Effects of Intranasal Naloxone on Hypoglycemia-Associated Autonomic Failure (HAAF) in Susceptible Individuals.

CONTEXT: Hypoglycemia-associated autonomic failure (HAAF), defined as blunting of counter-regulatory hormone and symptom responses to recurrent hypoglycemia, remains a therapeutic challenge in diabetes treatment. The opioid system may play a role in HAAF pathogenesis since activation of opioid receptors induces HAAF. Blockade of opioid receptors with intravenous naloxone ameliorates HAAF experimentally, yet is not feasible therapeutically. OBJECTIVE: To investigate the effects of opioid receptor blockade with intranasal naloxone on experimentally-induced HAAF. DESIGN: Randomized, double-blinded, placebo-controlled crossover study. SETTING: Academic research center. PARTICIPANTS: Healthy non-diabetic volunteers. INTERVENTIONS: Paired two-day studies, 5-10 weeks apart, each consisting of three consecutive hypoglycemic episodes (hyperinsulinemic hypoglycemic clamps, glucose nadir: 54 mg/dL): two on day 1 with administration of intranasal naloxone vs. placebo, followed by the third episode on day 2. MAIN OUTCOME MEASURES: Differences in counter-regulatory hormones responses and hypoglycemia symptoms between first and third hypoglycemic episodes in naloxone vs. placebo studies. RESULTS: Out of 17 participants, 9 developed HAAF, confirming variable inter-individual susceptibility. Among participants susceptible to HAAF, naloxone maintained some hormonal and symptomatic responses to hypoglycemia and prevented the associated requirement for increased glucose infusion. Unexpectedly, naloxone reduced plasma epinephrine and growth hormone responses to the first hypoglycemic episode but prevented further reduction with subsequent hypoglycemia. CONCLUSIONS: This is the first study to report that intranasal naloxone, a widely used opioid receptor antagonist, may ameliorate some features of HAAF. Further investigation is warranted into mechanisms of variable inter-individual susceptibility to HAAF and the effects of intranasal naloxone in people with diabetes at risk for HAAF.

Atypical hemolytic uremic syndrome during induction chemotherapy in neuroblastoma, a rare phenomenon or common congenital predisposition?

Atypical hemolytic uremic syndrome (aHUS) is a complement-mediated thrombotic microangiopathy sometimes associated with germline variants in genes of the complement system. Clinical findings of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury arise due to aberrant complement protein activation in the circulation. A 13-month-old boy with metastatic neuroblastoma (NB) developed aHUS during his first cycle of induction chemotherapy with germline testing revealing a complement factor H (CFH) gene mutation, currently classified as a variant of uncertain significance (VUS). Now he is in disease remission after successful complement blockade therapy, thus highlighting a unique presentation of aHUS in a patient with newly diagnosed NB.

HLH and Recurrent EBV Lymphoma as the presenting manifestation of MAGT1 Deficiency: A Systematic Review of the Expanding Disease Spectrum.

Magnesium transporter 1 (MAGT1) gene loss-of-function variants lead to X-linked MAGT1 deficiency with increased susceptibility to EBV infection and N-glycosylation defect (XMEN), a condition with a variety of clinical and immunological effects. In addition, MAGT1 deficiency has been classified as a congenital disorder of glycosylation (CDG) due to its unique role in glycosylation of multiple substrates including NKG2D, necessary for viral protection. Due to the predisposition for EBV, this etiology has been linked with hemophagocytic lymphohistiocytosis (HLH), however only limited literature exists. Here we present a complex case with HLH and EBV-driven classic Hodgkin lymphoma (cHL) as the presenting manifestation of underlying immune defect. However, the patient's underlying immunodeficiency was not identified until his second recurrence of Hodgkin disease, recurrent episodes of Herpes Zoster, and after he had undergone autologous hematopoietic stem cell transplant (HSCT) for refractory Hodgkin lymphoma. This rare presentation of HLH and recurrent lymphomas without some of the classical immune deficiency manifestations of MAGT1 deficiency led us to review the literature for similar presentations and to report the evolving spectrum of disease in published literature. Our systematic review showcased that MAGT1 predisposes to multiple viruses (including EBV) and adds risk of viral-driven neoplasia. The roles of MAGT1 in the immune system and glycosylation were highlighted through the multiple organ dysfunction showcased by the previously validated Immune Deficiency and Dysregulation Activity (IDDA2.1) score and CDG-specific Nijmegen Pediatric CDG Rating Scale (NPCRS) score for the patient cohort in the systematic review.

Tuning Displacement Fields in a Two-Dimensional Topological Insulator Using Nanopatterned Gates.

Epitaxial heterostructures with topological insulators enable novel quantum phases and practical device applications. Their topological electronic states are sensitive to the microscopic parameters, including structural inversion asymmetry (SIA), which is an inherent feature of many real heterostructures. Controlling SIA is challenging, because it requires the ability to tune the displacement field across the topological film. Here, using nanopatterned gates, we demonstrate a tunable displacement field in a heterostructure of the two-dimensional topological insulator cadmium arsenide. Transport studies in magnetic fields reveal an extreme sensitivity of the band inversion to SIA. We show that a relatively small displacement field (∼50 mV/nm) converts the crossing of the two zeroth Landau levels in magnetic field to an avoided crossing, signaling a change to trivial band order. This work demonstrates a universal methodology for tuning electronic states in topological thin films.

Temporal memory for threatening events encoded in a haunted house.

Despite the salient experience of encoding threatening events, these memories are prone to distortions and often non-veridical from encoding to recall. Further, threat has been shown to preferentially disrupt the binding of event details and enhance goal-relevant information. While extensive work has characterised distinctive features of emotional memory, research has not fully explored the influence threat has on temporal memory, a process putatively supported by the binding of event details into a temporal context. Two primary competing hypotheses have been proposed; that threat can impair or enhance temporal memory. We analysed two datasets to assess temporal memory for an in-person haunted house experience. In study 1, we examined the temporal structure of memory by characterising memory contiguity in free recall as a function of individual levels of heart rate as a proxy of threat. In study 2, we replicated marginal findings of threat-related increases in memory contiguity found in study 1. We extended these findings by showing threat-related increases in recency discriminations, an explicit test of temporal memory. Together, these findings demonstrate that threat enhances temporal memory regarding free recall structure and during explicit memory judgments.

Evaluating thromboprophylaxis in the sickle cell disease population: Navigating the evidence gap.

Sickle cell disease (SCD) arises from beta-globin gene mutations, with global estimates indicating around 500 000 affected neonates in 2021. In the United States, it is considered rare, impacting fewer than 200 000 individuals. The key pathogenic flaw lies in mutant haemoglobin S, prone to polymerization under low oxygen conditions, causing erythrocytes to adopt a sickled shape. This leads to complications like vascular occlusion, haemolytic anaemia, inflammation and organ damage. Beyond erythrocyte abnormalities however, there is a body of literature highlighting the hypercoagulable state that is likely a contributor to many of the complications we see in SCD. The persistent activation of the coagulation cascade results in thromboembolic events, notably venous thromboembolism (VTE) which is independently associated with increased mortality in both adults and children with SCD. While the increased risk of VTE in the SCD population seems well established, there is a lack of guidelines for thromboprophylaxis in this population. This Wider Perspective will describe the hypercoagulable state and increased thrombosis risk in the SCD population, as well as advocate for the development of evidence-based guidelines to aid in the prevention of VTE in SCD.

Effectiveness of Angle-Based Minimally Invasive Glaucoma Surgery after Laser Trabeculoplasty: An Analysis of the IRIS® Registry (Intelligent Research in Sight).

OBJECTIVE: Angle-based minimally invasive glaucoma surgery (ab-MIGS) has grown substantially, although long-term efficacy is poorly understood. We analyze ab-MIGS effectiveness with and without preceding laser trabeculoplasty (LTP). DESIGN: Retrospective cohort study. SUBJECTS: Eyes undergoing ab-MIGS (Canaloplasty, Goniotomy, Trabectome, and iStent) with and without prior laser trabeculoplasty (< 2 years preceding MIGS) were identified in the IRIS® Registry (Intelligent Research in Sight) 2013 to 2018. METHODS: Propensity score matching (PSM) was undertaken to define the following 4 cohorts: (1) standalone ab-MIGS, no prior LTP vs. (2) standalone ab-MIGS, with prior LTP; and (3) ab-MIGS + phacoemulsification, no prior LTP vs. (4) ab-MIGS + phacoemulsification, with prior LTP. MAIN OUTCOME MEASURES: Failure was defined as subsequent glaucoma reoperation after ab-MIGS (either MIGS or traditional glaucoma surgery). Time-to-event outcome and incidence rates were calculated using survival analysis, and adjusted hazard ratios (aHRs) were generated using multivariate Cox proportional hazards models. Medication data were not available for analysis. RESULTS: A total of 164 965 unique MIGS procedures were performed, from 2013 to 2018. After PSM, we identified 954 eyes undergoing standalone ab-MIGS and 7522 undergoing ab-MIGS + phacoemulsification. For eyes undergoing standalone ab-MIGS, those with prior LTP (n = 477) were more likely to undergo reoperation vs. those without LTP (n = 477) at 6 and 12 months. In multivariable models, those with prior LTP were more likely to undergo reoperation over the 36-month period vs. those without prior LTP (aHR, 1.53; CI, 1.15-2.04; P = 0.004). For eyes undergoing ab-MIGS + phacoemulsification, those with prior LTP (n = 3761) were more likely to undergo reoperation vs. those without LTP (n = 3761) at 12, 24, and 36 months. In multivariable models, those with prior LTP were more likely to undergo reoperation over the 36-month period vs. those without prior LTP (aHR, 1.53 CI, 1.15-2.04; P = 0.004). CONCLUSIONS: Prior LTP may be associated with a higher chance of subsequent glaucoma surgery following ab-MIGS, either with or without concurrent phacoemulsification. These findings have important implications for understanding who may benefit most from ab-MIGS, and for guiding patient and surgeon treatment expectations. FINANCIAL DISCLOSURES: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Sustained intraoperative allergic reaction to chlorhexidine: A case report.

Physicians should be prepared for the presentation and treatment of an anaphylactic reaction in a patient who has been exposed to chlorhexidine perioperatively and consider a sustained source of allergic exposure when faced with a refractory response to treatment.

Comparison of trends of inpatient charges among primary and revision shoulder arthroplasty over a decade: a regional database study.

Background: This study examined trends in inpatient charges for primary anatomic total shoulder arthroplasty (aTSA) and reverse total shoulder arthroplasty (rTSA), hemiarthroplasty (HA), and revision total shoulder arthroplasty (revTSA) over the past decade. Methods: The New York Statewide Planning and Research Cooperative System was queried for patients undergoing primary aTSA, rTSA, HA, and revTSA from 2010 to 2020 using International Classification of Diseases procedure codes. The primary outcome measured was total charges per encounter. Secondary outcomes included accommodation and ancillary charges, charges covered by insurance, and facility volume. Ancillary charges were defined as fees for diagnostic and therapeutic services and accommodation charges were defined as fees associated with room and board. Subgroup analysis was performed to assess differences between high- and low-volume centers. Results: During the study period, 46,044 shoulder arthroplasty cases were performed: 18,653 aTSA, 4002 HA, 19,253 rTSA, and 4136 revTSA. An exponential increase in rTSA (2428%) and considerable decrease in HA (83.9%) volumes were observed during this period. Total charges were the highest for rTSA and revTSA and the lowest for aTSA. Subgroup analysis of revTSA by indication revealed that total charges were the highest for periprosthetic fractures. For aTSA, rTSA, and HA, high-volume centers achieved significantly lower total charges compared to low-volume centers. Over the study period, total inpatient charges increased by 57.2%, 38.4%, 102.4%, and 68.4% for aTSA, rTSA, HA, and revTSA, outpacing the inflation rate of 18.7%. Conclusion: Total inpatient charges for all arthroplasty types increased dramatically from 2010 to 2020, outpacing inflation rates, but high-volume centers demonstrated greater success at mitigating charge increases compared to low-volume centers.

Metasurface Light-Emitting Diodes with Directional and Focused Emission.

Phased-array metasurfaces enable the imprinting of complex beam structures onto coherent incident light. Recent demonstrations of photoluminescent phased-array metasurfaces highlight possibilities for achieving similar control in electroluminescent light-emitting diodes (LEDs). However, phased-array metasurface LEDs have not yet been demonstrated owing to the complexities of integrating device stacks and electrodes within nanopatterned metasurfaces. Here, we demonstrate metasurface LEDs that emit directional or focused light. We first design nanoribbon elements that achieve the requisite phase control within typical LED device constraints. Subsequently, we demonstrate unidirectional emission that can be engineered at will via phased-array concepts. This control is further exhibited in metasurface LEDs that directly emit focused beams. Finally, we show that these metasurface LEDs exhibit external quantum efficiencies (EQEs) superior to those of unpatterned LEDs. These results demonstrate metasurface designs that are compatible with high-EQE metal-free LED devices and portend opportunities for new classes of metasurface LEDs that directly produce complex beam structures.

Venous thromboembolism prophylaxis practices for patients with sickle cell disease prior to and during the COVID-19 pandemic.

Patients with sickle cell disease (SCD) are predisposed to a hypercoagulable state due to alterations in the coagulation system. Despite concern for the development of venous thromboembolism (VTE) in this population, there are no standardized guidelines for routine thromboprophylaxis. The objective of this study was to assess thromboprophylaxis practices of adult and pediatric treaters of SCD before and during the coronavirus disease of 2019 (COVID-19) pandemic. A cross-sectional electronic survey was distributed to pediatric and adult hematology oncology practitioners through seven SCD-specific interest groups between May 29, 2020, and July 13, 2020. Of 93 total responses, 14% ( N  = 13) reported they only treat patients more than 21 years old; 38.7% ( N  = 36) only treat patients 0-21 years old and 47.3% ( N  = 44) reported they treat both. Our study showed that before the COVID-19 pandemic, 96% of adult practitioners would recommend pharmacologic thromboprophylaxis, mechanical thromboprophylaxis or both for hospitalized adults with thromboprophylaxis, but only 76% of pediatric treaters would recommend any thromboprophylaxis in hospitalized children ( P  < 0.0001), with 24% of pediatric treaters choosing no thromboprophylaxis at all. During the COVID-19 pandemic, pharmacologic thromboprophylaxis specifically was recommended for adults by 94% of treaters and for pediatric patients by 76% of treaters. These findings suggest that despite the lack of evidence-based thromboprophylaxis guidelines in adults and children with thromboprophylaxis, subspecialty treaters routinely provide pharmacologic thromboprophylaxis in their adult patients and will modify their practice in pediatric patients who are considered at a high risk for VTE.

The intestinal microbiota predicts COVID-19 severity and fatality regardless of hospital feeding method.

SARS-CoV-2-positive patients exhibit gut and oral microbiome dysbiosis, which is associated with various aspects of COVID-19 disease (1-4). Here, we aim to identify gut and oral microbiome markers that predict COVID-19 severity in hospitalized patients, specifically severely ill patients compared to moderately ill ones. Moreover, we investigate whether hospital feeding (solid versus enteral), an important cofounder, influences the microbial composition of hospitalized COVID-19 patients. We used random forest classification machine learning models with interpretable secondary analyses. The gut, but not the oral microbiota, was a robust predictor of both COVID-19-related fatality and severity of hospitalized patients, with a higher predictive value than most clinical variables. In addition, perturbations of the gut microbiota due to enteral feeding did not associate with species that were predictive of COVID-19 severity. IMPORTANCE SARS-CoV-2 infection leads to wide-ranging, systemic symptoms with sometimes unpredictable morbidity and mortality. It is increasingly clear that the human microbiome plays an important role in how individuals respond to viral infections. Our study adds to important literature about the associations of gut microbiota and severe COVID-19 illness during the early phase of the pandemic before the availability of vaccines. Increased understanding of the interplay between microbiota and SARS-CoV-2 may lead to innovations in diagnostics, therapies, and clinical predictions.

Reparations for people living with dementia: Recognition, accountability, change, now!

There is a significant and longstanding problem of harm to people living with dementia in long term care institutions ('LTC institutions', referred to by others as 'care homes', 'nursing homes', 'long term care', 'residential aged care facilities'), along with a failure to redress the harm or hold people accountable for this harm. This article reports on an Australian project that found reparations must be a response to harm to people living with dementia in residential aged care. Using a disability human rights methodology, focus groups were conducted with people living with dementia, care partners and family members, advocates and lawyers to explore perspectives on why and how to redress harm to people living with dementia in Australian LTC institutions. Researchers found four key themes provide the basis for the necessity and design of a reparative approach to redress - recognition, accountability, change, now. The article calls for further attention to reparations in dementia scholarship, with a particular focus on the role that can be played in the delivery of reparations by the LTC industry, dementia practitioners, and dementia scholars. Ultimately, this article provides a new understanding of responses to violence, abuse, neglect and other harms experienced by people living with dementia in LTC institutions, which centres justice, rights, and transformative change.

Sn/InAs Josephson Junctions on Selective Area Grown Nanowires with in Situ Shadowed Superconductor Evaporation.

Superconductor-semiconductor nanowire hybrid structures are useful in fabricating devices for quantum information processing. While selective area growth (SAG) offers the flexibility to grow semiconductor nanowires in arbitrary geometries, in situ evaporation of superconductors ensures pristine superconductor-semiconductor interfaces, resulting in strong induced superconductivity in the semiconducting nanowire. In this work, we used high-aspect-ratio SiOx dielectric walls to in situ evaporate islands of superconductor tin on in-plane InAs SAG nanowires. Our technique enables customization in the designs of such hybrid nanostructures, while simultaneously performing the nanowire and superconductor growth without breaking vacuum. Using this technique, we grew super(S)-normal(N)-super(S), NS, and SNSNS junctions. We performed cryogenic electron transport measurements revealing the presence of gate and field tunable supercurrents. We further measured the superconducting gap and critical fields in the hybrid nanostructures and the crossover from 2e to 1e periodicity in the SNSNS junctions as a proof of the usability of these hybrid nanostructures.

Fairness and generalizability of OCT normative databases: a comparative analysis.

PURPOSE: In supervised Machine Learning algorithms, labels and reports are important in model development. To provide a normality assessment, the OCT has an in-built normative database that provides a color base scale from the measurement database comparison. This article aims to evaluate and compare normative databases of different OCT machines, analyzing patient demographic, contrast inclusion and exclusion criteria, diversity index, and statistical approach to assess their fairness and generalizability. METHODS: Data were retrieved from Cirrus, Avanti, Spectralis, and Triton's FDA-approval and equipment manual. The following variables were compared: number of eyes and patients, inclusion and exclusion criteria, statistical approach, sex, race and ethnicity, age, participant country, and diversity index. RESULTS: Avanti OCT has the largest normative database (640 eyes). In every database, the inclusion and exclusion criteria were similar, including adult patients and excluding pathological eyes. Spectralis has the largest White (79.7%) proportionately representation, Cirrus has the largest Asian (24%), and Triton has the largest Black (22%) patient representation. In all databases, the statistical analysis applied was Regression models. The sex diversity index is similar in all datasets, and comparable to the ten most populous contries. Avanti dataset has the highest diversity index in terms of race, followed by Cirrus, Triton, and Spectralis. CONCLUSION: In all analyzed databases, the data framework is static, with limited upgrade options and lacking normative databases for new modules. As a result, caution in OCT normality interpretation is warranted. To address these limitations, there is a need for more diverse, representative, and open-access datasets that take into account patient demographics, especially considering the development of supervised Machine Learning algorithms in healthcare.

Fairness and generalisability in deep learning of retinopathy of prematurity screening algorithms: a literature review.

BACKGROUND: Retinopathy of prematurity (ROP) is a vasoproliferative disease responsible for more than 30 000 blind children worldwide. Its diagnosis and treatment are challenging due to the lack of specialists, divergent diagnostic concordance and variation in classification standards. While artificial intelligence (AI) can address the shortage of professionals and provide more cost-effective management, its development needs fairness, generalisability and bias controls prior to deployment to avoid producing harmful unpredictable results. This review aims to compare AI and ROP study's characteristics, fairness and generalisability efforts. METHODS: Our review yielded 220 articles, of which 18 were included after full-text assessment. The articles were classified into ROP severity grading, plus detection, detecting treatment requiring, ROP prediction and detection of retinal zones. RESULTS: All the article's authors and included patients are from middle-income and high-income countries, with no low-income countries, South America, Australia and Africa Continents representation.Code is available in two articles and in one on request, while data are not available in any article. 88.9% of the studies use the same retinal camera. In two articles, patients' sex was described, but none applied a bias control in their models. CONCLUSION: The reviewed articles included 180 228 images and reported good metrics, but fairness, generalisability and bias control remained limited. Reproducibility is also a critical limitation, with few articles sharing codes and none sharing data. Fair and generalisable ROP and AI studies are needed that include diverse datasets, data and code sharing, collaborative research, and bias control to avoid unpredictable and harmful deployments.

Portable thermal scanners to detect and monitor small endotherms: A comparative assessment of available equipment to guide practitioners.

Detection is essential to studying and monitoring wild animals; however, detection is challenging for small endotherms that are nocturnal or best detected at night. Techniques such as trapping or spotlighting disturb focal species, and the effectiveness of spotlighting can be limited for cryptic species, resulting in low detection rates that hinder our ability to monitor and study some endotherms at night. Thermal scanners detect infrared wavelengths not otherwise visible to humans. With improvements in equipment size and cost, thermal scanners have emerged as a valuable tool for passive detection of endotherms. Here we seek to provide objective guidance on thermal tool selection to practitioners who wish to adopt such tools to detect and monitor small endotherms. We compared the efficacy of three handheld thermal scanners (of varying resolutions) and a traditional spotlight for detecting small, cryptic endotherms at night. Random arrays of artificially heated small bird models (representing small, cryptic endotherms) were established along transects in native grasslands that support a range of small threatened endotherms, including the Critically Endangered Plains-wanderer (Pedionomus torquatus). Transects were independently surveyed by five observers, blind to model locations and model density. Performance measures representing detection capability were assessed for all devices, and usability of each device was assessed with a survey completed by all observers. Detection rates, detection distances, and survey accuracy were greater for thermal scanners with resolutions of 320 × 240 and 640 × 480 than for the spotlight. A low-resolution thermal scope (160 × 120) performed poorly for all performance measures. There was a consensus among users that a video camera-style thermal scanner was most comfortable to hold and view while traversing the transect, as opposed to thermal scopes where users look directly through the lens. These results suggest that high-resolution thermal scanners (≥320 × 240) provide improved detection capabilities compared to traditional spotlights. Higher detection rates provide opportunities for detecting and monitoring small endotherms at night where this was once difficult or impossible.