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Using contrast ultrasound and measures of vascular stiffness, we compared vascular and metabolic responses to insulin in patients with type 1 diabetes with age-matched controls. The patients with type 1 diabetes demonstrated both vascular and metabolic insulin resistance with more than half of the patients with diabetes having a paradoxical vasoconstrictive vascular response to insulin.

The covid-19 era has changed the world, including more “open access” publications, the increasing importance of digital research materials, and engagement in digital interactions of increased importance in the humanities. Perspectives of isolated scholars, in this case, working on the history of Indonesia during World War II from a small national university in a remote city in northern Japan, provide an essential perspective on conducting research and creating digital archives. Far closer to Indonesian students and researchers than researchers in major universities in the West, such practical perspectives are urgently needed to achieve the full potential of digital humanities. Some archives and public library collections have developed digital collections for readers and researchers, however smaller collections of materials made by scholars in the course of their research are also of significant importance but present a large number of unique problems, including dependence on low-budget efforts by individual scholars in their “spare time” to do all the planning and digitizing of their research materials. A coordinated effort by a group of scholars in northern Japan to digitize materials on Indonesian history is making progress but faces different problems than those of large institutions. These problems include long-term support, determining and coding materials for their accessibility, depending on the nature of the material and the rights involved. None-the-less, it is hoped that innovative collaboration will allow some of these materials to be made available to the general public and outside researchers while minimizing the disadvantages. Era covid-19 telah membawa perubahan bagi dunia, termasuk lebih banyak publikasi “akses terbuka”, semakin pentingnya bahan penelitian digital, dan keterlibatan dalam interaksi digital yang semakin penting dalam humaniora. Perspektif sarjana yang terisolasi, dalam hal ini, bekerja pada sejarah Indonesia selama Perang Dunia II dari sebuah universitas nasional kecil di kota terpencil di Jepang utara, memberikan perspektif penting dalam melakukan penelitian dan membuat arsip digital. Jauh lebih dekat dengan mahasiswa dan peneliti Indonesia daripada peneliti di universitas-universitas besar di Barat, perspektif praktis seperti itu sangat dibutuhkan untuk mencapai potensi penuh humaniora digital. Sejumlah arsip dan koleksi perpustakaan umum telah mengembangkan koleksi digital untuk pembaca dan peneliti, namun koleksi bahan yang lebih kecil yang dibuat oleh para sarjana dalam perjalanan penelitian mereka juga sangat penting tetapi menghadirkan sejumlah besar masalah unik, termasuk ketergantungan pada rendahnya sumber daya. upaya anggaran oleh para sarjana individu di "waktu luang" mereka untuk melakukan semua perencanaan dan digitalisasi bahan penelitian mereka. Upaya terkoordinasi oleh sekelompok cendekiawan di Jepang utara untuk mendigitalkan materi tentang sejarah Indonesia sedang mengalami kemajuan tetapi menghadapi masalah yang berbeda dari masalah lembaga besar. Masalah-masalah ini termasuk dukungan jangka panjang, penentuan dan pengkodean materi untuk aksesibilitas mereka, tergantung pada sifat materi dan hak-hak yang terlibat. Meskipun demikian, kolaborasi yang inovatif diharapkan akan memungkinkan beberapa materi ini tersedia untuk masyarakat umum dan peneliti luar sambil meminimalkan kerugian. Cite this article: Horton, W.B. (2022). Digital Humanities in the Covid Era: The Perspective of a Historian of Modern Indonesia from Northern Japan. Paramita: Historical Studies Journal, 32(2), 243-252. http://dx.doi.org/10.15294/paramita.v32i2.35583

This is the accepted manuscript version of the work published in its final form as Carroll, R. S., Olney, R. C., Duker, A. L., Coghlan, R. F., Mackenzie, W. G., Ditro, C. P., Brown, C. J., O’Connell, D. A., Horton, W. A., Johnstone, B., Espiner, E. A., Prickett, T. C. R., & Bober, M. B. (2022). Collagen X Marker Levels are Decreased in Individuals with Achondroplasia.Calcified Tissue International. https://doi.org/10.1007/s00223-022-00966-0 Deposited byshareyourpaper.organdopenaccessbutton.org. We've taken reasonable steps to ensure this content doesn't violate copyright. However, if you think it does you can request a takedown by emailinghelp@openaccessbutton.org.

Arterial stiffness and endothelial dysfunction are both reported in children with type 1 diabetes (DM1) and may predict future cardiovascular events. In health, nitric oxide (NO) relaxes arteries and increases microvascular perfusion. The relationships between NO-dependent macro- and microvascular functional responses and arterial stiffness have not been studied in adolescents with DM1. Here, we assessed macro- and microvascular function in DM1 adolescents and age-matched controls at baseline and during an oral glucose challenge (OGTT). DM1 adolescents (

Context Interventions that decrease mean glucose have reduced rates of micro- and macrovascular complications in type 1 diabetes (T1D). However, the difference in cardiovascular risk between people with T1D and the general population endures, suggesting that factors beyond hemoglobin A1C (HbA1c) normalization drive cardiovascular outcomes. Objective To determine whether various HbA1c metrics predict anatomic cardiovascular disease (CVD) risk factors and/or CVD events in people with T1D. Methods We used linear regression to analyze the relationship of several HbA1c metrics to anatomic CVD risk factors and then used Cox regression to model their relationship to incident CVD events in the CACTI Study (ClinicalTrials.gov Identifier: NCT00005754). Results In linear regression models adjusted for age, sex, and T1D duration, baseline Hba1c (b = 0.3998, P = 0.0236), mean HbA1c (b = 0.5385, P = 0.0109), and HbA1c SD (b = 1.1521, P = 0.0068) were each positively associated with square root transformed coronary artery calcium volume. Conversely, only mean HbA1c (b = 1.659, P = 0.0048) positively associated with pericardial adipose tissue volume. In survival models adjusted for age, sex, and T1D duration, baseline HbA1c [hazard ratio (HR): 1.471, 95% CI: 1.257-1.721], mean HbA1c (HR: 1.850, 95% CI: 1.511-2.264), time-varying HbA1c (HR: 1.500, 95% CI: 1.236-1.821), and HbA1c SD (HR: 1.665, 95% CI: 1.022-2.711) each independently predicted CVD events over 14.3 ± 5.2 person-years of follow-up. Conclusions/interpretation We found that various HbA1c metrics positively correlated with CAC volume and independently predicted incident CVD events in the CACTI T1D cohort. These associations with CVD events persisted for baseline HbA1c, mean HbA1c, and time-varying HbA1c even after adjustment for numerous CVD risk factors.

ObjectiveTo quantify the accuracy of and clinical events associated with a risk alert threshold for impending hypoglycemia during ICU admissions.DesignRetrospective electronic health record review of clinical events occurring ≥1 and ≤12 hours after the hypoglycemia risk alert threshold was met.SettingAdult ICU admissions from June 2020 through April 2021 at the University of Virginia Medical Center.Patients342 critically-ill adults that were 63.5% male with median age 60.8 years, median weight 79.1 kg, and median body mass index of 27.5 kg/m2.InterventionsReal-world testing of our validated predictive model as a clinical decision support tool for ICU hypoglycemia.Measurements and Main ResultsWe retrospectively reviewed 350 hypothetical alerts that met inclusion criteria for analysis. The alerts correctly predicted 48 cases of Level 1 hypoglycemia that occurred ≥1 and ≤12 hours after the alert threshold was met (positive predictive value= 13.7%). Twenty-one of these 48 cases (43.8%) involved Level 2 hypoglycemia. Notably, three myocardial infarctions, one medical emergency team call, two initiations of cardiopulmonary resuscitation, 6 unplanned surgeries, 19 deaths, 20 arrhythmias, and 38 blood or urine cultures were identified or obtained ≥1 and ≤12 hours after an alert threshold was met. Alerts identified 102 total events of hypoglycemia and/or clinical deterioration, yielding a positive predictive value for any event of 29.1%.ConclusionsAlerts generated by a validated ICU hypoglycemia prediction model had positive predictive value of 29.1% for hypoglycemia and other associated adverse clinical events.Key PointsQuestionWhat are the accuracy of and clinical events associated with a risk alert threshold for ICU hypoglycemia?FindingsWe retrospectively reviewed 350 hypothetical alerts that correctly predicted 48 cases of Level 1 hypoglycemia occurring ≥1 and ≤12 hours after the alert threshold was met (positive predictive value= 13.7%). Notably, three myocardial infarctions, one medical emergency team call, two initiations of cardiopulmonary resuscitation, 6 unplanned surgeries, 19 deaths, 20 arrhythmias, and 38 blood or urine cultures were identified or obtained ≥1 and ≤12 hours after an alert threshold was met.MeaningAlerts generated by a validated ICU hypoglycemia prediction model had positive predictive value of 29.1% for hypoglycemia and other associated adverse clinical events.

Inadequate diet and frequent symptomatic infections are considered major causes of growth stunting in low-income countries, but interventions targeting these risk factors have achieved limited success. Asymptomatic infections can restrict growth, but little is known about their role in global stunting prevalence. We investigated factors related to length-for-age Z-score (LAZ) at 24 months by constructing an interconnected network of various infections, biomarkers of inflammation (as assessed by alpha-1-acid glycoprotein [AGP]), and growth (insulin-like growth factor 1 [IGF-1] and collagen X biomarker [CXM]) at 18 months, as well as other children, maternal, and household level factors. Among 604 children, there was a continuous decline in mean LAZ and increased mean length deficit from birth to 24 months. At 18 months of age, the percentage of asymptomatic children who carried each pathogen was: 84.5% enterovirus, 15.5% parechovirus, 7.7% norovirus, 4.6% rhinovirus, 0.6% rotavirus, 69.6% Campylobacter, 53.8% Giardia lamblia, 11.9% malaria parasites, 10.2% Shigella, and 2.7% Cryptosporidium. The mean plasma IGF-1 concentration was 12.5 ng/ml and 68% of the children had systemic inflammation (plasma AGP concentration >1 g/L). Shigella infection was associated with lower LAZ at 24 months through both direct and indirect pathways, whereas enterovirus, norovirus, Campylobacter, Cryptosporidium, and malaria infections were associated with lower LAZ at 24 months indirectly, predominantly through increased systemic inflammation and reduced plasma IGF-1 and CXM concentration at 18 months. publishedVersion

Vosoritide, an analog of C-type natriuretic peptide, has been developed for the treatment of children with achondroplasia. The pharmacokinetics of vosoritide and relationships between plasma exposure and efficacy, biomarkers, and safety endpoints were evaluated in a phase II, open-label, dose-escalation study (N = 35 patients aged 5–14 years who received daily subcutaneous injections for 24 months) and a phase III, double-blind, placebo-controlled study (N = 60 patients aged 5–18 years randomized to receive daily subcutaneous injections for 52 weeks). Pharmacokinetic parameters for both studies were obtained from non-compartmental analysis. Potential correlations between vosoritide exposure and changes in annualized growth velocity, collagen type X marker (CXM; a biomarker of endochondral ossification), cyclic guanosine monophosphate (cGMP; a biomarker of pharmacological activity), heart rate, and systolic and diastolic blood pressures were then evaluated. The exposure–response relationships for changes in both annualized growth velocity and the CXM biomarker saturated at 15 μg/kg, while systemic pharmacological activity, as measured by urinary cGMP, was near maximal or saturated at exposures obtained at the highest dose studied (i.e. 30 μg/kg). This suggested that the additional bioactivity was likely in tissues not related to endochondral bone formation. In the phase III study, following subcutaneous administration at the recommended dose of 15 μg/kg to patients with achondroplasia aged 5–18 years, vosoritide was rapidly absorbed with a median time to maximal plasma concentration (Cmax) of 15 minutes, and cleared with a mean half-life of 27.9 minutes after 52 weeks of treatment. Vosoritide exposure (Cmax and area under the concentration-time curve [AUC]) was consistent across visits. No evidence of accumulation with once-daily dosing was observed. Total anti-vosoritide antibody (TAb) responses were detected in the serum of 25 of 60 (42%) treated patients in the phase III study, with no apparent impact of TAb development noted on annualized growth velocity or vosoritide exposure. Across the exposure range obtained with 15 µg/kg in the phase III study, no meaningful correlations between vosoritide plasma exposure and changes in annualized growth velocity or CXM, or changes from predose heart rate, and systolic or diastolic blood pressures were observed. The results support the recommended dose of vosoritide 15 µg/kg for once-daily subcutaneous administration in patients with achondroplasia aged ≥ 5 years whose epiphyses are not closed. NCT02055157, NCT03197766, and NCT01603095.

Opioid misuse is a critical public health crisis in the United States that results in over 50,000 deaths per year and a substantial economic burden to society. Human epidemiological data suggest that exposure to stress is one of many risk factors for opioid misuse; however, opioid abusers tend to have multiple risk factors and use other drugs in addition to opioids. To identify causal mechanisms by which stress may increase risk, preclinical animal experiments provide a means to conduct experimental manipulations and maintain precise controls over environmental and drug exposures. The current review examines how stressful experiences alter opioid addiction-related behaviors in animal models, with a focus on how age of stress exposure affects drug outcomes. The findings summarized here suggest that neonatal or adult stress increase behaviors indicative of opioid intake and reward in rodent models, but that adolescent social stress may protect against later opioid addiction-related behaviors, which contradicts human epidemiological literature. We highlight three important areas to consider across this body of literature: the species and/or strain used, stressor type, and inclusion of both sexes. Finally, we suggest areas where additional research is warranted. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Introduction: Interventions that decrease mean glucose have reduced rates of type 1 diabetes (T1D) vascular complications, but the difference in cardiovascular disease (CVD) risk between people with T1D and the general population endures. This suggests that factors beyond hemoglobin A1c (HbA1c) normalization may drive T1D CVD outcomes. HbA1c variability is an established predictor of T1D microvascular disease, but thus far only the FinnDiane Study has implicated it as a risk factor for T1D CVD events. No studies have examined the relationship of HbA1c variability to both CVD risk factors and events in a prospective T1D cohort. Methods: We used multivariable logistic regression to analyze the Coronary Artery Calcification in Type 1 Diabetes (CACTI) T1D cohort (N=597) . Primary outcomes were square root-transformed coronary artery calcium (CAC) volume and CVD events. CVD events were defined as myocardial infarction, coronary artery bypass grafting, angioplasty, or cardiovascular death. HbA1c variability was defined as a 1-standard deviation increment in HbA1c and calculated as standard deviation of all HbA1c values for each subject. Results: After adjustment for age, sex, and T1D duration, HbA1c variability predicted both CVD events (HR: 1.562, 95% CI: 1.052-2.318, P=0.0269) and CAC volume (rpartial= 0.3346, P Conclusion: HbA1c variability may be a risk factor for both coronary atherosclerosis and CVD events in T1D, and the appropriate care strategy for this population may include maintaining an HbA1c value over time that is both at-target and stable. Disclosure W.B.Horton: None. J.K.Snell-bergeon: Stock/Shareholder; GlaxoSmithKline plc. Funding National Institutes of Health (R01DK116731) National Institutes of Health (R01HL113029)

Traditionally, the prevention and management of chronic complications in individuals with type 1 (T1D) and type 2 diabetes (T2D) has been focused on of nephropathy, retinopathy, neuropathy, and atherosclerotic cardiovascular disease (including ischemic heart disease, stroke or peripheral vascular disease) (1). However, heart failure (HF) has been recognized as a common complication of diabetes, with a prevalence of up to 22% in individuals with diabetes and increasing incidence rates (2–4). This recognition stems in part from trials focused on cardiovascular safety of newer drugs to treat diabetes. Data also suggest HF may develop in individuals with diabetes even in the absence of hypertension, coronary heart disease, or valvular heart disease and, as such, represents a major cardiovascular complication in this vulnerable population (5). Given that during the past decade, the prevalence of diabetes (particularly T2D) has risen by 30% globally (6) (with prevalence expected to increase further), the burden of HF on the health care system will continue to rise. The scope of this American Diabetes Association (ADA) consensus report with designated representation from the American College of Cardiology (ACC) is to provide clear guidance and to recommend best approaches to general internists, family physicians, and endocrinologists for HF screening, diagnosis, and management in individuals with T1D, T2D, or prediabetes to mitigate the risks of serious complications, leveraging prior policy statements by the ACC (7) and American Heart Association (AHA) (2). This consensus report was developed by the writing group convened by ADA with representation from ACC through a series of conference calls, emails, and independent work from March 2021 through March 2022. Traditionally, the prevention and management of chronic complications in individuals with type 1 (T1D) and type 2 diabetes (T2D) has been focused on of nephropathy, retinopathy, neuropathy, and atherosclerotic cardiovascular disease (including ischemic heart disease, stroke or peripheral vascular disease) (1). However, heart failure (HF) has been recognized as a common complication of diabetes, with a prevalence of up to 22% in individuals with diabetes and increasing incidence rates (2–4). This recognition stems in part from trials focused on cardiovascular safety of newer drugs to treat diabetes. Data also suggest HF may develop in individuals with diabetes even in the absence of hypertension, coronary heart disease, or valvular heart disease and, as such, represents a major cardiovascular complication in this vulnerable population (5). Given that during the past decade, the prevalence of diabetes (particularly T2D) has risen by 30% globally (6) (with prevalence expected to increase further), the burden of HF on the health care system will continue to rise. The scope of this American Diabetes Association (ADA) consensus report with designated representation from the American College of Cardiology (ACC) is to provide clear guidance and to recommend best approaches to general internists, family physicians, and endocrinologists for HF screening, diagnosis, and management in individuals with T1D, T2D, or prediabetes to mitigate the risks of serious complications, leveraging prior policy statements by the ACC (7) and American Heart Association (AHA) (2). This consensus report was developed by the writing group convened by ADA with representation from ACC through a series of conference calls, emails, and independent work from March 2021 through March 2022.

Context Researchers have traditionally used motion capture to quantify discrete data points (peak values) during hop testing. However, these analyses restrict the evaluation to a single time point (ie, certain percentage of stance) and provide only a narrow view of movement. Applying more comprehensive analyses may help investigators identify important characteristics that are masked by discrete analyses often used to screen patients for activity. Objective To examine the utility of functional data analyses to reveal asymmetries that are undetectable using discrete (ie, single time point) evaluations in participants with a history of anterior cruciate ligament reconstruction (ACLR) who achieved clinical hop symmetry. Design Cross-sectional study. Setting Laboratory. Patients or Other Participants Fifteen participants with unilateral ACLR (age = 21 ± 3 years, time from surgery = 4 ± 3 years) and 15 control participants without ACLR (age = 23 ± 2 years). Intervention(s) Lower extremity biomechanics during the triple–hop-for-distance task for the ACLR and contralateral limbs of patients and a representative limb of control participants were measured. Main Outcome Measure(s) Peak sagittal-plane joint power, joint work, and power profiles were determined. Results Using discrete analyses, we identified lower peak knee power and work in the ACLR limb compared with the contralateral and control limbs (P < .05) but were unable to demonstrate differences at the ankle or hip. Using functional data analyses, we observed asymmetries at the ankle, knee, and hip between the ACLR and contralateral or control limbs throughout stance (P < .05), and it was revealed that these asymmetries stemmed from knee power deficits that were prominent during early loading. Conclusions Despite achieving hop-distance symmetry, the ACLR knees absorbed less power. Although this information was revealed using discrete analyses, underlying asymmetries at the ankle and hip were masked. Using functional data analyses, we found interlimb asymmetries at the ankle, knee, and hip. Importantly, we found that functional data analyses more fully elucidated the extent and source of asymmetries, which can be used by clinicians and researchers alike to aid in clinical decision making.

Key points Multiple clinical studies report that acute hyperglycaemia (induced by mixed meal or oral glucose) decreases arterial vascular function in healthy humans. Feeding, however, impacts autonomic output, blood pressure, and insulin and incretin secretion, which may themselves alter vascular function. No prior studies have examined the effect of acute hyperglycaemia on both macro- and microvascular function while controlling plasma insulin concentrations. Macrovascular and microvascular functional responses to euglycaemia and hyperglycaemia were compared. Octreotide was infused throughout both protocols to prevent endogenous insulin release. Acute hyperglycaemia (induced by intravenous glucose) enhanced brachial artery flow-mediated dilatation, increased skeletal muscle microvascular blood volume and flow, and expanded cardiac muscle microvascular blood volume. Compared to other published findings, the results suggest that vascular responses to acute hyperglycaemia differ based on the study population (i.e. normal weight vs. overweight/obese) and/or glucose delivery method (i.e. intravenous vs. oral glucose). Abstract High glucose concentrations acutely provoke endothelial cell oxidative stress and are suggested to trigger diabetes-related macro- and microvascular injury in humans. Multiple clinical studies report that acute hyperglycaemia (induced by mixed meal or oral glucose) decreases arterial vascular function in healthy humans. Feeding, however, impacts autonomic output, blood pressure, and insulin and incretin secretion, which may each independently alter vascular function and obscure the effect of acute hyperglycaemia per se. Surprisingly, no studies have examined the acute effects of intravenous glucose-induced hyperglycaemia on both macro- and microvascular function while controlling plasma insulin concentrations. In this randomized study of healthy young adults, we compared macrovascular (i.e. brachial artery flow-mediated dilatation, carotid-femoral pulse wave velocity and post-ischaemic brachial artery flow velocity) and microvascular (heart and skeletal muscle perfusion by contrast-enhanced ultrasound) functional responses to euglycaemia and hyperglycaemia. Octreotide was infused throughout both protocols to prevent endogenous insulin release. Acute intravenous glucose-induced hyperglycaemia enhanced brachial artery flow-mediated dilatation (P = 0.004), increased skeletal muscle microvascular blood volume and flow (P = 0.001), and expanded cardiac muscle microvascular blood volume (P = 0.014). No measure of vascular function changed during octreotide-maintained euglycaemia. Our findings suggest that unlike meal-provoked acute hyperglycaemia, 4 h of intravenous glucose-induced hyperglycaemia enhances brachial artery flow-mediated dilatation, provokes cardiac and skeletal muscle microvascular function, and does not impair aortic stiffness. Previous findings of acute large artery vascular dysfunction during oral glucose or mixed meal ingestion may be due to differences in study populations and meal-induced humoral or neural factors beyond hyperglycaemia per se. (ClinicalTrials.gov number NCT03520569.).

Prospective comparative study. Evaluate the correlation of CXM with established measures of growth. Theoretically higher CXM levels would correlate with rapid longitudinal bone growth and lower levels with growth cessation. Assessment of growth status in patients with pediatric spinal deformity is critical. The current gold standards for assessing skeletal maturity are based on radiographic measures and have large standard errors (SE). Type X collagen (COLX) is produced in the growing physis during enchondral ossification. CXM is a COLX breakdown product that can be measured in blood products. CXM, thus, is a direct measure of enchondral ossification. IRB-approved prospective study. Q6mo anthropometrics and spine PA biplanar slot scanner images including the hand were assessed for major Cobb, Risser score (RS), triradiate cartilage status (TRC), Greulich and Pyle bone age (BA), and Sanders Score (SS). Serial dried blood spots (DBS) to obtain CXM levels were collected 3 consecutive days Q1–2 months based on SS. 47 idiopathic scoliosis patients, Cobb ≥ 20 were enrolled. Mean enrollment age was 11.8 years (range 7.1–16.6 years). 3103 DBS samples were assayed in quadruplicate. CXM results were highly reproducible with a 3% intraassay coefficient of variation (CV), and 12% interassay CV%. The CXM 3-day average was significantly correlated with BA R = 0.9, p

This review takes an inclusive approach to microvascular dysfunction in diabetes mellitus and cardiometabolic disease. In virtually every organ, dynamic interactions between the microvasculature and resident tissue elements normally modulate vascular and tissue function in a homeostatic fashion. This regulation is disordered by diabetes mellitus, by hypertension, by obesity, and by dyslipidemia individually (or combined in cardiometabolic disease), with dysfunction serving as an early marker of change. In particular, we suggest that the familiar retinal, renal, and neural complications of diabetes mellitus are late-stage manifestations of microvascular injury that begins years earlier and is often abetted by other cardiometabolic disease elements (eg, hypertension, obesity, dyslipidemia). We focus on evidence that microvascular dysfunction precedes anatomic microvascular disease in these organs as well as in heart, muscle, and brain. We suggest that early on, diabetes mellitus and/or cardiometabolic disease can each cause reversible microvascular injury with accompanying dysfunction, which in time may or may not become irreversible and anatomically identifiable disease (eg, vascular basement membrane thickening, capillary rarefaction, pericyte loss, etc.). Consequences can include the familiar vision loss, renal insufficiency, and neuropathy, but also heart failure, sarcopenia, cognitive impairment, and escalating metabolic dysfunction. Our understanding of normal microvascular function and early dysfunction is rapidly evolving, aided by innovative genetic and imaging tools. This is leading, in tissues like the retina, to testing novel preventive interventions at early, reversible stages of microvascular injury. Great hope lies in the possibility that some of these interventions may develop into effective therapies.

Context Height velocity (HV) is difficult to assess because growth is very slow. The current practice of calculating it from measurements taken at several-month intervals is insufficient for managing children with growth disorders. We identified a bone growth by-product (collagen X biomarker, CXM) in blood that in preliminary analysis in healthy children correlated strongly with conventionally determined HV and displayed a pattern resembling published norms for HV vs age. Objective The goal was to confirm our initial observations supporting the utility of CXM as an HV biomarker in a larger number of individuals and establish working reference ranges for future studies. Design, Settings, and Participants CXM was assessed in archived blood samples from 302 healthy children and 10 healthy adults yielding 961 CXM measurements. A total of 432 measurements were plotted by age, and sex-specific reference ranges were calculated. Serial values from 116 participants were plotted against observed HV. Matched plasma, serum, and dried blood spot readings were compared. Results A correlation of blood CXM with conventional HV was confirmed. Scatter plots of CXM vs age showed a similar pattern to current HV norms, and CXM levels demarcated the pubertal growth spurt both in girls and boys. CXM levels differed little in matched serum, plasma, and dried blood spot samples. Conclusions Blood CXM offers a potential means to estimate HV in real time. Our results establish sex-specific, working reference ranges for assessing skeletal growth, especially over time. CXM stability in stored samples makes it well suited for retrospective studies.

Currently, there are no standardized methods for quantitatively measuring fracture repair. Physicians rely on subjective physical examinations and qualitative evaluation of radiographs to detect mineralized tissue. Since most fractures heal indirectly through a cartilage intermediate, these tools are limited in their diagnostic utility of early repair. Prior to converting to the bone, cartilage undergoes hypertrophic maturation, characterized by the deposition of a provisional collagen X matrix. The objective of this study was to characterize the kinetics of a novel collagen X biomarker relative to other biological measurements of fracture healing using a murine model of endochondral fracture repair in which a closed, mid-shaft tibia fracture was created using the classic drop-weight technique. Serum was collected 5 to 42 days post-fracture in male and female mice and compared to uninjured controls (n = 8-12). Collagen X in the serum was quantified using a recently validated ELISA-based bioassay ("Cxm")1 and compared to genetic and histological markers of fracture healing and inflammation. We found the Cxm biomarker reliably increased from baseline to a statistically unique peak 14 days post-fracture that then resolved to pre-fracture levels by 3 weeks following injury. The shape and timing of the Cxm curve followed the genetic and histological expression of collagen X but did not show a strong correlation with local inflammatory states. Assessment of fracture healing progress is crucial to making correct and timely clinical decisions for patients. This Cxm bioassay represents a minimally invasive, inexpensive technique that could provide reliable information on the biology of the fracture to significantly improve clinical care.

Objective: In this descriptive study, we evaluated perceptions and knowledge of inpatient glycemic control among resident physicians. Methods: We performed this study at four academic medical centers: the University of Mississippi Medical Center, University of Virginia Health System, University of Louisville Health Sciences Center, and Emory University. We designed a questionnaire, and Institutional Review Board approval was granted at each institution prior to study initiation. We then administered the questionnaire to Internal Medicine and Medicine-Pediatric resident physicians. Results: A total of 246 of 438 (56.2%) eligible resident physicians completed the Inpatient Glycemic Control Questionnaire (IGCQ). Most respondents (85.4%) reported feeling comfortable treating and managing inpatient hyperglycemia, and a majority (66.3%) agreed they had received adequate education. Despite self-reported comfort with knowledge, only 51.2% of respondents could identify appropriate glycemic targets in critically ill patients. Only 45.5% correctly identified appropriate inpatient random glycemic target values in noncritically ill patients, and only 34.1% of respondents knew appropriate preprandial glycemic targets in noncritically ill patients. A small majority (54.1%) were able to identify the correct fingerstick glucose value that defines hypoglycemia. System issues were the most commonly cited barrier to successful inpatient glycemic control. Conclusion: Most respondents reported feeling comfortable managing inpatient hyperglycemia but had difficulty identifying appropriate inpatient glycemic target values. Future interventions could utilize the IGCQ as a pre- and postassessment tool and focus on early resident education along with improving system environments to aid in successful inpatient glycemic control. Abbreviations: DM = diabetes mellitus; Emory = Emory University Healthcare; IGC = inpatient glycemic control; IGCQ = Inpatient Glycemic Control Questionnaire; IRB = Institutional Review Board; PGY = postgraduate year; UMMC = University of Mississippi Medical Center; UVA = University of Virginia Health System; UL = University of Louisville Health Sciences Center

Collagen X marker (CXM) is a degradation fragment of collagen type X. It is a real-time biomarker of height velocity with established norms. Plasma C-type natriuretic peptide (CNP) and NTproCNP levels have also been found to correlate with growth velocity in the general population and are elevated in individuals with achondroplasia compared with age- and sex-matched controls. Collagen X marker levels in people with fibroblast growth factor receptor 3 (FGFR3)-opathies have never been systematically measured. The objective of this study was to measure CXM in a population of dwarfism caused by FGFR3-opathies. Using the same cohort in which CNP and NTproCNP levels were previously measured, archived serum aliquots from 63 children with achondroplasia, six with hypochondroplasia, and two with thanatophoric dysplasia had CXM concentrations measured. Results were plotted against age- and sex-specific norms, and standard deviation scores were plotted for comparison between clinical diagnoses. CXM levels were significantly decreased (p 0.0001) in children with achondroplasia compared with age- and sex-matched controls. Temporal patterns of change in CXM levels were sex-dependent. As the FGFR3 pathway was more constitutively active, CXM levels decreased. New tools are emerging to study impact of skeletal dysplasia on growth plate regulation and function.

BackgroundThe Endocrine Self-Assessment Program In-Training Examination (ESAP-ITE) has the novel formative approach of allowing open access to all questions and answers after secure examination administration is complete, resulting in the creation of an entirely new in-training examination annually.ObjectiveTo determine whether scores on the novel ESAP-ITE predict pass/fail outcomes on the American Board of Internal Medicine Endocrinology, Diabetes, and Metabolism Certification Examination (ABIM-ECE).MethodsAll endocrine fellows-in-training who took the ESAP-ITE between 2016 and 2019 and then subsequently attempted the ABIM-ECE within the same calendar year were included (n = 982). Primary analyses used the ESAP-ITE score from the final year of fellowship training. Covariates included sex, age on date of ABIM-ECE, medical school country, fellowship program region, pass/fail outcomes on the ABIM Internal Medicine Certification Examination, and ESAP-ITE score. All variables were analyzed using multivariable logistic regression.ResultsESAP-ITE score (P ConclusionsIn addition to serving as an important learning instrument for endocrine fellowship programs, ESAP-ITE is a robust predictive tool for pass/fail outcomes on the ABIM-ECE.

IntroductionIndividuals with type 1 diabetes have increased arterial stiffness compared to age-matched healthy controls. Our aim was to determine which hemodynamic and demographic factors predict arterial stiffness in this population.Research Design and MethodsCarotid-femoral pulse wave velocity (cfPWV) was examined in 41 young adults and adolescents with type 1 diabetes without microvascular complications. Two ordinary least squares regression analyses were performed to determine multivariate relationships between cfPWV [loge] and: 1) age, duration of diabetes, sex, and HbA1c, and 2) augmentation index (AIx), mean arterial pressure, flow-mediated dilation (FMD), and heart rate. We also examined differences in macrovascular outcome measures between sexes.ResultsAge, sex, and FMD provided unique predictive information about cfPWV in these participants with type 1 diabetes. Despite having similar cardiovascular risk factors, males had higher cfPWV compared to females but no differences were observed in other macrovascular outcomes (including FMD and AIx).ConclusionsOnly age, sex, and FMD were uniquely associated with arterial stiffness in adolescents and adults with uncomplicated type 1 diabetes. Females had less arterial stiffness and similar nitric-oxide dependent endothelial function compared to males. Larger, prospective investigation is warranted to determine the temporal order of and sex-differences in arterial dysfunction in type 1 diabetes.Significance of this studyWhat is already known about this subject?A measure of central artery stiffness, carotid-femoral pulse wave velocity (cfPWV) predicts renal outcomes, cardiovascular events, and mortality in persons with type 1 diabetes.Age, race, mean arterial pressure, waist-to-height ratio/body mass index, presence of microalbuminuria have all been uniquely associated with cfPWV in populations with type 1 diabetes.The relationship between cfPWV and flow mediated dilation (FMD), a measure of nitric oxide dependent endothelial function at the brachial artery, has not been defined in type 1 diabetes, and the relationship between diabetes duration and these vascular measures are unclear.What are the new findings?Arterial stiffness and NO-dependent endothelial dysfunction were highly prevalent even within 5 years of diabetes diagnosis (16.7% and 83.3% respectively) in this cohort of adolescents and adults with uncomplicated type 1 diabetes.FMD was uniquely associated with cfPWV.Augmentation index (AIx), mean arterial pressure, and diabetes duration were not predictive of cfPWV.Despite a greater excess cardiovascular risk associated with type 1 diabetes in females compared to males, macrovascular function was no worse in females when examining sex differences. Females had a lower cfPWV and similar AIx and FMD compared to males.How might these results change the focus of research or clinical practice?Larger, prospective clinical investigation is needed in type 1 diabetes to determine the temporal order of and sex-differences in arterial dysfunction.

Many birds undertake long biannual voyages during the night. During these times of the year birds drastically reduce their amount of sleep, yet curiously perform as well on tests of physical and cognitive performance than during non-migrating times of the year. This inherent physiological protection disappears when birds are forced to stay awake at other times of the year; thus these protective changes are only associated with the nocturnal migratory state. The goal of the current study was to identify the physiological mechanisms that confer protection against the consequences of sleep loss while simultaneously allowing for the increased physical performance required for migration. We performed RNA-seq analyses of heart and liver collected from birds at different times of day under different migratory states and analyzed these data using differential expression, pathway analysis and WGCNA. We identified changes in gene expression networks implicating multiple systems and pathways. These pathways regulate many aspects of metabolism, immune function, wound repair, and protection of multiple organ systems. Consequently, the circannual program controlling the appearance of the migratory phenotype involves the complex regulation of diverse gene networks associated with the physical demands of migration.

Abnormalities in the structure and/or processing of type I collagen cause osteogenesis imperfecta and result in bone fragility, abnormal bone growth and short stature. Type I collagen is expressed in the growth plate but the mechanisms by which abnormalities in collagen I contribute to growth plate dysfunction and growth retardation are unknown. The non-collagenous domain (NC1) of type X collagen (CXM) is released from the hypertrophic zone of active growth plates and is a marker for new endochondral bone formation. Serum CXM levels are strongly correlated with the rate of growth in healthy children. We hypothesized that CXM levels in children with OI would be abnormal when compared to normally growing children. Using participants from the Brittle Bone Disease Consortium Natural History Study we analyzed the distribution of CXM over the ages of 8 months to 40 years in 187 subjects with OI (89 type I and 98 types III/IV) as well as analyzed the relationship between growth velocity and CXM levels in a subset of 100 children16 years old with OI (44 type I and 56 types III/IV). CXM levels in both control and OI children demonstrated a similar pattern of variation by age with higher levels in early life and puberty followed by a post-pubertal drop. However, there was greater variability within the OI cohort and the relationship with growth velocity was weaker. The ratio of CXM level to growth velocity was elevated in children with type III/IV OI compared to controls. These results suggest that the relationship between hypertrophic zone function and the end point of skeletal growth is disrupted in OI.

Hypoadiponectinemia is speculated to play a key role in the relationship between obesity and COVID‐19 respiratory failure. However, only one study has examined adiponectin levels in COVID‐19 patients, and none have investigated adiponectin levels strictly in patients with acute respiratory failure. In this study, we performed a retrospective case‐control study of adipokine levels in patients with acute respiratory failure caused by either COVID‐19 or other viral/bacterial source. All patients with COVID‐19 respiratory failure in the University of Virginia Biorepository and Tissue Research database were included. We also selected patients with non‐COVID‐19 infectious respiratory failure from the same biorepository to serve as a comparison cohort. Plasma adipokine levels were measured on three occasions during the first 72 hours of hospitalization. Twelve patients with COVID‐19 respiratory failure and 17 patients with other infectious respiratory failure were studied. Adiponectin levels were significantly lower in patients with COVID‐19 respiratory failure, even after adjustment for age, sex, BMI, and other covariates. In conclusion, adiponectin levels appear to be reduced in COVID‐19 respiratory failure. Larger studies are needed to confirm this report.

Deaths related to opioid use have skyrocketed in the United States, leading to a public health epidemic. Research has shown that both biological (genes) and environmental (stress) precursors are linked to opioid use. In particular, stress during adolescence–a critical period of frontal lobe development–influences the likelihood of abusing drugs. However, little is known about the biological mechanisms through which adolescent stress leads to long-term risk of opioid use, or whether genetic background moderates this response. Male and female C57BL/6J and BALB/cJ mice were exposed to chronic variable social stress (CVSS) or control conditions throughout adolescence and then tested for morphine locomotor sensitization or morphine consumption in adulthood. To examine possible mechanisms that underlie stress-induced changes in morphine behaviors, we assessed physiological changes in response to acute stress exposure and prefrontal cortex (PFC) miRNA gene expression. Adolescent stress did not influence morphine sensitization or consumption in BALB/cJ animals, and there was limited evidence of stress effects in female C57BL/6J mice. In contrast, male C57BL/6J mice exposed to adolescent CVSS had blunted morphine sensitization compared to control animals; no differences were observed in the acute locomotor response to morphine administration or morphine consumption. Physiologically, C57BL/6J mice exposed to CVSS had an attenuated corticosterone recovery following an acute stressor and downregulation of twelve miRNA in the PFC compared to control mice. The specificity of the effects for C57BL/6J vs. BALB/cJ mice provides evidence of a gene-environment interaction influencing opioid behaviors. However, this conclusion is dampened by limited locomotor sensitization observed in BALB/cJ mice. It remains possible that results may differ to other doses of morphine or other behavioral responses. Long-term differences in stress reactivity or miRNA expression in C57BL/6J mice suggests two possible biological mechanisms to evaluate in future research.

1AbstractDeaths related to opioid use have skyrocketed in the United States, leading to a public health epidemic. Research has shown that both biological (genes) and environmental (stress) precursors are linked to opioid use. In particular, stress during adolescence – a critical period of frontal lobe development – influences the likelihood of abusing drugs. However, little is known about the biological mechanisms through which adolescent stress leads to long-term risk of opioid use, or whether genetic background moderates this response. Male and female C57BL/6J and BALB/cJ mice were exposed to chronic variable social stress (CVSS) or control conditions throughout adolescence and then tested for morphine locomotor sensitization or morphine consumption in adulthood. To examine possible mechanisms that underlie stress-induced changes in morphine behaviors, we assessed physiological changes in response to acute stress exposure and prefrontal cortex miRNA gene expression. Adolescent stress did not influence morphine sensitization or consumption in BALB/cJ animals, and there was limited evidence of stress effects in female C57BL/6J mice. In contrast, male C57BL/6J mice exposed to adolescent CVSS had blunted morphine sensitization compared to control animals; no differences were observed in the acute locomotor response to morphine administration or morphine consumption. Physiologically, C57BL/6J mice exposed to CVSS had an attenuated corticosterone recovery following an acute stressor and downregulation of twelve miRNA in the prefrontal cortex compared to control mice. The specificity of the effects for C57BL/6J versus BALB/cJ mice provides evidence of a gene by environmental interaction influencing opioid behaviors. Long-term differences in stress reactivity or miRNA expression suggests two possible biological mechanisms to evaluate in future research.

Introduction: Increasing arterial stiffness is a feature of vascular aging that is accelerated by conditions that enhance cardiovascular risk, including diabetes mellitus. Multiple studies demonstrate divergence of carotid-femoral pulse wave velocity and augmentation index in persons with diabetes mellitus, though mechanisms responsible for this are unclear.Materials and Methods: We tested the effect of acutely and independently increasing plasma glucose, plasma insulin, or both on hemodynamic function and markers of arterial stiffness (including carotid-femoral pulse wave velocity, augmentation index, forward and backward wave reflection amplitude, and wave reflection magnitude) in a four-arm, randomized study of healthy young adults.Results: Carotid-femoral pulse wave velocity increased only during hyperglycemic-hyperinsulinemia (+0.36 m/s; p=0.032), while other markers of arterial stiffness did not change (all p>0.05). Heart rate (+3.62 bpm; p=0.009), mean arterial pressure (+4.14 mmHg; p=0.033), central diastolic blood pressure (+4.16 mmHg; p=0.038), and peripheral diastolic blood pressure (+4.09 mmHg; p=0.044) also significantly increased during hyperglycemic-hyperinsulinemia.Conclusions: We conclude that the acute combination of moderate hyperglycemia and hyperinsulinemia preferentially stiffens central elastic arteries. This effect may be due to increased sympathetic activity. (ClinicalTrials.gov number NCT03520569; registered 9 May 2018).

Background: Increasing arterial stiffness is a physiological feature of vascular aging that is accelerated by conditions that enhance cardiovascular risk, including diabetes mellitus. Emerging evidence demonstrates that reversal of the normal central-to-peripheral arterial stiffness gradient predicts adverse cardiovascular consequences, including target organ damage. Preferential stiffening of central over peripheral arteries has been reported in type 2 diabetes, though mechanisms for this remain unclear.Methods: We tested the effect of acutely increasing plasma glucose, plasma insulin, or both on central arterial stiffness (carotid-femoral pulse wave velocity) and peripheral arterial stiffness (radial artery augmentation index) in a randomized, four-way, crossover study of 19 healthy young adults. We also measured myocardial oxygen supply-demand (subendocardial viability ratio) and hemodynamic function. Results: Carotid-femoral pulse wave velocity increased during hyperglycemic-hyperinsulinemia (+0.4 m/s; p=0.02) but not with euglycemia, hyperglycemia, or euglycemic-hyperinsulinemia. There were no significant changes in radial artery augmentation index within any protocol (all p>0.05), though this value trended lower with hyperglycemic-hyperinsulinemia (opposite of the observed effect on carotid-femoral pulse wave velocity). No changes were observed in subendocardial viability ratio within any protocol. Heart rate significantly increased only during hyperglycemic-hyperinsulinemia (+3.62 bpm; p=0.02). There was a significant inverse correlation between peripheral and arterial stiffness during hyperglycemic-hyperinsulinemia. Conclusions: We conclude that combined hyperglycemia and hyperinsulinemia acutely increases aortic stiffness, diminishes the normal central-to-peripheral arterial stiffness gradient, and increases heart rate in healthy humans. (ClinicalTrials.gov number NCT03520569; registered 9 May 2018).Clinical Trial Information: ClinicalTrials.gov identifier NCT03520569 (registered 9 May 2018).

Theory-of-mind (ToM) is an integral part of social cognition, but how it develops remains a critical question. There is evidence that children can gain insight into ToM through experience, including language training and explanatory interactions. But this still leaves open the question of how children gain these insights-what processes drive this learning? We propose that analogical comparison is a key mechanism in the development of ToM. In Experiment 1, children were shown true- and false-belief scenarios and prompted to engage in multiple comparisons (e.g., belief vs. world). In Experiments 2a, 2b, and 3, children saw a series of true- and false-belief events, varying in order and in their alignability. Across these experiments, we found that providing support for comparing true- and false-belief scenarios led to increased performance on false-belief tests. These findings show that analogical comparison can support ToM learning.

Diabetes mellitus accelerates vascular disease through multiple biochemical pathways driven by hyperglycemia, with insulin resistance and/or hyperinsulinemia also contributing. Persons with diabetes mellitus experience premature large vessel and microvascular disease when compared with normoglycemic controls. Currently, there is a paucity of clinical data identifying how acutely the vasculature responds to hyperglycemia and whether other physiological factors (e.g., vasoactive hormones) contribute. To our knowledge, no prior studies have examined the dynamic effects of acute hyperglycemia on insulin-mediated actions on both micro- and macrovascular function in the same subjects. In this randomized crossover trial, healthy young adults underwent two infusion protocols designed to compare the effects of insulin infusion during euglycemia and hyperglycemia on micro- and macrovascular function. Both euglycemic- and hyperglycemic-hyperinsulinemia increased skeletal (but not cardiac) muscle microvascular blood volume (each P < 0.02) and blood flow (each P < 0.04) significantly, and these increases did not differ between protocols. Hyperglycemic-hyperinsulinemia trended toward increased carotid-femoral pulse wave velocity (indicating increased aortic stiffness; P = 0.065 after Bonferroni adjustment), whereas euglycemic-hyperinsulinemia did not. There were no changes in postischemic flow velocity or brachial artery flow-mediated dilation during either protocol. Plasma endothelin-1 levels significantly decreased during both protocols (each P < 0.02). In this study, acute hyperglycemia for 4 h did not inhibit insulin’s ability to increase skeletal muscle microvascular perfusion but did provoke a slight increase in aortic stiffness. Hyperglycemia also did not adversely affect myocardial microvascular perfusion or endothelial function or prevent the decline of endothelin-1 during insulin infusion.

Introduction: Insulin exerts several opposing hemodynamic vascular actions, including stimulation of both nitric oxide-mediated vasodilation and endothelin-1-mediated vasoconstriction. Notably, hyperglycemia switches the vascular response to insulin from dilation to constriction in pre-clinical studies. To our knowledge, hyperglycemia’s effect on insulin’s action on vascular stiffness in humans is unknown. The American Heart Association recently recommended that vascular stiffness be determined noninvasively by carotid-femoral pulse wave velocity (cfPWV) and/or using wave separation analyses (WSA) instead of aortic augmentation index (AIx). Methods: Thirteen lean, healthy subjects twice received a 1 mU/kg/min 2-hour insulin clamp. In one study, subjects were euglycemic and in the second, hyperglycemic (∼200 mg/dL) for 2 hours before and throughout the clamp. In each study, octreotide was infused to block endogenous insulin secretion. We assessed vascular stiffness with cfPWV, AIx, and WSA at baseline and after the 2-hour insulin clamp. Linear mixed model was used for statistical analysis, with Bonferroni correction for between-study comparisons. Spearman correlation was used to evaluate the relationship between PWV and WSA components. Results: Compared to baseline, insulin increased cfPWV (p=0.03) during hyperglycemia without affecting AIx or components of WSA. No changes were observed during euglycemia, and insulin levels did not differ between groups. Neither AIx nor WSA components (i.e., backward and forward wave amplitude and reflection magnitude) correlated with cfPWV. Discussion: We provide the first evidence that 4 hours of moderate hyperglycemia unmasks an action of physiologic hyperinsulinemia to increase central aortic stiffness (as measured by cfPWV) in healthy humans. Second, our results suggest that neither AIx nor WSA components correlate with cfPWV as measures of vascular stiffness. Disclosure W.B. Horton: None. L. Jahn: None. L. Hartline: None. J.T. Patrie: None. E. Barrett: None.

The effects of random errors and of nonconstant heat of vaporization upon the estimation of the second and third law heats of vaporization are examined. The most important conclusion is that the often noticed marked improvement in precision of the third law heat over that for the second law heat is real and is a natural consequence of the difference between the two estimators. The effects of systematic errors upon the two heats are not investigated here. Other results of interest, but of less importance because of the small magnitude of the effects, include: (1) the two heats are negatively correlated, (2) the second law heat is generally biased, (3) the third law heat is not the minimum variance unbiased estimator of the heat of vaporization, and (4) the standard deviation obtained from least squares fitting consistently overestimates the true standard deviation, but by a negligible amount. Any reversible process for which the equilibrium constant, is treated by a similar procedure is governed by the same considerations. The results apply approximately at any temperature although the stimulus for these considerations comes from high temperature chemistry.

Studies exploring the influence of executive functions (EF) on perspective-taking have focused on inhibition and working memory in young adults or clinical populations. Less consideration has been given to more complex capacities that also involve switching attention between perspectives, or to changes in EF and concomitant effects on perspective-taking across the lifespan. To address this, we assessed whether individual differences in inhibition and attentional switching in healthy adults (ages 17–84) predict performance on a task in which speakers identified targets for a listener with size-contrasting competitors in common or privileged ground. Modification differences across conditions decreased with age. Further, perspective taking interacted with EF measures: youngest adults’ sensitivity to perspective was best captured by their inhibitory performance; oldest adults’ sensitivity was best captured by switching performance. Perspective-taking likely involves multiple aspects of EF, as revealed by considering a wider range of EF tasks and individual capacities across the lifespan.

Atypical substitutions in the S6 activation gate sequence distinguish “regulatory” Kv subunits, which cannot homotetramerize due to T1 self-incompatibility. Pisupati et al. show that such substitutions in Kv6 work together with self-incompatibility to restrict Kv2:Kv6 heteromeric stoichiometry to 3:1., The Shaker-like family of voltage-gated K+ channels comprises four functionally independent gene subfamilies, Shaker (Kv1), Shab (Kv2), Shaw (Kv3), and Shal (Kv4), each of which regulates distinct aspects of neuronal excitability. Subfamily-specific assembly of tetrameric channels is mediated by the N-terminal T1 domain and segregates Kv1–4, allowing multiple channel types to function independently in the same cell. Typical Shaker-like Kv subunits can form functional channels as homotetramers, but a group of mammalian Kv2-related genes (Kv5.1, Kv6s, Kv8s, and Kv9s) encodes subunits that have a “silent” or “regulatory” phenotype characterized by T1 self-incompatibility. These channels are unable to form homotetramers, but instead heteromerize with Kv2.1 or Kv2.2 to diversify the functional properties of these delayed rectifiers. While T1 self-incompatibility predicts that these heterotetramers could contain up to two regulatory (R) subunits, experiments show a predominance of 3:1R stoichiometry in which heteromeric channels contain a single regulatory subunit. Substitution of the self-compatible Kv2.1 T1 domain into the regulatory subunit Kv6.4 does not alter the stoichiometry of Kv2.1:Kv6.4 heteromers. Here, to identify other channel structures that might be responsible for favoring the 3:1R stoichiometry, we compare the sequences of mammalian regulatory subunits to independently evolved regulatory subunits from cnidarians. The most widespread feature of regulatory subunits is the presence of atypical substitutions in the highly conserved consensus sequence of the intracellular S6 activation gate of the pore. We show that two amino acid substitutions in the S6 gate of the regulatory subunit Kv6.4 restrict the functional stoichiometry of Kv2.1:Kv6.4 to 3:1R by limiting the formation and function of 2:2R heteromers. We propose a two-step model for the evolution of the asymmetric 3:1R stoichiometry, which begins with evolution of self-incompatibility to establish the regulatory phenotype, followed by drift of the activation gate consensus sequence under relaxed selection to limit stoichiometry to 3:1R.

Speakers in conversation often tailor referring expressions in ways that reflect beliefs about the knowledge and perspectives of specific addressees. In this study we examined whether such audience...

Gestational primary hyperparathyroidism (GPHPT) is a rare condition with fewer than 200 cases reported. We present the case of a 21-year-old woman who presented at 10 weeks’ gestation with severe hypercalcemia. Laboratory investigation was consistent with primary hyperparathyroidism. Neck ultrasound did not reveal any parathyroid enlargement. Due to the persistence of severe hypercalcemia, she was treated with 4 weeks of cinacalcet therapy, which was poorly tolerated due to nausea and vomiting. At 14 weeks’ gestation, she underwent neck exploration with right lower, left upper, and partial right upper parathyroid gland excision. Intra- and postoperative parathyroid hormone (PTH) and calcium levels remained elevated. After a thorough discussion of risks/benefits, the patient requested further treatment. A parathyroid sestamibi scan (PSS) revealed an ectopic adenoma in the left mediastinum. The adenoma was removed via video-assisted thorascopic parathyroidectomy with intraoperative PTH declining to nearly undetectable levels. She ultimately delivered a physically and developmentally normal infant at 37 weeks’ gestation. Appropriate treatment of severe GPHPT may prevent the maternal and fetal complications of hypercalcemia. This case, in which cinacalcet therapy and PSS were used, adds to the body of literature regarding treatment of severe GPHPT., We present a case of gestational primary hyperparathyroidism due to ectopic parathyroid adenoma that was successfully diagnosed and treated with parathyroid sestamibi scan, cinacalcet, and surgery.