College of Physicians.)

Background: Preoperative type and screen and type and cross are routinely obtained in patients undergoing elective cervical spine surgeries. This is despite low perioperative transfusion rates, particularly in patients undergoing anterior cervical discectomy and fusion (ACDF)., Methods: We conducted a retrospective cohort study at a single tertiary medical center of all patients 18 years of age or older undergoing elective ACDF for degenerative cervical spine disease between January 2016 and January 2021. Our primary outcome measures included the frequency of type and screen/crossmatch orders, rate of perioperative transfusion, and crossmatch to transfusion (C/T) ratio. Secondary outcomes included differences between preoperative and postoperative hemoglobin and hematocrit., Results: In total, 1,162 patients were identified. There were no cases of intraoperative transfusion. The overall transfusion rate was less than 1%, with only 1 patient receiving a blood product transfusion during their hospital admission. This patient received 2 units of platelets for severe preoperative thrombocytopenia. Yet, 961 patients (83%) received ABO/Rh blood typing and screening and 647 patients (56%) had their blood typed and crossed. A total of 1,318 units of blood were crossmatched, with no units of packed red blood cells (pRBCs) transfused and only 2 units of platelets transfused, achieving a high crossmatch to transfusion (C/T) ratio of 659:1., Conclusions: Among 1,162 patients who underwent elective ACDF at our institution, there were no patients who required an intraoperative or emergent blood transfusion. Furthermore, routine type and screen and crossmatch in patients undergoing elective ACDF at our insitution is associated with a high C/T ratio, suggestive of inefficient usage of blood products., Competing Interests: The authors report no conflicts of interest in this work. No funding was received to facilitate conduction of this work., (© 2023 The Author(s).)

Hidradenitis suppurativa (HS), more commonly known as acne inversa, occurs due to chronic inflammation of the body's apocrine glands, most commonly affecting areas of the body where there is prolonged skin-on-skin friction. HS affects approximately 4% of the United States population, most commonly women in their second or third decade of life, especially those of African American ethnicity. HS presents as tender subcutaneous nodules which often rupture, leading to the formation of painful dermal abscesses which undergo fibrosis and lead to the formation of extensive sinus tracts, a phenomenon known as "tunneling". HS is staged clinically using the Hurley staging system, where the stage determines what treatment modalities are used. These modalities can include medical management such as antibiotics, or biologics such as tumor necrosis factor (TNF)-alpha inhibitors like adalimumab, as well as surgical options including incision with or without drainage. Due to the similar presentation of HS with other conditions, this disease is commonly misdiagnosed, often leading to delayed treatment initiation and worse outcomes for patients. Presented is a case report of a 30-year-old African American male with perianal HS and the potential long-term complications and challenges of management of this disease., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Russell et al.)