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Introduction There are no established methods to identify children with atypical diabetes for further study. We aimed to develop strategies to systematically ascertain cases of atypical pediatric diabetes using electronic medical records (EMR).Research design and methods We tested two strategies in a large pediatric hospital in the USA. Strategy 1: we designed a questionnaire to rule out typical diabetes and applied it to the EMR of 100 youth with diabetes. Strategy 2: we built three electronic queries to generate reports of three atypical pediatric diabetes phenotypes: unknown type, type 2 diabetes (T2D) diagnosed

Objective: To follow up patients with post-COVID-19 condition (PCC) 6 months after a multidisciplinary team assessment in specialist care regarding symptoms of pain, anxiety, depression, fatigue and cognition, level of activity, physical activity and sick leave. Methods: A prospective pilot study conducted in a clinical setting of patients (n = 22) with PCC referred from primary healthcare to a specialist clinic for a 2 day-multidisciplinary team assessment followed by a subsequent rehabilitation plan. Data were collected through questionnaires filled in prior to the team assessment and 6 months later. Results: Fifteen of the initial 22 patients participated in the follow-up. No statistically significant improvements were seen in any of the questionnaires after 6 months. However, 76.9% of the participants perceived the intervention as being helpful. This differed between the genders, where all the women 100% (n = 8) perceived it as being helpful, compared with 40% (n = 2) of the men (p = 0.012). Conclusions: Based on these findings, the benefit of a multidisciplinary team assessment of PCC is not fully convincing. However, since the participants themselves perceived the intervention as being helpful, the team assessment seems to be of some value. Further studies with larger populations would be of interest.

Abstract Global change research has largely focused on the effects of drought on forest dynamics while the importance of excessive rainfall that can cause waterlogged soils has largely been assessed in riparian zones or seasonally flooded sites. However, increased rainfall may also cause decreased growth and survival of tree species in lowland aseasonal tropical forests due to increased risk from potentially more extensive and frequent waterlogged soils. We used a Bayesian modelling approach on a tree dynamics dataset from 2004 to 2017 to test the concomitant effects of rainfall excess and deficit and dry period length on tree growth and survival across a network of experimentally planted trees in a primary aseasonal forest in Malaysia. Growth declined in 48% of the species and survival decreased in 92% of the species during periods of high rainfall while as little as 4% of species had decreased growth or survival with drought and long dry periods. Climate change is projected to cause more frequent and severe rainfall deficit and excess, and our results suggest increased rainfall may have stronger negative effects on aseasonal tropical forests than that of severe drought.

ImportanceRadiotherapy combined with androgen deprivation therapy (ADT) is a standard of care for high-risk prostate cancer. However, the interplay between radiotherapy dose and the required minimum duration of ADT is uncertain.ObjectiveTo determine the specific ADT duration threshold that provides a distant metastasis-free survival (DMFS) benefit in patients with high-risk prostate cancer receiving external beam radiotherapy (EBRT) or EBRT with a brachytherapy boost (EBRT+BT).Design, settings, and participantsThis was a cohort study of 3 cohorts assembled from a multicenter retrospective study (2000-2013); a post hoc analysis of the Randomized Androgen Deprivation and Radiotherapy 03/04 (RADAR; 2003-2007) randomized clinical trial (RCT); and a cross-trial comparison of the RADAR vs the Deprivación Androgénica y Radio Terapía (Androgen Deprivation and Radiation Therapy; DART) 01/05 RCT (2005-2010). In all, the study analyzed 1827 patients treated with EBRT and 1108 patients treated with EBRT+BT from the retrospective cohort; 181 treated with EBRT and 203 with EBRT+BT from RADAR; and 91 patients treated with EBRT from DART. The study was conducted from October 15, 2020, to July 1, 2021, and the data analyses, from January 5 to June 15, 2021.ExposuresHigh-dose EBRT or EBRT+BT for an ADT duration determined by patient-physician choice (retrospective) or by randomization (RCTs).Main outcomes and measuresThe primary outcome was DMFS; secondary outcome was overall survival (OS). Natural cubic spline analysis identified minimum thresholds (months).ResultsThis cohort study of 3 studies totaling 3410 men (mean age [SD], 68 [62-74] years; race and ethnicity not collected) with high-risk prostate cancer found a significant interaction between the treatment type (EBRT vs EBRT+BT) and ADT duration (binned to

NASA's Global Ecosystem Dynamics Investigation (GEDI) is collecting spaceborne full waveform lidar data with a primary science goal of producing accurate estimates of forest aboveground biomass density (AGBD). This paper presents the development of the models used to create GEDI's footprint-level (~25 m) AGBD (GEDI04_A) product, including a description of the datasets used and the procedure for final model selection. The data used to fit our models are from a compilation of globally distributed spatially and temporally coincident field and airborne lidar datasets, whereby we simulated GEDI-like waveforms from airborne lidar to build a calibration database. We used this database to expand the geographic extent of past waveform lidar studies, and divided the globe into four broad strata by Plant Functional Type (PFT) and six geographic regions. GEDI's waveform-to-biomass models take the form of parametric Ordinary Least Squares (OLS) models with simulated Relative Height (RH) metrics as predictor variables. From an exhaustive set of candidate models, we selected the best input predictor variables, and data transformations for each geographic stratum in the GEDI domain to produce a set of comprehensive predictive footprint-level models. We found that model selection frequently favored combinations of RH metrics at the 98th, 90th, 50th, and 10th height above ground-level percentiles (RH98, RH90, RH50, and RH10, respectively), but that inclusion of lower RH metrics (e.g. RH10) did not markedly improve model performance. Second, forced inclusion of RH98 in all models was important and did not degrade model performance, and the best performing models were parsimonious, typically having only 1-3 predictors. Third, stratification by geographic domain (PFT, geographic region) improved model performance in comparison to global models without stratification. Fourth, for the vast majority of strata, the best performing models were fit using square root transformation of field AGBD and/or height metrics. There was considerable variability in model performance across geographic strata, and areas with sparse training data and/or high AGBD values had the poorest performance. These models are used to produce global predictions of AGBD, but will be improved in the future as more and better training data become available.

Abstract Background Core symptoms in attention deficit hyperactivity disorder (ADHD) are inattention, impulsivity and hyperactivity. Many individuals with this disorder also have a sedentary lifestyle, co-morbid mental illness such as depressive and anxiety disorders, and reduced quality of life. People with ADHD often have impaired executive function, which among other things may include difficulty in time management and structuring of everyday life. Pharmacological treatment is often the first-line option, but non-pharmacological treatment is also available and is used in clinical settings. In children and adolescents with ADHD, physical exercise is used as a non-pharmacological treatment. However, the evidence for the effectiveness of exercise in adults is sparse. Objective To implement the START intervention (START = Stöd i Aktivitet, Rörelse och Träning [Support in activity, movement and exercise]) consisting of a 12-week, structured mixed exercise programme with or without a cognitive intervention, in adults with ADHD, and study whether it has an effect on core symptoms of ADHD as well as physical, cognitive, mental and everyday functioning compared with usual treatment. A secondary aim is to investigate the participants’ experiences of the intervention and its possible benefits, and to evaluate the cost-effectiveness of START compared with usual treatment. Methods This is a randomized controlled trial planned to be conducted in 120 adults with ADHD, aged 18–65. The intervention will be given as an add-on to standard care. Participants will be randomized to three groups. Group 1 will be given a physiotherapist-led mixed exercise programme for 12 weeks. Group 2 will receive the same intervention as group 1 with the addition of occupational therapist-led cognitive skills training. Group 3 will be the control group who will receive standard care only. The primary outcome will be reduction of ADHD symptoms measured using the World Health Organization (WHO) Adult ADHD Self-Report Scale (ASRS-v1.1), Clinical Global Impression-Severity scale (CGI-S) and CGI-Improvement scale (CGI-I). The effect will be measured within 1 week after the end of the intervention and 6 and 12 months later. Discussion Data collection began in March 2021. The final 12-month follow-up is anticipated to be completed by autumn 2024. Trial registration ClinicalTrials.gov (Identifier: NCT05049239). Registered on 20 September 2021 (last verified: May 2021).

Early detection of diseases such as COVID-19 could be a critical tool in reducing disease transmission by helping individuals recognize when they should self-isolate, seek testing, and obtain early medical intervention. Consumer wearable devices that continuously measure physiological metrics hold promise as tools for early illness detection. We gathered daily questionnaire data and physiological data using a consumer wearable (Oura Ring) from 63,153 participants, of whom 704 self-reported possible COVID-19 disease. We selected 73 of these 704 participants with reliable confirmation of COVID-19 by PCR testing and high-quality physiological data for algorithm training to identify onset of COVID-19 using machine learning classification. The algorithm identified COVID-19 an average of 2.75 days before participants sought diagnostic testing with a sensitivity of 82% and specificity of 63%. The receiving operating characteristic (ROC) area under the curve (AUC) was 0.819 (95% CI [0.809, 0.830]). Including continuous temperature yielded an AUC 4.9% higher than without this feature. For further validation, we obtained SARS CoV-2 antibody in a subset of participants and identified 10 additional participants who self-reported COVID-19 disease with antibody confirmation. The algorithm had an overall ROC AUC of 0.819 (95% CI [0.809, 0.830]), with a sensitivity of 90% and specificity of 80% in these additional participants. Finally, we observed substantial variation in accuracy based on age and biological sex. Findings highlight the importance of including temperature assessment, using continuous physiological features for alignment, and including diverse populations in algorithm development to optimize accuracy in COVID-19 detection from wearables.

Background Sodium-calcium (Ca2+) exchanger isoform 1 (NCX1) is the dominant Ca2+ efflux mechanism in cardiomyocytes and is critical to maintaining Ca2+ homeostasis during excitation-contraction coupling. NCX1 activity has been implicated in the pathogenesis of cardiovascular diseases, but a lack of specific NCX1 blockers complicates experimental interpretation. Our aim was to develop a tamoxifen-inducible NCX1 knockout (KO) mouse to investigate compensatory adaptations of acute ablation of NCX1 on excitation-contraction coupling and intracellular Ca2+ regulation, and to examine whether acute KO of NCX1 confers resistance to triggered arrhythmia and ischemia/reperfusion injury. Methods and Results We used the α-myosin heavy chain promoter (Myh6)-MerCreMer promoter to create a tamoxifen-inducible cardiac-specific NCX1 KO mouse. Within 1 week of tamoxifen injection, NCX1 protein expression and current were dramatically reduced. Diastolic Ca2+ increased despite adaptive reductions in Ca2+ current and action potential duration and compensatory increases in excitation-contraction coupling gain, sarcoplasmic reticulum Ca2+ ATPase 2 and plasma membrane Ca2+ ATPase. As these adaptations progressed over 4 weeks, diastolic Ca2+ normalized and SR Ca2+ load increased. Left ventricular function remained normal, but mild fibrosis and hypertrophy developed. Transcriptomics revealed modification of cardiovascular-related gene networks including cell growth and fibrosis. NCX1 KO reduced spontaneous action potentials triggered by delayed afterdepolarizations and reduced scar size in response to ischemia/reperfusion. Conclusions Tamoxifen-inducible NCX1 KO mice adapt to acute genetic ablation of NCX1 by reducing Ca2+ influx, increasing alternative Ca2+ efflux pathways, and increasing excitation-contraction coupling gain to maintain contractility at the cost of mild Ca2+-activated hypertrophy and fibrosis and decreased survival. Nevertheless, KO myocytes are protected against spontaneous action potentials and ischemia/reperfusion injury.

Traumatic brain injury (TBI) is a major cause of death and disability among the American population, but the impact TBIs have on the school experience of high school, and post-secondary students, is poorly understood. In this study, a cohort of 79 students, ages 15?22, with mild-to-severe TBIs, were retrospectively identified from the University of Washington Traumatic Brain Injury Database and Sample Repository. The Sickness Impact Profile (SIP) was used to determine the frequency at which schooling was impacted by a TBI and identify the most common self-reported issues students faced in their return to school. At 1 month post-injury, 70% of students either had not returned to school as a result of their TBI or had returned to school but experienced issues related to their TBI. The most-reported issues at 1 month were a difficulty keeping up with school work as a result of it taking longer to complete assignments, tiring easily, having to take frequent rests, and grades that were not as good as they used to be. At 1 year post-injury, the number of students whose TBIs were affecting their school situation dropped 20 percentage points to 49%. The most reported issues at 1 year were forgetting more quickly what was learned in class and having more difficulty understanding new concepts and material. These findings indicate that TBIs have a profound effect on a student's school experiences up to at least 1 year post-injury.

Abstract Background Although cancer mortality has been decreasing since 1991, many cancers are still not detected until later stages with poorer outcomes. Screening for early-stage cancer can save lives because treatments are generally more effective at earlier than later stages of disease. Evidence of the aggregate benefits of guideline-recommended single-site cancer screenings has been limited. This article assesses the benefits in terms of life-years gained and associated value from major cancer screening technologies in the United States. Methods A mathematical model was built to estimate the aggregate benefits of screenings for breast, colorectal, cervical, and lung cancer over time since the start of US Preventive Services Task Force (USPSTF) recommendations. For each type, the full potential benefits under perfect adherence and the benefits considering reported adherence rates were estimated. The effectiveness of each screening technology was abstracted from published literature on the life-years gained per screened individual. The number of individuals eligible for screening per year was estimated using US Census data matched to the USPSTF recommendations, which changed over time. Adherence rates to screening protocols were based on the National Health Interview Survey results with extrapolation. Results Since initial USPSTF recommendations, up to 417 million people were eligible for cancer screening. Assuming perfect adherence to screening recommendations, the life-years gained from screenings are estimated to be 15.5–21.3 million (2.2–4.9, 1.4–3.6, 11.4–12.3, and 0.5 million for breast, colorectal, cervical, and lung cancer, respectively). At reported adherence rates, combined screening has saved 12.2–16.2 million life-years since the introduction of USPSTF recommendations, ~ 75% of potential with perfect adherence. These benefits translate into a value of $8.2-$11.3 trillion at full potential and $6.5-$8.6 trillion considering current adherence. Therefore, single-site screening could have saved an additional 3.2–5.1 million life-years, equating to $1.7-$2.7 trillion, with perfect adherence. Conclusions Although gaps persist between the full potential benefit and benefits considering adherence, existing cancer screening technologies have offered significant value to the US population. Technologies and policy interventions that can improve adherence and/or expand the number of cancer types tested will provide significantly more value and save significantly more patient lives.

Essential tremor (ET) is characterized by bilateral upper limb postural and/or kinetic tremor, but also cognitive deficits. Tremor in ET, as well as aspects of cognitive deficits associated with ET, have been suggested to be linked to dysfunction in the cerebello-thalamo-cerebral circuit. In ET patients with disabling and medically intractable motor symptoms, Deep Brain Stimulation (DBS) is effective in reducing tremor. DBS in the caudal Zona incerta (cZi) has been shown to modulate the activity of the sensorimotor cerebello-cerebral circuit during motor tasks. Whether the activity in the cerebello-cerebral circuit is modulated by DBS during tasks involving working memory is unknown. The present study therefore aimed to investigate the possible effects of cZi DBS on working-memory processing in ET patients by means of task-based blood oxygen level-dependent (BOLD) fMRI.Thirteen ET patients completed a working-memory task during DBS OFF and ON conditions. The task involved three conditions: maintenance, manipulation, and control. Behaviorally, there was no significant effect from DBS on accuracy, but a marginally significant Task x DBS interaction was detected for response times (RTs). However, post hoc comparisons for each condition failed to reach statistical significance. FMRI analyses revealed that DBS did not alter BOLD signal in regions of interest (lateral prefrontal cortex, parietal cortex, and the cerebellum), or in a complementary whole-brain analysis.The present study indicates that DBS in the cZi in patients with ET has at most marginal effects on working memory, which is consistent with the results of pre- and post-DBS neuropsychological assessment showing minimal cognitive effects of surgery.

The natural history of radiorecurrent high-risk prostate cancer (HRPCa) is not well-described. To better understand its clinical course, we evaluated rates of distant metastases (DM) and prostate cancer-specific mortality (PCSM) in a cohort of 978 men with radiorecurrent HRPCa who previously received either external beam radiation therapy (EBRT, n = 654, 67%) or EBRT + brachytherapy (EBRT + BT, n = 324, 33%) across 15 institutions from 1997 to 2015. In men who did not die, median follow-up after treatment was 8.9 yr and median follow-up after biochemical recurrence (BCR) was 3.7 yr. Local and systemic therapy salvage, respectively, were delivered to 21 and 390 men after EBRT, and eight and 103 men after EBRT + BT. Overall, 435 men developed DM, and 248 were detected within 1 yr of BCR. Measured from time of recurrence, 5-yr DM rates were 50% and 34% after EBRT and EBRT + BT, respectively. Measured from BCR, 5-yr PCSM rates were 27% and 29%, respectively. Interval to BCR was independently associated with DM (p

ObjectiveMultiple genome-wide association studies have identified a strong genetic linkage between the SKAP2 locus and type 1 diabetes (T1D), but how this leads to disease remains obscure. Here, we characterized the functional consequence of a novel SKAP2 coding mutation in a patient with T1D to gain further insight into how this impacts immune tolerance.Research design and methodsWe identified a 24-year-old individual with T1D and other autoimmune and inflammatory conditions. The proband and first-degree relatives were recruited for whole-exome sequencing. Functional studies of the protein variant were performed using a cell line and primary myeloid immune cells collected from family members.ResultsSequencing identified a de novo SKAP2 variant (c.457G>A, p.Gly153Arg) in the proband. Assays using monocyte-derived macrophages from the individual revealed enhanced activity of integrin pathways and a migratory phenotype in the absence of chemokine stimulation, consistent with SKAP2 p.Gly153Arg being constitutively active. The p.Gly153Arg variant, located in the well-conserved lipid-binding loop, induced similar phenotypes when expressed in a human macrophage cell line. SKAP2 p.Gly153Arg is a gain-of-function, pathogenic mutation that disrupts myeloid immune cell function, likely resulting in a break in immune tolerance and T1D.ConclusionsSKAP2 plays a key role in myeloid cell activation and migration. This particular mutation in a patient with T1D and multiple autoimmune conditions implicates a role for activating SKAP2 variants in autoimmune T1D.

Recently developed methods for transforming 2D patterns of thin-film materials into 3D mesostructures create many interesting opportunities in microsystems design. A growing area of interest is in multifunctional thermal, electrical, chemical, and optical interfaces to biological tissues, particularly 3D multicellular, millimeter-scale constructs, such as spheroids, assembloids, and organoids. Herein, examples of 3D mechanical interfaces are presented, in which thin ribbons of parylene-C form the basis of transparent, highly compliant frameworks that can be reversibly opened and closed to capture, envelop, and mechanically restrain fragile 3D tissues in a gentle, nondestructive manner, for precise measurements of viscoelastic properties using techniques in nanoindentation. Finite element analysis serves as a design tool to guide selection of geometries and material parameters for shape-matching 3D architectures tailored to organoids of interest. These computational approaches also quantitate all aspects of deformations during the processes of opening and closing the structures and of forces imparted by them onto the surfaces of enclosed soft tissues. Studies of cerebral organoids by nanoindentation show effective Youngs moduli in the range from 1.5 to 2.5 kPa depending on the age of the organoid. This collection of results suggests broad utility of compliant 3D mesostructures in noninvasive mechanical measurements of millimeter-scale, soft biological tissues.

Impella devices are increasingly utilized for hemodynamic support in high-risk percutaneous coronary intervention or cardiogenic shock despite a lack of randomized clinical trial data showing clinical benefit and newer observational data suggesting harm. In this retrospective analysis, our aim was to determine the most common adverse events associated with Impella usage reported annually to the Food and Drug Administration Manufacturer and User Facility Device Experience (MAUDE) database and to estimate via the National Inpatient Sample (NIS) database the number of percutaneous ventricular assist devices utilized and associated with inpatient mortality since introduction of the Impella. Among the 885 complete reports submitted to the MAUDE database from 2008 to 2019 related to Impella usage, there were 1,206 complications coded; 88.2% of reports occurred from 2016 to 2019. Among patients with adverse events reported, bleeding (32.8%), device deployment or retrieval issues (18.2%), vascular complications (15.8%), and death (12.4%) were the most common, and 7.9% of all complications were attributable to operator decision-making or technique. From 2007 to 2017 there was a >100-fold increase in percutaneous ventricular assist devices use with an increase and plateau in in-hospital mortality to 31% from 2012 to 2016 based on NIS data. In conclusion, Impella use has increased substantially over the last decade but remains associated with high inpatient mortality and serious complications based on data from the NIS and MAUDE databases. These findings emphasize the need for high quality randomized controlled trials to determine the clinical utility of Impella in high-risk percutaneous coronary intervention and cardiogenic shock.

We investigated the reaction kinetics and initial chemical conditions in the production of silicon alloys, employing aluminum as the reductant for calcium silicate slag, to enhance process economics and scalability to industrial levels. The apparent kinetics and transient chemical conditions were studied by immersing solid aluminum into molten slag, allowing the reaction to proceed for varying durations without external agitation, before quenching the reaction for chemical and microscopic analyses of the resulting silicon alloy and slag. The majority of the conversion was observed within the first 15 s at 1650 °C, driven by significant chemical interactions and interfacial turbulence introduced upon aluminum immersion. For Al-SiO2 stoichiometries ranging from 0.5 to 1.2, the slag phase reaction conformed to first-order kinetics during the initial two minutes, when it approached equilibrium. The mass transfer coefficients for Al2O3 were estimated at 1–2 × 10−4 m/s, comparable to those for SiO2 and CaO. A constant mass transfer coefficient could not be established for stoichiometries of 1.6 and 2, as these deviated from the standard slag mass transfer relationship and did not adhere to established relationships. Despite near-complete reactions, alloy–slag mixing was extensive, decreasing with lower stoichiometry values.

To achieve better process control of silicon (Si) alloy production using aluminum as a reductant of calcium silicate (CaO-SiO2) slag, it is necessary to understand the reaction phenomena concerning the behavior of formed phases at the metal-slag interface during conversion. The interfacial interaction behavior of non-agitated melt was investigated using the sessile drop method for varying time and temperature, followed by EPMA phase analysis at the vicinity of the metal–slag interface. The most remarkable features of the reaction were the accumulation of solid calcium aluminate product layers at the Al alloy–slag interface and spontaneous emulsion of Si-alloy droplets in the slag phase. The reduction is strictly limited at 1550 °C due to the slow transfer of calcium aluminates away from the metal-slag interface into the partially liquid bulk slag. Reduction was significantly improved at 1600–1650 °C despite an interfacial layer being present, where the conversion rate is most intense in the first minutes of the liquid–liquid contact. A high mass transfer rate across the interface was shown related to the apparent interfacial tension depression of the wetting droplet along with a significant perturbed interface and emulsion due to Kelvin–Helmholtz instability driven by built-up interfacial charge at the interface. The increased reaction rate observed from 1550 °C to 1600–1650 °C for the non-agitated melt was attributed to the advantageous physical properties of the slag phase, which can be further regulated by the stoichiometry of metal–slag interactions and the composition of the slag.

AimsTo test whether a long-acting GLP-1 receptor agonist would improve glucose control in patients with type 1 diabetes (T1D) and to determine whether the presence of residual beta cell function would affect the response. In addition, we sought to determine whether the drug would affect beta cell function.MethodsWe performed a randomized placebo-controlled trial of exenatide extended release (ER) in participants with T1D with and without detectable levels of C-peptide. Seventy-nine participants were randomized to exenatide ER 2 mcg weekly, or placebo, stratified by the presence or absence of detectable C-peptide levels. The primary outcome was the difference in glycated haemoglobin (HbA1c) levels at 24 weeks. Participants were followed for another 6 months off study drug.ResultsAt week 24, the time of the primary outcome, the least squares (LS) mean HbA1c level was 7.76% (95% confidence interval [CI] 7.42, 8.10) in the exenatide ER group versus 8.0% (95% CI 7.64, 8.35) in the placebo group (P = 0.08). At week 12 the LS mean HbA1c levels were 7.71% (95% CI 7.37, 8.05) in the exenatide ER group versus 8.05% (95% CI 7.7, 8.4) in the placebo group (P = 0.01). The improvement at week 12 was driven mainly by those with detectable levels of C-peptide. Those treated with exenatide ER lost weight at 12 and 24 weeks compared to those treated with placebo (P

Na/Ca exchange is the dominant calcium (Ca) efflux mechanism in cardiac myocytes. Although our knowledge of exchanger function (NCX1 in the heart) was originally established using biochemical and electrophysiological tools such as cardiac sarcolemmal vesicles and the giant patch technique [1-4], many advances in our understanding of the physiological/pathophysiological roles of NCX1 in the heart have been obtained using a suite of genetically modified mice. Early mouse studies focused on modification of expression levels of NCX1 in the ventricles, with transgenic overexpressors, global NCX1 knockout (KO) mice (which were embryonic lethal if homozygous), and finally ventricular-specific NCX1 KO [5-12]. We found, to our surprise, that ventricular cardiomyocytes lacking NCX1 can survive and function by engaging a clever set of adaptations to minimize Ca entry, while maintaining contractile function through an increase in excitation-contraction (EC) coupling gain [5,6,13]. Having studied ventricular NCX1 ablation in detail, we more recently focused on elucidating the role of NCX1 in the atria through altering NCX1 expression. Using a novel atrial-specific NCX1 KO mouse, we found unexpected changes in atrial cell morphology and calcium handling, together with dramatic alterations in the function of sinoatrial node (SAN) pacemaker activity. In this review, we will discuss these findings and their implications for cardiac disease.

Objective: People with blindness and low vision face substantial challenges when navigating both indoor and outdoor environments. While various solutions are available to facilitate travel to and from public transit hubs, there is a notable absence of solutions for navigating within transit hubs, often referred to as the “middle mile”. Although research pilots have explored the middle mile journey, no solutions exist at scale, leaving a critical gap for commuters with disabilities. In this paper, we proposed a novel mobile application, Commute Booster, that offers full trip planning and real-time guidance inside the station. Methods and procedures: Our system consists of two key components: the general transit feed specification (GTFS) and optical character recognition (OCR). The GTFS dataset generates a comprehensive list of wayfinding signage within subway stations that users will encounter during their intended journey. The OCR functionality enables users to identify relevant navigation signs in their immediate surroundings. By seamlessly integrating these two components, Commute Booster provides real-time feedback to users regarding the presence or absence of relevant navigation signs within the field of view of their phone camera during their journey. Results: As part of our technical validation process, we conducted tests at three subway stations in New York City. The sign detection achieved an impressive overall accuracy rate of 0.97. Additionally, the system exhibited a maximum detection range of 11 meters and supported an oblique angle of approximately 110 degrees for field of view detection. Conclusion: The Commute Booster mobile application relies on computer vision technology and does not require additional sensors or infrastructure. It holds tremendous promise in assisting individuals with blindness and low vision during their daily commutes. Clinical and Translational Impact Statement: Commute Booster translates the combination of OCR and GTFS into an assistive tool, which holds great promise for assisting people with blindness and low vision in their daily commute.

Antigen heterogeneity that results in tumor antigenic escape is one of the major obstacles to successful chimeric antigen receptor (CAR) T cell therapies in solid tumors including glioblastoma multiforme (GBM). To address this issue and improve the efficacy of CAR T cell therapy for GBM, we developed an approach that combines CAR T cells with inhibitor of apoptosis protein (IAP) antagonists, a new class of small molecules that mediate the degradation of IAPs, to treat GBM. Here, we demonstrated that the IAP antagonist birinapant could sensitize GBM cell lines and patient-derived primary GBM organoids to apoptosis induced by CAR T cell-derived cytokines, such as tumor necrosis factor. Therefore, birinapant could enhance CAR T cell-mediated bystander death of antigen-negative GBM cells, thus preventing tumor antigenic escape in antigen-heterogeneous tumor models in vitro and in vivo. In addition, birinapant could promote the activation of NF-κB signaling pathways in antigen-stimulated CAR T cells, and with a birinapant-resistant tumor model we showed that birinapant had no deleterious effect on CAR T cell functions in vitro and in vivo. Overall, we demonstrated the potential of combining the IAP antagonist birinapant with CAR T cells as a novel and feasible approach to overcoming tumor antigen heterogeneity and enhancing CAR T cell therapy for GBM.

Abstract Background HNF1A-MODY is a monogenic form of diabetes caused by variants in the HNF1A gene. Different HNF1A variants are associated with differences in age of disease onset, but other factors are postulated to influence this trait. Here, we searched for genetic variants influencing age of HNF1A-MODY onset. Methods Blood samples from 843 HNF1A-MODY patients from Czech Republic, France, Poland, Slovakia, the UK and the US were collected. A validation set consisted of 121 patients from the US. We conducted a genome-wide association study in 843 HNF1A-MODY patients. Samples were genotyped using Illumina Human Core arrays. The core analysis was performed using the GENESIS package in R statistical software. Kinship coefficients were estimated with the KING and PC-Relate algorithms. In the linear mixed model, we accounted for year of birth, sex, and location of the HNF1A causative variant. Results A suggestive association with age of disease onset was observed for rs2305198 (p = 2.09E−07) and rs7079157 (p = 3.96E−06) in the HK1 gene, rs2637248 in the LRMDA gene (p = 2.44E−05), and intergenic variant rs2825115 (p = 2.04E−05). Variant rs2637248 reached nominal significance (p = 0.019), while rs7079157 (p = 0.058) and rs2825115 (p = 0.068) showed suggestive association with age at diabetes onset in the validation set. Conclusions rs2637248 in the LRMDA gene is associated with age at diabetes onset in HNF1A-MODY patients.

Abstract Maturity‐onset of diabetes of the young (MODY) are monogenic forms of diabetes characterized by early onset diabetes with autosomal dominant inheritance. Since its first description about six decades ago, there have been significant advancements in our understanding of MODY from clinical presentations to molecular diagnostics and therapeutic responses. The prevalence of MODY is estimated as at least 1.1–6.5% of the pediatric diabetes population with a high degree of geographic variability that might arise from several factors in the criteria used to ascertain cases. GCK‐MODY, HNF1A‐MODY, and HNF4A‐MODY account for >90% of MODY cases. While some MODY forms do not require treatment (i.e., GCK‐MODY), some others are highly responsive to oral agents (i.e., HNF1A‐MODY). The risk of micro‐ and macro‐vascular complications of diabetes also differ significantly between MODY forms. Despite its high clinical impact, 50–90% of MODY cases are estimated to be misdiagnosed as type 1 or type 2 diabetes. Although there are many clinical features suggestive of MODY diagnosis, there is no single clinical criterion. An online MODY Risk Calculator can be a useful tool for clinicians in the decision‐making process for MODY genetic testing in some situations. Molecular genetic tests with a commercial gene panel should be performed in cases with a suspicion of MODY. Unresolved atypical cases can be further studied by exome or genome sequencing in a clinical or research setting, as available.

A three-arm, randomized, double-masked, placebo-controlled phase 2b trial performed by the Type 1 Diabetes TrialNet Study Group previously demonstrated that low-dose anti-thymocyte globulin (ATG) (2.5 mg/kg) preserved β-cell function and reduced HbA1c for 1 year in new-onset type 1 diabetes. Subjects (N = 89) were randomized to 1) ATG and pegylated granulocyte colony-stimulating factor (GCSF), 2) ATG alone, or 3) placebo. Herein, we report 2-year area under the curve (AUC) C-peptide and HbA1c, prespecified secondary end points, and potential immunologic correlates. The 2-year mean mixed-meal tolerance test-stimulated AUC C-peptide, analyzed by ANCOVA adjusting for baseline C-peptide, age, and sex (n = 82) with significance defined as one-sided P < 0.025, was significantly higher in subjects treated with ATG versus placebo (P = 0.00005) but not ATG/GCSF versus placebo (P = 0.032). HbA1c was significantly reduced at 2 years in subjects treated with ATG (P = 0.011) and ATG/GCSF (P = 0.022) versus placebo. Flow cytometry analyses demonstrated reduced circulating CD4:CD8 ratio, increased regulatory T-cell:conventional CD4 T-cell ratios, and increased PD-1+CD4+ T cells following low-dose ATG and ATG/GCSF. Low-dose ATG partially preserved β-cell function and reduced HbA1c 2 years after therapy in new-onset type 1 diabetes. Future studies should determine whether low-dose ATG might prevent or delay the onset of type 1 diabetes.

Indonesia is the country with the most active volcanoes, several of which are renowned for climate-changing eruptions. Here the authors show a rather moderate sulfur emissions budget and reinforce the idea that sulfur-rich eruptions reflect long-term accumulation of volatiles in the reservoirs.

Abstract Early detection of diseases such as COVID-19 could be a critical tool in reducing disease transmission by helping individuals recognize when they should self-isolate, seek testing, and obtain early medical intervention. Consumer wearable devices that continuously measure physiological metrics hold promise as tools for early illness detection. We gathered daily questionnaire data and physiological data using a consumer wearable (Oura Ring) from 63,153 participants, of whom 704 self-reported possible COVID-19 disease. We selected 73 of these 704 participants with reliable confirmation of COVID-19 by PCR testing and high-quality physiological data for algorithm training to identify onset of COVID-19 using machine learning classification. The algorithm identified COVID-19 an average of 2.75 days before participants sought diagnostic testing with a sensitivity of 82% and specificity of 63%. The receiving operating characteristic (ROC) area under the curve (AUC) was 0.819 (95% CI [0.809, 0.830]). Including continuous temperature yielded an AUC 4.9% higher than without this feature. For further validation, we obtained SARS CoV-2 antibody in a subset of participants and identified 10 additional participants who self-reported COVID-19 disease with antibody confirmation. The algorithm had an overall ROC AUC of 0.819 (95% CI [0.809, 0.830]), with a sensitivity of 90% and specificity of 80% in these additional participants. Finally, we observed substantial variation in accuracy based on age and biological sex. Findings highlight the importance of including temperature assessment, using continuous physiological features for alignment, and including diverse populations in algorithm development to optimize accuracy in COVID-19 detection from wearables.

Abstract Bromo is among the very active volcanoes in Indonesia and is known for its recurrent and long-lasting eruptive manifestations. Past volcanic gas studies have revealed Bromo as one of the principal sources of volcanic degassing in Indonesia. This high degassing from Bromo volcano is further characterized in this work, based on more than 10 years of intermittent ground-based gas measurements, combined with daily SO2 mass, captured by the OMI sensor. Over the past decade, Bromo has released 0.7 Tg of SO2 into the atmosphere, representing 3% of the volcanic degassing budget of Indonesia and 0.3% of the global volcanic SO2 emission budget outside eruptive periods. Results also reveal that 18.8 Tg of H2O, 2.0 Tg of CO2, 0.1 Tg of H2S, and 0.005 Tg of H2 were released from the Bromo volcano in one decade. About 81% of these gases are released passively between eruptive events. The chemistry of the eruptive products, sampled between 2001 and 2019, indicate that Bromo volcanic activity is sustained by a basaltic-andesite to basalt trachy-andesite magma source with a transition from medium-K to high-K composition. Such an evolution associated to a C-rich gas likely resulted from a low partial melting and sediment contribution to the genesis of the source magma. New magma injections into the reservoir and fractional crystallization have further amplified the changes of magma composition. Finally, we speculate that the shallow reservoir replenishment, in response to the continuous strong degassing is the driving mechanism behind the Bromo frequent eruptive events.

Abstract Background Accumulation of the signal adaptor protein p62 has been demonstrated in many forms of cancer, including pancreatic ductal adenocarcinoma (PDAC). Although data from experimental studies suggest that p62 accumulation accelerates the development of PDAC, the association between p62 protein expression and survival in PDAC patients is unclear. Methods Thirty-three tumor specimens from PDAC patients treated by primary surgery were obtained. Immunohistochemical expression of p62, microtubule-associated protein 1A/1B-light chain 3 (LC3), and nuclear factor-erythroid factor 2-related factor 2 (NRF2) in tumor tissue was examined for associations with clinicopathological characteristics and disease-specific survival (DSS). Results There was no association between p62 expression and any of the clinicopathological variables. However, high p62 protein expression in tumor cells was significantly associated with shorter DSS (7 months vs. 29 months, p = 0.017). The hazard ratio for death in patients with high p62 protein expression in tumor cells was 2.88 (95% confidence interval: 1.17–7.11, p = 0.022). In multivariable analysis, high p62 expression was an independent prognostic factor for shorter DSS (p = 0.020) when follow up time was more than 5 years. LC3 and NRF2 staining was not associated with survival or other clinicopathological parameters. Conclusion Our results show that high p62 protein expression in tumor cells is associated with shorter survival following pancreatic tumor resection. This association supports a role for p62 as a prognostic marker in patients with PDAC treated by primary surgery.