Case Study of Severe Accidental Hypothermia with Rapid Cooling, Preserved Shivering, and Consciousness with a Summary of Similar Case Reports.

We describe a case of severe accidental hypothermia of a kayaker with preserved consciousness and shivering despite a rectal temperature of 22.9°C following a 50-min immersion in 3°C water with an estimated core temperature cooling rate of 10.6°C/h. Based on survival at sea prediction curves and cooling rates from physiology studies, cold water (eg, 0-5°C) immersion is expected to drop core temperature by 2 to 4°C/h. Furthermore, accidental hypothermia classification systems predict that severely hypothermic patients are usually unconscious and not shivering. The patient in this report rewarmed rapidly at 3.6°C/h with only minimally invasive measures and was discharged fully neurologically intact. In 41 similar cases of survival in moderate to severe hypothermia with core temperatures <32°C due to cold water immersion, cold air exposure, or avalanche burial, mean cooling rates were 4.3±3.3°C/h (range 0.4-10.6°C/h). Including the current patient, shivering was reported in only four cases. We found several other cases of rewarming from moderate to severe hypothermia with only minimally invasive measures. The current and summarized cases lead us to conclude that patients may be at risk of severe hypothermia in <60 min of cold water immersion and that it is possible for severely hypothermic patients to have preserved consciousness, close to normal vital signs, and shivering. Minimally invasive or noninvasive rewarming of patients with severe hypothermia is also possible, especially in those who continue to shiver. Hypothermia management should not necessarily be guided by classification systems or core temperature alone but rather by a careful consideration of the entire clinical picture.

Cost Effectiveness of Definitive Treatment Strategies for Autonomously Functioning Thyroid Nodules.

OBJECTIVE: Autonomously functioning thyroid nodules (AFTN) can be treated with antithyroid drugs, radioactive iodine (RAI), thyroid lobectomy or radiofrequency ablation (RFA). Although surgery is most definitive, some patients require lifelong hormone supplementation. RFA avoids this sequela, but its efficacy depends on nodule size. This study aims to compare the relative cost-effectiveness of RAI, RFA and lobectomy for treatment of AFTNs. STUDY DESIGN: A Markov analysis model was created to simulate clinical outcomes, costs and utilities for three AFTN treatments: (1) thyroid lobectomy, (2) RAI, and (3) RFA. PATIENTS: This mathematical model was created using published literature and modeling. MEASUREMENTS: Transition probabilities, utilities and costs were extracted from published literature, Medicare, and RedBook. The willingness to pay threshold was set to $100,000 per quality-adjusted life year. The model simulated 2-year outcomes, reflecting RFA literature. Sensitivity analyses were conducted to account for uncertainty in model variables. RESULTS: In the base model, RAI dominated both lobectomy and RFA, with lower estimated cost ($2000 vs. $9452 and $10,087) and higher cumulative utility (1.89 vs. 1.82 and 1.78 quality-adjusted life years). One-way sensitivity analyses demonstrated that relative cost-effectiveness between surgery and RFA was driven by the probability of euthyroidism after RFA and hypothyroidism after lobectomy. RFA becomes more cost-effective than surgery if the rate of euthyroidism after ablation is higher than 69% (baseline 54%). CONCLUSION: Based on published data, RAI is most cost-effective in treating most AFTN. Surgery is more cost-effective than RFA in most scenarios, but RFA may be more resource-efficient for smaller nodules with a high likelihood of complete treatment.

Therapeutic antibodies in oncology: an immunopharmacological overview.

The biotechnological development of monoclonal antibodies and their immunotherapeutic use in oncology have grown exponentially in the last decade, becoming the first-line therapy for some types of cancer. Their mechanism of action is based on the ability to regulate the immune system or by interacting with targets that are either overexpressed in tumor cells, released into the extracellular milieu or involved in processes that favor tumor growth. In addition, the intrinsic characteristics of each subclass of antibodies provide specific effector functions against the tumor by activating antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, and antibody-dependent cellular phagocytosis, among other mechanisms. The rational design and engineering of monoclonal antibodies have improved their pharmacokinetic and pharmacodynamic features, thus optimizing the therapeutic regimens administered to cancer patients and improving their clinical outcomes. The selection of the immunoglobulin G subclass, modifications to its crystallizable region (Fc), and conjugation of radioactive substances or antineoplastic drugs may all improve the antitumor effects of therapeutic antibodies. This review aims to provide insights into the immunological and pharmacological aspects of therapeutic antibodies used in oncology, with a rational approach at molecular modifications that can be introduced into these biological tools, improving their efficacy in the treatment of cancer.

Prokaryotic communities profiling of Indonesian hot springs using long-read Oxford Nanopore sequencing.

OBJECTIVES: Indonesia's location at the convergence of multiple tectonic plates results in a unique geomorphological feature with abundant hot springs. This study pioneers the metagenomic exploration of Indonesian hot springs, harbouring unique life forms despite high temperatures. The microbial community of hot springs is taxonomically versatile and biotechnologically valuable. 16s rRNA amplicon sequencing of the metagenome is a viable option for the microbiome investigation. This study utilized Oxford Nanopore's long-read 16 S rRNA sequencing for enhanced species identification, improved detection of rare members, and a more detailed community composition profile. DATA DESCRIPTION: Water samples were taken from three hot springs of the Bali, Indonesia (i) Angseri, 8.362503 S, 115.133452 E; (ii) Banjar, 8.210270 S, 114.967063 E; and (iii) Batur, 8.228806 S, 115.404829 E. BioLit Genomic DNA Extraction Kit (SRL, Mumbai, India) was used to isolate DNA from water samples. The quantity and quality of the DNA were determined using a NanoDrop™ spectrophotometer and a Qubit fluorometer (Thermo Fisher Scientific, USA). The library was created using Oxford Nanopore Technology kits, and the sequencing was done using Oxford Nanopore's GridION platform. All sequencing data was obtained in FASTQ files and filtered using NanoFilt software. This dataset is valuable for searching novel bacteria diversity and their existence.

A cross-sectional study of associations between the 13C-sucrose breath test, the lactulose rhamnose assay, and growth in children at high risk of environmental enteropathy.

BACKGROUND: Environmental enteropathy' (EE) is common among children who are highly exposed to enteric pathogens in low-resource settings. We optimised and validated a stable isotope-based breath test of intestinal sucrase activity (13C-SBT) as a non-invasive test of carbohydrate digestion and metabolism. OBJECTIVES: The primary objective of this study was to assess the relationship between the 13C-SBT and the lactulose/rhamnose ratio (LR) and growth in children. Secondary objectives were to assess the relationship between the 13C-SBT and additional biomarkers of EE. We also characterised the relationship between the 13C-SBT and child sex anddietary diversity, and household socioeconomic status and food security. METHODS: In this cross-sectional study, 12-to-15-month-old children were recruited in Bangladesh, India, Kenya, and Peru. Children were assessed with a 4-hour 13C-SBT and a 90-minute LR test. Plasma was collected for the determination of citrulline and the kynurenine/tryptophan ratio. Length and weight were measured, and other variables were assessed through questionnaires. For a subset of children, anthropometry was re-measured after three months. inear regression was used to examine associations corresponding to each objective. RESULTS: Three sites generated 13C-SBT breath curves that enabled pooled analysis. Differences in 13C-SBT breath curves, LR ratios, and other EE biomarkers were observed between sites. No associations were observed for 13C-SBT summary measures and LR, or child growth (e.g., association between LR and cumulative percent dose recovered at 90 minutes (cPDR90): -0.39, 95%CI: -1.79, 0.70). Length-for-age and weight-for-age were positively associated with the time to 50% of dose recovered (T50) (0.05, 95%CI: 0.01, 0.09, and 0.05, 95%CI: 0.02, 0.07, respectively), and dietary diversity was associated with T50 and cPDR90(-0.10, 95%CI: -0.18, -0.02 and 2.67, 95%CI: 0.47, 4.88, respectively). CONCLUSIONS: In children at risk of EE there were no associations between the 13C-SBT, LR or other EE biomarkers encompassing different pathophysiological domains of EE. TRIAL REGISTRY: https://clinicaltrials.gov/study/NCT04109352.

Is there dietary macronutrient malabsorption in children with environmental enteropathy?

Assessing the digestive and absorptive capacity of the gastro-intestinal tract (GIT) using minimally- or non-invasive methods, particularly in children, has been difficult owing to the complex physiology and variability in functional measurements. However, measuring GIT function is increasingly important with the emerging relevance of childhood environmental enteropathy (EE) as a mediating factor in linear growth faltering, severe acute malnutrition, poor oral vaccine uptake and impaired cognition. In EE, sub-optimal nutrient digestion and absorption (malabsorption) forms the critical link to the conditions mentioned above. The present narrative review discusses probable mechanisms that can cause malabsorption of macronutrients, along with mechanistic and experimental evidence, in children (if not, in adults) with EE. The strengths and limitations of the human experimental studies are examined in relation to a battery of existing and potential tests that are used to measure malabsorption. From the available studies conducted in children, lactose and fat malabsorption are more likely to occur in EE. Breath tests (non-invasive) measuring carbohydrate (13C-starch/sucrose/lactose), fat (13C-mixed triglyceride) and dipeptide (benzoyl-L-tyrosyl-L-1-13C-alanine) malabsorption with modifications to the existing protocols seem suitable for use in children with EE. Future research should focus on understanding the degree of macronutrient malabsorption using these tests, in different settings, and link them to functional outcomes (such as growth, muscle strength, cognition).

White shark comparison reveals a slender body for the extinct megatooth shark, Otodus megalodon (Lamniformes: Otodontidae).

The megatooth shark, †Otodus megalodon, which likely reached at least 15 m in total length, is an iconic extinct shark represented primarily by its gigantic teeth in the Neogene fossil record. As one of the largest marine carnivores to ever exist, understanding the biology, evolution, and extinction of †O. megalodon is important because it had a significant impact on the ecology and evolution of marine ecosystems that shaped the present-day oceans. Some attempts inferring the body form of †O. megalodon have been carried out, but they are all speculative due to the lack of any complete skeleton. Here we highlight the fact that the previous total body length estimated from vertebral diameters of the extant white shark (Carcharodon carcharias) for an †O. megalodon individual represented by an incomplete vertebral column is much shorter than the sum of anteroposterior lengths of those fossil vertebrae. This factual evidence indicates that †O. megalodon had an elongated body relative to the body of the modern white shark. Although its exact body form remains unknown, this proposition represents the most parsimonious empirical evidence, which is a significant step towards deciphering the body form of †O. megalodon.

Toward diversification of acute stressors and precision stress research: A stage 2 Registered Report validating a reward-salient stress task in emerging adults.

Stress is one of, if not the, most ubiquitously studied risk factor across the health sciences. This is unlikely to change given that the primary drivers of mortality and disability are chronic, stress-mediated illnesses (often highly comorbid with psychopathology). We argue that an important limitation of stress research is the consistency with which the Trier Social Stress Test is used when the research questions are not specific to social stress. We advocate for precision stress research using qualitatively different stressors to facilitate exploration of how different types of stressors might differentially impact health outcomes, including psychopathology. This registered report validates a reward-salient stress task (a modified Anger Incentive Delay Task) in a sample of 101 emerging adults, over half of whom reported clinically relevant anxiety, hypo/mania, depression, and/or suicidal ideation, who participated in a study between 2020 and 2022. This task involves teaching participants a game where they can win money. Part way through, the "goal frustration" condition changes the rules such that correct responses to trials with anticipatory stimuli indicating the possibility to win money actually lose money on 56% of trials despite visual feedback indicating that responses were successful. Results consistently indicated that the Anger Incentive Delay Task successfully reduced positive emotions and motivation and increased negative emotions. The magnitude of these responses was predicted by individual differences in reward and punishment sensitivity. Given the breadth of psychopathologies that share both (a) stress and (b) reward and punishment sensitivity as risk factors, a reward-salient acute stress task is an important tool for precision psychopathology research. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Golgi-localized Ring Finger Protein 121 is necessary for MYCN-driven neuroblastoma tumorigenesis.

MYCN amplification predicts poor prognosis in childhood neuroblastoma. To identify MYCN oncogenic signal dependencies we performed N-ethyl-N-nitrosourea (ENU) mutagenesis on the germline of neuroblastoma-prone TH-MYCN transgenic mice to generate founders which had lost tumorigenesis. Sequencing of the mutant mouse genomes identified the Ring Finger Protein 121 (RNF121WT) gene mutated to RNFM158R associated with heritable loss of tumorigenicity. While the RNF121WT protein localised predominantly to the cis-Golgi Complex, the RNF121M158R mutation in Helix 4 of its transmembrane domain caused reduced RNF121 protein stability and absent Golgi localisation. RNF121WT expression markedly increased during TH-MYCN tumorigenesis, whereas hemizygous RNF121WT gene deletion reduced TH-MYCN tumorigenicity. The RNF121WT-enhanced growth of MYCN-amplified neuroblastoma cells depended on RNF121WT transmembrane Helix 5. RNF121WT directly bound MYCN protein and enhanced its stability. High RNF121 mRNA expression associated with poor prognosis in human neuroblastoma tissues and another MYC-driven malignancy, laryngeal cancer. RNF121 is thus an essential oncogenic cofactor for MYCN and a target for drug development.

Development of an Automated Triage System for Longstanding Dizzy Patients Using Artificial Intelligence.

Objective: To report the first steps of a project to automate and optimize scheduling of multidisciplinary consultations for patients with longstanding dizziness utilizing artificial intelligence. Study Design: Retrospective case review. Setting: Quaternary referral center. Methods: A previsit self-report questionnaire was developed to query patients about their complaints of longstanding dizziness. We convened an expert panel of clinicians to review diagnostic outcomes for 98 patients and used a consensus approach to retrospectively determine what would have been the ideal appointments based on the patient's final diagnoses. These results were then compared retrospectively to the actual patient schedules. From these data, a machine learning algorithm was trained and validated to automate the triage process. Results: Compared with the ideal itineraries determined retrospectively with our expert panel, visits scheduled by the triage clinicians showed a mean concordance of 70%, and our machine learning algorithm triage showed a mean concordance of 79%. Conclusion: Manual triage by clinicians for dizzy patients is a time-consuming and costly process. The formulated first-generation automated triage algorithm achieved similar results to clinicians when triaging dizzy patients using data obtained directly from an online previsit questionnaire.

Quantitative insights into the mechanism of proton conduction and selectivity for the human voltage-gated proton channel Hv1.

Human voltage-gated proton (hHv1) channels are crucial for regulating essential biological processes such as immune cell respiratory burst, sperm capacitation, and cancer cell migration. Despite the significant concentration difference between protons and other ions in physiological conditions, hHv1 demonstrates remarkable proton selectivity. Our calculations of single-proton, cation, and anion permeation free energy profiles quantitatively demonstrate that the proton selectivity of the wild-type channel originates from its strong proton affinity via the titration of the key residues D112 and D174, although the channel imposes similar kinetic blocking effects for protons compared to other ions. A two-proton knock-on model is proposed to mathematically explain the electrophysiological measurements of the pH-dependent proton conductance in the conductive state. Moreover, it is shown that the anion selectivity of the D112N mutant channel is tied to impaired proton transport and substantial anion leakage.

Epidural Spinal Cord Recordings (ESRs): sources of neural-appearing artifact in stimulation evoked compound action potentials.

Evoked compound action potentials (ECAPs) measured during epidural spinal cord stimulation (SCS) can help elucidate fundamental mechanisms for the treatment of pain and inform closed-loop control of SCS. Previous studies have used ECAPs to characterize neural responses to various neuromodulation therapies and have demonstrated that ECAPs are highly prone to multiple sources of artifact, including post-stimulus pulse capacitive artifact, electromyography (EMG) bleed-through, and motion artifact. However, a thorough characterization has yet to be performed for how these sources of artifact may contaminate recordings within the temporal window commonly used to determine activation of A-beta fibers in a large animal model. We characterized sources of artifacts that can contaminate the recording of ECAPs in an epidural SCS swine model using the Abbott Octrode™ lead. Spinal ECAP recordings can be contaminated by capacitive artifact, short latency EMG from nearby muscles of the back, and motion artifact. The capacitive artifact can appear nearly identical in duration and waveshape to evoked A-beta responses. EMG bleed-through can have phase shifts across the electrode array, similar to the phase shift anticipated by propagation of an evoked A-beta fiber response. The short latency EMG is often evident at currents similar to those needed to activate A-beta fibers associated with the treatment of pain. Changes in CSF between the cord and dura, and motion induced during breathing created a cyclic oscillation in all evoked components of recorded ECAPs. Controls must be implemented to separate neural signal from sources of artifact in SCS ECAPs. We suggest experimental procedures and reporting requirements necessary to disambiguate underlying neural response from these confounds. These data are important to better understand the framework for recorded ESRs, with components such as ECAPs, EMG, and artifacts, and have important implications for closed-loop control algorithms to account for transient motion such as postural changes and cough.

Y and Mitochondrial Chromosomes in the Heterogeneous Stock Rat Population.

Genome-wide association studies typically evaluate the autosomes and sometimes the X Chromosome, but seldom consider the Y or mitochondrial Chromosomes. We genotyped the Y and mitochondrial Chromosomes in heterogeneous stock rats (Rattus norvegicus), an outbred population created from eight inbred strains. We identified 8 distinct Y and 4 distinct mitochondrial Chromosomes among the 8 founders. However, only two types of each nonrecombinant chromosome were observed in our modern heterogeneous stock rat population (generations 81-97). Despite the relatively large sample size, there were virtually no significant associations for behavioral, physiological, metabolome, or microbiome traits after correcting for multiple comparisons. However, both Y and mitochondrial Chromosomes were strongly associated with expression of a few genes located on those chromosomes, which provided a positive control. Our results suggest that within modern heterogeneous stock rats there are no Y and mitochondrial Chromosomes differences that strongly influence behavioral or physiological traits. These results do not address other ancestral Y and mitochondrial Chromosomes that do not appear in modern heterogeneous stock rats, nor do they address effects that may exist in other rat populations, or in other species.

miR-495 promotes intestinal epithelial cell apoptosis through downregulation of Sphingosine-1-phosphate.

Many pathological conditions lead to defects in intestinal epithelial integrity and loss of barrier function; Sphingosine-1-phosphate (S1P) has been shown to augment intestinal barrier integrity, though the exact mechanisms are not completely understood. We have previously shown that overexpression of Sphingosine Kinase 1 (SphK1), the rate limiting enzyme for S1P synthesis, significantly increased S1P production and cell proliferation. Here we show that microRNA 495 (miR-495) upregulation led to decreased levels of SphK1 resultant from a direct effect at the SphK1 mRNA. Increasing expression of miR-495 in intestinal epithelial cells resulted in decreased proliferation and increased susceptibility to apoptosis. Transgenic expression of miR-495 inhibited mucosal growth, as well as decreased proliferation in the crypts. The intestinal villi also expressed decreased levels of barrier proteins and exaggerated damage upon exposure to cecal ligation-puncture. These results implicate miR-495 as a critical negative regulator of intestinal epithelial protection and proliferation through direct regulation of SphK1, the rate limiting enzyme critical for production of S1P.

Building consensus on clinical outcome assessments for BCI devices. A summary of the 10th BCI society meeting 2023 workshop.

The 10th International Brain Computer Interface (BCI) Society Meeting, 'Balancing Innovation and Translation', was held from the 6th to 9th of June 2023 in Brussels, Belgium. This report provides a summary of the workshop 'Building Consensus on Clinical Outcome Assessments (COAs) for BCI Devices'. This workshop was intended to give participants an overview of the current state of BCI, future opportunities, and how different countries and regions provide regulatory oversight to support the BCI community to develop safe and effective devices for patients. Five presentations and a panel discussion including representatives from regulators, industry, and clinical research stakeholders focused on how various stakeholders and the BCI community might best work together to ensure studies provide data that is useful for evaluating safety and effectiveness, including reaching consensus on clinical outcome assessments (COAs) that represent clinically meaningful benefits and support regulatory and payor requirements. This report focuses on the regulatory and reimbursement requirements for medical devices and how to best measure safety and effectiveness and summarizes the presentations from five experts and the discussion between the panel and the audience. Consensus was reached on the following items specifically related to BCI: (i) the importance of and need for a new generation of COAs, (ii) the challenges facing the development of appropriate clinical outcome assessments, and (iii) that improvements in COAs should demonstrate obvious and clinically meaningful benefit(s). There was discussion on: (i) clinical trial design for BCIs and (ii) considerations for payor reimbursement and other funding. Whilst the importance of building community consensus on COAs was apparent, further collaboration will be required to reach consensus on which specific current and/or novel COAs could be used for the BCI field to evolve from research to market.

Loss of synovial tissue macrophage homeostasis precedes rheumatoid arthritis clinical onset.

This study performed an in-depth investigation into the myeloid cellular landscape in the synovium of patients with rheumatoid arthritis (RA), "individuals at risk" of RA, and healthy controls (HC). Flow cytometric analysis demonstrated the presence of a CD40-expressing CD206+CD163+ macrophage population dominating the inflamed RA synovium, associated with disease activity and treatment response. In-depth RNA sequencing and metabolic analysis demonstrated that this macrophage population is transcriptionally distinct, displaying unique inflammatory and tissue-resident gene signatures, has a stable bioenergetic profile, and regulates stromal cell responses. Single-cell RNA sequencing profiling of 67,908 RA and HC synovial tissue cells identified nine transcriptionally distinct macrophage clusters. IL-1B+CCL20+ and SPP1+MT2A+ are the principal macrophage clusters in RA synovium, displaying heightened CD40 gene expression, capable of shaping stromal cell responses, and are importantly enriched before disease onset. Combined, these findings identify the presence of an early pathogenic myeloid signature that shapes the RA joint microenvironment and represents a unique opportunity for early diagnosis and therapeutic intervention.

Word Choice and the Patient Encounter.

This JAMA Insights in the Communicating Medicine series explores how differences in word choice can affect both visit interactions and visit outcomes in patient encounters.

Objective and subjective measurement of sleep in people who use substances: Emerging evidence and recommendations from a systematic review.

People who use substances commonly experience sleep disruptions, affecting the regulation of physical and mental health, and presenting a significant barrier to treatment success. Sleep impairments are noted in all phases of substance use; however, differences between subjective versus objective methods used to measure sleep quality have been reported. While polysomnography is the gold-standard for sleep measurement, recent advances in actigraphy may help address the discordance between subjective and objective sleep reports. This systematic review examined emerging evidence (2016-present) for sleep impairment in people who use substances, with the twofold goal of: (1) identifying whether sleep outcomes vary across substance type (alcohol, nicotine, cannabis, cocaine, methamphetamine and opioids); and (2) contrasting results from subjective and objective measures. While some differences between subjective and objective sleep were noted, there was overwhelming evidence of clinically relevant sleep impairment in people who use alcohol, nicotine, cocaine, methamphetamine and opioids, with less consistent results for cannabis. Gaps in the literature are identified and future recommendations are presented, including utilization of common methodological frameworks, identification of mechanisms, and closer examination of sleep across stages of substance use and the interconnection between sleep and return to use.