First-line anti-tuberculosis drug challenge reactions in DRESS in an HIV endemic setting.

BACKGROUND: In high HIV prevalence settings, first line anti-tuberculosis drug (FLTD)-associated DRESS poses therapeutic challenges. Sequential and additive drug challenge (SADC) of FLTDs best identifies offending drug(s), avoids unnecessary exclusions, and optimises re-initiation of non-offending drugs. However, SADC-associated reaction complexities limit its utility. OBJECTIVE: We aimed to describe characteristics of FLTD-associated DRESS patients, their treatment-limiting SADC reactions and related outcomes. METHODS: Patients hospitalized with FLTD-associated DRESS from 2013-2023 in a South African tertiary hospital and enrolled (retrospectively or prospectively) in an existing registry were eligible. RESULTS: SADC was undertaken in 41 patients. Overall, 47 classifiable reactions occurred, 34/47(72%) in 29/41(71%) patients, were treatment-limiting and 12/41(29%) reinitiated FLTDs uneventfully. Fifteen single and eight multiple drug-reactors were identified. Rifampicin, in 13/23(57%) reactors was the commonest individual offender. Ethambutol was most frequently involved in multiple drug-reactors. Median(IQR) time to a detectable reaction was 24(12-120) hours, 6/34(18%) being immediate (<6hours). Itch (65%), eosinophilia (56%), fever (41%), atypical lymphocytosis (41%), rash (38%), transaminitis (32%) and facial oedema (18%), singly or in combination were commonest features. Three reactions, one epidermal necrolysis and two liver derangements, were CTCAE grade 4 (life-threatening) events. No predictors of multiple drug-reactivity were identified, but multiple reactors were hospitalised significantly longer, 125(100-134) versus 60(45-80) days. CONCLUSIONS: SADC optimises FLTD reinitiation. However, timing, clinical presentation and severity of SADC-associated reactions following FLTD-associated DRESS is markedly heterogenous. Additionally, multiple drug-reactors are a complex group requiring longer hospitalisation, and without routine biomarkers to differentiate true multiple drug hypersensitivity from non-specific flare-ups and guide long-term drug avoidance strategies.

V ˙ Lamax: determining the optimal test duration for maximal lactate formation rate during all-out sprint cycle ergometry.

PURPOSE: This study aimed to ascertain the optimal test duration to elicit the highest maximal lactate formation rate ( V ˙ Lamax), whilst exploring the underpinning energetics, and identifying the optimal blood lactate sampling period. METHODS: Fifteen trained to well-trained males (age 27 ± 6 years; peak power: 1134 ± 174 W) participated in a randomised cross-over design completing three all-out sprint cycling tests of differing test durations (10, 15, and 30 s). Peak and mean power output (W and W.kg-1), oxygen uptake, and blood lactate concentrations were measured. V ˙ Lamax and energetic contributions (phosphagen, glycolytic, and oxidative) were determined using these parameters. RESULTS: The shortest test duration of 10 s elicited a significantly (p = 0.003; p < 0.001) higher V ˙ Lamax (0.86 ± 0.17 mmol.L-1.s-1; 95% CI 0.802-0.974) compared with both 15 s (0.68 ± 0.18 mmol.L-1.s-1; 95% CI 0.596-0.794) and 30 s (0.45 ± 0.07 mmol.L-1.s-1; 95% CI 0.410-0.487). Differences in V ˙ Lamax were associated with large effect sizes (d = 1.07, d = 3.15). We observed 81% of the PCr and 53% of the glycolytic work completed over the 30 s sprint duration was attained after 10 s. BLamaxpost were achieved at 5 ± 2 min (ttest 10 s), 6 ± 2 min (ttest 15 s), and 7 ± 2 min (ttest 30 s), respectively. CONCLUSION: Our findings demonstrated a 10 s test duration elicited the highest V ˙ Lamax. Furthermore, the 10 s test duration mitigated the influence of the oxidative metabolism during all-out cycling. The optimal sample time to determine peak blood lactate concentration following 10 s was 5 ± 2 min.

Pediatric donor heart acceptance practices in the United States: What is really being considered?

BACKGROUND: Recent studies demonstrate high offer decline and organ non-utilization rates are associated with increased pediatric heart transplant waitlist mortality. We sought to determine which donor, candidate, and offer specific variables most importantly influenced these decisions using only data available at the time of each offer. METHODS: Retrospective review of pediatric (<18 years) heart donor offers made to pediatric candidates in the United States between 2010 and 2020. In addition to standard donor, candidate, and offer data available in UNOS, we extracted objective and qualitative valvar and myocardial function data from all available donor echocardiogram reports. RESULTS: During the study period, 5625 pediatric donor hearts produced 30 156 offers to 4905 unique candidates, of which 88.7% of all offers were declined and 39.2% of organs were not utilized by pediatric waitlisted candidates. Of the 60.8% utilized hearts, 89.7% had a 'cumulatively' normal echocardiogram at the time of offer acceptance; 62.9% of hearts not utilized for a pediatric candidate also had a cumulatively normal final echocardiogram. Random forest and logistic regression modeling demonstrated good predictive performance (AUROC ≥0.83) of likelihood to accept when utilizing donor, candidate, and offer specific variables. SHAP variable importance scores demonstrated number of prior offer declines and candidate institution's prior year acceptance rates as the two most important variables influencing offer decisions. CONCLUSIONS: Behavioral economics appear to play a significant role in pediatric heart transplant candidate institutions' acceptance practices, even when considering the arguably healthier pediatric donor population. Removal of prior institution's decisions from DonorNet may help increase donor utilization.

Neuroimmune Support of Neuronal Regeneration and Neuroplasticity following Cerebral Ischemia in Juvenile Mice.

Ischemic damage to the brain and loss of neurons contribute to functional disabilities in many stroke survivors. Recovery of neuroplasticity is critical to restoration of function and improved quality of life. Stroke and neurological deficits occur in both adults and children, and yet it is well documented that the developing brain has remarkable plasticity which promotes increased post-ischemic functional recovery compared with adults. However, the mechanisms underlying post-stroke recovery in the young brain have not been fully explored. We observed opposing responses to experimental cerebral ischemia in juvenile and adult mice, with substantial neural regeneration and enhanced neuroplasticity detected in the juvenile brain that was not found in adults. We demonstrate strikingly different stroke-induced neuroimmune responses that are deleterious in adults and protective in juveniles, supporting neural regeneration and plasticity. Understanding age-related differences in neuronal repair and regeneration, restoration of neural network function, and neuroimmune signaling in the stroke-injured brain may offer new insights for the development of novel therapeutic strategies for stroke rehabilitation.

A survey in the West Midlands of the United Kingdom of current practice in managing hypotension in lower segment caesarean section under spinal anaesthesia.

BACKGROUND: Spinal anaesthesia, the most common form of anaesthesia for caesarean section, leads to sympathetic blockade and profound maternal hypotension resulting in adverse maternal and neonatal outcomes. Hypotension, nausea and vomiting remain common but until the publication of the National Institute of Health and Care Excellence (NICE) 2021 guidance, no national guideline existed on how best to manage maternal hypotension following spinal anaesthesia for caesarean section. A 2017 international consensus statement recommended prophylactic vasopressor administration to maintain a systolic blood pressure of >90% of an accurate pre-spinal value, and to avoid a drop to <80% of this value. This survey aimed to assess regional adherence to these recommendations, the presence of local guidelines for management of hypotension during caesarean section under spinal anaesthesia, and the individual clinician's treatment thresholds for maternal hypotension and tachycardia. METHODS: The West Midlands Trainee-led Research in Anaesthesia and Intensive Care Network co-ordinated surveys of obstetric anaesthetic departments and consultant obstetric anaesthetists across 11 National Health Service Trusts in the Midlands, England. RESULTS: One-hundred-and-two consultant obstetric anaesthetists returned the survey and 73% of sites had a policy for vasopressor use; 91% used phenylephrine as the first-line drug but a wide range of recommended delivery methods was noted and target blood pressure was only listed in 50% of policies. Significant variation existed in both vasopressor delivery methods and target blood pressures. CONCLUSIONS: Although NICE has since recommended prophylactic phenylephrine infusion and a target blood pressure, the previous international consensus statement was not adhered to routinely.

The effectiveness of cognitive behavioural therapy for individuals with an intellectual disability and anxiety: a systematic review.

INTRODUCTION: Individuals with intellectual disability (ID) are at higher risk of experiencing difficulties with anxiety than the general population. However, there are major barriers for individuals to receive appropriate services. There is a growing understanding of the importance of developing appropriate psychological interventions for this group. The objective of the current review was to systematically evaluate the findings of studies investigating the effectiveness of cognitive behavioural therapy (CBT) for individuals with ID and anxiety. Another aim was to explore which adaptions to CBT and treatment components were currently being utilised within the field. METHOD: The electronic databases of CINAHL, EMBASE, Medline, PsycINFO, Psychology and Behavioural Sciences Collection and Scopus were searched to identify relevant studies. The methodological quality of these studies was assessed using established quality assessment tools by the National Institutes of Health for pre and post studies and case series. RESULTS: Nine studies were included in this systematic review, all of which reported improvements in anxiety severity for some participants (25%-100%; N = 60) following CBT. Only three studies reported moderate effect sizes for CBT interventions on anxiety for individuals with ID. DISCUSSION AND CONCLUSIONS: There is emerging literature supporting the effectiveness of CBT for individuals with mild ID. Findings highlight that CBT for individuals with anxiety and mild ID, including cognitive components, may be feasible and tolerable. While the field is gradually receiving more attention, there are significant methodological flaws present, which limit the conclusions that can be drawn regarding the effectiveness of CBT for individuals with ID. However, there is emerging evidence for techniques such as cognitive restructuring and thought replacement and modifications such as visual aids, modelling and smaller groups based on this review. Future research is warranted to investigate whether individuals with more severe ID can benefit from CBT, as well as further exploring what are the necessary components and modifications.

Intrinsic thermalization of the honeycomb optical lattice.

Ultracold atoms confined to optical lattices provide a platform for simulation of phenomena not readily accessible in condensed matter and chemical systems. One area of growing interest is the mechanism by which isolated condensed matter systems can thermalize. The mechanism for thermalization of quantum systems has been directly linked to a transition to chaos in their classical counterpart. Here we show that the broken spatial symmetries of the honeycomb optical lattice leads to a transition to chaos in the single-particle dynamics which, in turn, causes mixing of the energy bands of the quantum honeycomb lattice. For systems with single-particle chaos, "soft" interactions between atoms can cause the system to thermalize (achieve a Fermi-Dirac distribution for fermions or a Bose-Einstein distribution for bosons).

Long-term HIV and tuberculosis outcomes in patients hospitalised with severe cutaneous adverse reactions.

Background: Treatment-limiting severe cutaneous adverse reactions (SCAR) occur more commonly amongst persons with HIV-associated tuberculosis (TB). The impact of SCAR on long-term HIV/TB outcomes is unknown. Methods: Patients with TB and/or HIV admitted to Groote Schuur Hospital, Cape Town, South Africa with SCAR between 1/10/2018 and 30/09/2021 were eligible. Follow-up data was collected for 6- and 12-month outcomes: mortality, TB and antiretroviral therapy (ART) regimen changes, TB treatment completion, and CD4 count recovery. Results: Forty-eight SCAR admissions included: 34, 11, and 3 HIV-associated TB, HIV-only and TB-only patients with 32, 13 and 3 cases of drug reaction with eosinophilia and systemic symptoms, Stevens-Johnson syndrome/toxic epidermal necrolysis and generalised bullous fixed-drug eruption respectively. Nine (19%), all HIV-positive (eight co-infected with TB), were deceased at 12-months, and 12(25%) were lost to follow-up. Amongst TB-SCAR patients, seven (21%) were discharged on all four first-line anti-TB drugs (FLTD), while 12(33%) had regimens with no FLTDs; 24/37(65%) completed TB treatment. Amongst HIV-SCAR patients, 10/31(32%) changed ART regimen. If retained in care (24/36), median (IQR) CD4 counts increased at 12-months post-SCAR (115(62-175) vs. 319(134-439) cells/uL). Conclusion: SCAR admission amongst patients with HIV-associated TB results in substantial mortality, and considerable treatment complexity. However, if retained in care, TB regimens are successfully completed, and immune recovery is good despite SCAR.

National Joint Registry recorded untoward intraoperative events during primary total hip arthroplasty: an investigation into the data accuracy, causal mechanisms and attributability.

INTRODUCTION: Untoward intraoperative events occurring during total hip arthroplasty are recorded by the National Joint Registry through Minimum Data Set (MDS) forms. This data may be used to assess the safety of implants. The aim of this study is to evaluate the accuracy of the untoward intraoperative events, assess the mechanism and ascertain whether these events were attributable to the implants inserted. METHODS: A retrospective analysis was undertaken of primary total hip arthroplasties performed between 2005 and 2018 in which an untoward intraoperative event was recorded. RESULTS: Of 12,802 primary hip replacements, 64 patients (0.5%) had untoward intraoperative events recorded on the MDS form. In 43 of 64 cases, the intraoperative untoward event recorded on the MDS form matched the operation notes. Among these 43 cases, in 30 (69%) patients the intraoperative event could be attributed to the implant recorded. In the remaining 13 (31%) cases, the events recorded could not be attributed to the implant. In six cases, the untoward events were attributed to implants used to manage the events rather than the implants which caused them. In seven cases, the untoward events were related to surgical technique rather than to the implant or instrumentation. CONCLUSIONS: Our analysis highlights that all untoward intraoperative events recorded on the NJR form are not implant related or attributable to the implant inserted. Provision should be made on the MDS form to clarify whether a particular untoward intraoperative event was related to the implant inserted.

Polarity of the CRISPR roadblock to transcription.

CRISPR (clustered regularly interspaced short palindromic repeats) utility relies on a stable Cas effector complex binding to its target site. However, a Cas complex bound to DNA may be removed by motor proteins carrying out host processes and the mechanism governing this removal remains unclear. Intriguingly, during CRISPR interference, RNA polymerase (RNAP) progression is only fully blocked by a bound endonuclease-deficient Cas (dCas) from the protospacer adjacent motif (PAM)-proximal side. By mapping dCas-DNA interactions at high resolution, we discovered that the collapse of the dCas R-loop allows Escherichia coli RNAP read-through from the PAM-distal side for both Sp-dCas9 and As-dCas12a. This finding is not unique to RNAP and holds for the Mfd translocase. This mechanistic understanding allowed us to modulate the dCas R-loop stability by modifying the guide RNAs. This work highlights the importance of the R-loop in dCas-binding stability and provides valuable mechanistic insights for broad applications of CRISPR technology.

Northward Expansion of Amblyomma americanum (Acari: Ixodidae) into Southwestern Michigan.

Amblyomma americanum (Linnaeus) (Acari: Ixodidae) (lone star tick) is an aggressive, generalist parasite that vectors numerous important human and animal pathogens. In recent decades its geographic range has expanded northwards from endemic regions in the southeastern and southcentral United States. In 2019 five questing A. americanum ticks, comprising two life stages were detected at one site in southwestern Michigan, satisfying one CDC criterium for an established population for the first time in recent history in the state. To better characterize the extent of emerging A. americanum, we conducted active surveillance (i.e., drag sampling) in summer 2020 throughout Michigan's southern counties and detected one adult A. americanum from each of six widespread sites, including where they had been detected in 2019. A larger established population was identified at another site in Berrien County, which yielded 691 A. americanum comprising three life stages, and questing phenologies here were similar to that reported for other endemic regions. Statewide surveillance in 2021 revealed no A. americanum outside of Berrien County, but establishment criteria were met again at the two sites where established populations were first detected respectively in 2019 and 2020. These observations may represent the successful invasion of A. americanum into Michigan. Data from passive (1999-2020) and active surveillance (2004-2021) efforts, including a domestic animal sentinel program (2015-2018), are reported to provide context for this nascent invasion. Continued active surveillance is needed to help inform the public, medical professionals, and public health officials of the health risks associated with this vector.

Vertebral Trabecular Bone Mechanical Properties Vary Among Functional Groups of Cetaceans.

Since their appearance in the fossil record 34 million years ago, modern cetaceans (dolphins, whales, and porpoises) have radiated into diverse habitats circumglobally, developing vast phenotypic variations among species. Traits such as skeletal morphology and ecologically linked behaviors denote swimming activity; trade-offs in flexibility and rigidity along the vertebral column determine patterns of caudal oscillation. Here, we categorized 10 species of cetaceans (families Delphinidae and Kogiidae; N = 21 animals) into functional groups based on vertebral centra morphology, swimming speeds, diving behavior, and inferred swimming patterns. We quantified trabecular bone mechanical properties (yield strength, apparent stiffness, and resilience) among functional groups and regions of the vertebral column (thoracic, lumbar, and caudal). We extracted 6 mm3 samples from vertebral bodies and tested them in compression in 3 orientations (rostrocaudal, dorsoventral, and mediolateral) at 2 mm min-1. Overall, bone from the pre-fluke/fluke boundary had the greatest yield strength and resilience, indicating that the greatest forces are translated to the tail during caudal oscillatory swimming. Group 1, composed of 5 shallow-diving delphinid species, had the greatest vertebral trabecular bone yield strength, apparent stiffness, and resilience of all functional groups. Conversely, Group 3, composed of 2 deep-diving kogiid species, had the least strong, stiff, and resilient bone, while Group 2 (3 deep-diving delphinid species) exhibited intermediate values. These data suggest that species that incorporate prolonged glides during deep descents in the water column actively swim less, and place relatively smaller loads on their vertebral columns, compared with species that execute shallower dives. We found that cetacean vertebral trabecular bone properties differed from the properties of terrestrial mammals; for every given bone strength, cetacean bone was less stiff by comparison. This relative lack of material rigidity within vertebral bone may be attributed to the non-weight-bearing locomotor modes of fully aquatic mammals.

Desde su aparición en el registro fósil 34 Mya, los cetáceos modernos (delfines, ballenas y marsopas) se han radiado a diversos hábitats a nivel mundial, desarrollando vastas variaciones fenotípicas entre especies. Rasgos como la morfología esquelética y los comportamientos vinculados ecológicamente denotan actividad de natación; las compensaciones en flexibilidad y rigidez a lo largo de la columna vertebral determinan los patrones de oscilación caudal. Aquí, categorizamos 10 especies de cetáceos (familias Delphinidae y Kogiidae; N = 21 animales) en grupos funcionales basados ​​en la morfología de los centros vertebrales, velocidades de nado, comportamiento de buceo y patrones de nado inferidos. Cuantificamos las propiedades mecánicas del hueso trabecular (límite elástico, rigidez aparente y resiliencia) entre grupos funcionales y regiones de la columna vertebral (torácica, lumbar y caudal). Extrajimos muestras de 6 mm3 de cuerpos vertebrales y las probamos en compresión en tres orientaciones (rostrocaudal, dorsoventral y mediolateral) a 2 mm min-1. En general, el hueso de la platija tuvo el mayor límite elástico y resiliencia, lo que indica que las mayores fuerzas se trasladan a la cola durante la natación oscilatoria caudal. El grupo 1, compuesto por cinco especies de delfínidos de buceo superficial, tuvo el mayor límite elástico del hueso trabecular vertebral, rigidez aparente y resiliencia de todos los grupos funcionales. Por el contrario, el Grupo 3, compuesto por dos especies de kogiidos de inmersión profunda, tenía el hueso menos fuerte, rígido y resistente, mientras que el Grupo 2 (tres especies de delfínidos de inmersión profunda) exhibió valores intermedios. Estos datos sugieren que las especies que incorporan deslizamientos prolongados durante descensos profundos en la columna de agua nadan menos activamente y colocan cargas relativamente más pequeñas en sus columnas vertebrales, en comparación con las especies que realizan inmersiones menos profundas. Encontramos que las propiedades del hueso trabecular vertebral de los cetáceos diferían de las propiedades de los mamíferos terrestres; por cada resistencia ósea dada, el hueso de cetáceo era menos rígido en comparación. Esta relativa falta de rigidez del material dentro del hueso vertebral puede atribuirse a los modos locomotores que no soportan peso de los mamíferos totalmente acuáticos.

Resonator nanophotonic standing-wave array trap for single-molecule manipulation and measurement.

Nanophotonic tweezers represent emerging platforms with significant potential for parallel manipulation and measurements of single biological molecules on-chip. However, trapping force generation represents a substantial obstacle for their broader utility. Here, we present a resonator nanophotonic standing-wave array trap (resonator-nSWAT) that demonstrates significant force enhancement. This platform integrates a critically-coupled resonator design to the nSWAT and incorporates a novel trap reset scheme. The nSWAT can now perform standard single-molecule experiments, including stretching DNA molecules to measure their force-extension relations, unzipping DNA molecules, and disrupting and mapping protein-DNA interactions. These experiments have realized trapping forces on the order of 20 pN while demonstrating base-pair resolution with measurements performed on multiple molecules in parallel. Thus, the resonator-nSWAT platform now meets the benchmarks of a table-top precision optical trapping instrument in terms of force generation and resolution. This represents the first demonstration of a nanophotonic platform for such single-molecule experiments.

Cognitive profile of young children with Williams syndrome.

BACKGROUND: There is very little research on the cognitive profile of young children with Williams syndrome (WS). METHOD: The present study utilised the Differential Ability Scales - Second Edition to examine the early cognitive abilities of 22 young children with WS (aged 3.98 to 7.70 years, 10 male and 12 female participants). RESULTS: Overall, IQ ranged from 38 (severely impaired) to 81.00 (low average). Consistent with Mervis et al. who looked at an older sample, over half (59.08%) of our young WS sample showed a significant and abnormal weakness in spatial ability relative to verbal ability. Moreover, 81.82% showed a significant and clinically unusual weakness in spatial ability relative to nonverbal reasoning ability. At the subtest level, only 4.55% of our sample showed a significant strength in naming vocabulary compared with verbal comprehension, while 13.64% showed a significant weakness in naming vocabulary relative to verbal comprehension. CONCLUSIONS: The results of the present study show cognitive heterogeneity, consistent with the literature on older children and adults with WS. There were variable levels of intellect and variable patterns of cognitive strength and weakness across both index and subtest scores. Findings highlight the need for individual assessment and management of young children with WS but also indicate that for the majority of WS individuals spatial skills are indeed an area of significant and abnormal weakness and should be a focus for early intervention.

Predator-Prey Interactions Examined Using Lionfish Spine Puncture Performance.

Puncture mechanics can be studied in the context of predator-prey interactions and provide bioinspiration for puncture tools and puncture-resistant materials. Lionfish have a passive puncture system where venomous spines (dorsal, anal, and pelvic), the tool, may embed into a predator's skin, the target material, during an encounter. To examine predator-prey interactions, we quantified the puncture performance of red lionfish, Pterois volitans, spines in buccal skin from two potential predators and porcine skin, a biological model for human skin. We punctured dorsal, anal, and pelvic lionfish spines into three regions of buccal skin from the black grouper (Mycteroperca bonaci) and the blacktip shark (Carcharhinus limbatus), and we examined spine macro-damage (visible without a microscope) post puncture. Lionfish spines were more effective, based on lower forces measured and less damage incurred, at puncturing buccal skin of groupers compared to sharks. Anal and dorsal spines incurred the most macro-damage during successful fish skin puncture trials, while pelvic spines did not incur any macro-damage. Lionfish spines were not damaged during porcine skin testing. Anal spines required the highest forces, while pelvic spines required intermediate forces to puncture fish skin. Dorsal spines required the lowest forces to puncture fish skins, but often incurred macro-damage of bent tips. All spine regions required similar forces to puncture porcine skin. These data suggest that lionfish spines may be more effective at puncturing humans such as divers than potential fish predators. These results emphasize that puncture performance is ultimately determined by both the puncture tool and target material choice. Lionfish puncture performance varies among spine region, when taking into account both the puncture force and damage sustained by the spine.

Development of a bio-optical model for the Barents Sea to quantitatively link glider and satellite observations.

A bio-optical model for the Barents Sea is determined from a set of in situ observations of inherent optical properties (IOPs) and associated biogeochemical analyses. The bio-optical model provides a pathway to convert commonly measured parameters from glider-borne sensors (CTD, optical triplet sensor-chlorophyll and CDOM fluorescence, backscattering coefficients) to bulk spectral IOPs (absorption, attenuation and backscattering). IOPs derived from glider observations are subsequently used to estimate remote sensing reflectance spectra that compare well with coincident satellite observations, providing independent validation of the general applicability of the bio-optical model. Various challenges in the generation of a robust bio-optical model involving dealing with partial and limited quantity datasets and the interpretation of data from the optical triplet sensor are discussed. Establishing this quantitative link between glider-borne and satellite-borne data sources is an important step in integrating these data streams and has wide applicability for current and future integrated autonomous observation systems. This article is part of the theme issue 'The changing Arctic Ocean: consequences for biological communities, biogeochemical processes and ecosystem functioning'.