bluuebunny/crossref_metadata_2025 huggingface dataset:
Baseline [18F]GTP1 tau PET imaging is associated with subsequent cognitive decline in Alzheimer’s disease
Authors: Teng Edmond , Manser Paul T. , Sanabria Bohorquez Sandra , Wildsmith Kristin R. , Pickthorn Karen , Baker Suzanne L. , Ward Michael , Kerchner Geoffrey A. , Weimer Robby M.
Published: December 2021

Background

The role and implementation of tau PET imaging for predicting subsequent cognitive decline in Alzheimer’s disease (AD) remains uncertain. This study was designed to evaluate the relationship between baseline [18F]GTP1 tau PET and subsequent longitudinal change across multiple cognitive measures over 18 months.

Methods

Our analyses incorporated data from 67 participants, including cognitively normal controls (n = 10) and β-amyloid (Aβ)-positive individuals ([18F] florbetapir Aβ PET) with prodromal (n = 26), mild (n = 16), or moderate (n = 15) AD. Baseline measurements included cortical volume (MRI), tau burden ([18F]GTP1 tau PET), and cognitive assessments [Mini-Mental State Examination (MMSE), Clinical Dementia Rating (CDR), 13-item version of the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog13), and Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)]. Cognitive assessments were repeated at 6-month intervals over an 18-month period. Associations between baseline [18F]GTP1 tau PET indices and longitudinal cognitive performance were assessed via univariate (Spearman correlations) and multivariate (linear mixed effects models) approaches. The utility of potential prognostic tau PET cut points was assessed with ROC curves.

Results

Univariate analyses indicated that greater baseline [18F]GTP1 tau PET signal was associated with faster rates of subsequent decline on the MMSE, CDR, and ADAS-Cog13 across regions of interest (ROIs). In multivariate analyses adjusted for baseline age, cognitive performance, cortical volume, and Aβ PET SUVR, the prognostic performance of [18F]GTP1 SUVR was most robust in the whole cortical gray ROI. When AD participants were dichotomized into low versus high tau subgroups based on baseline [18F]GTP1 PET standardized uptake value ratios (SUVR) in the temporal (cutoff = 1.325) or whole cortical gray (cutoff = 1.245) ROIs, high tau subgroups demonstrated significantly more decline on the MMSE, CDR, and ADAS-Cog13.

Conclusions

Our results suggest that [18F]GTP1 tau PET represents a prognostic biomarker in AD and are consistent with data from other tau PET tracers. Tau PET imaging may have utility for identifying AD patients at risk for more rapid cognitive decline and for stratification and/or enrichment of participant selection in AD clinical trials.

Trial registration

ClinicalTrials.gov NCT02640092. Registered on December 28, 2015
Rabies is still a fatal but neglected disease: a case report
Authors: Amoako Y. A. , El-Duah P. , Sylverken A. A. , Owusu M. , Yeboah R. , Gorman R. , Adade T. , Bonney J. , Tasiame W. , Nyarko-Jectey K. , Binger T. , Corman V. M. , Drosten C. , Phillips R. O.
Published: December 2021

Background

Rabies, caused by a lyssavirus, is a viral zoonosis that affects people in many parts of the world, especially those in low income countries. Contact with domestic animals, especially dogs, is the main source of human infections. Humans may present with the disease only after a long period of exposure. Nearly half of rabies cases occur in children <15 years old. We report on a fatal case of rabies in a Ghanaian school child 5 years after the exposure incident, and the vital role of molecular tools in the confirmation of the diagnosis.

Case presentation

The patient, an 11-year-old junior high school Ghanaian student from the Obuasi Municipality in Ghana, presented with aggressive behavior, which rapidly progressed to confusion and loss of consciousness within a day of onset. Her parents reported that the patient had experienced a bite from a stray dog on her right leg 5 years prior to presentation, for which no antirabies prophylaxis was given. The patient died within minutes of arrival in hospital (within 24 hours of symptom onset). Real-time polymerase chain reaction testing of cerebrospinal fluid obtained after her death confirmed the diagnosis of rabies. Subsequent phylogenetic analysis showed the virus to belong to the Africa 2 lineage of rabies viruses, which is one of the predominant circulating lineages in Ghana.

Conclusion

The incubation period of rabies is highly variable so patients may only present with symptoms long after the exposure incident. Appropriate molecular testing tools, when available as part of rabies control programmes, are vital in confirming cases of rabies.
Native glycan fragments detected by MALDI mass spectrometry imaging are independent prognostic factors in pancreatic ductal adenocarcinoma
Authors: Sun Na , Trajkovic-Arsic Marija , Li Fengxia , Wu Yin , Münch Corinna , Kunzke Thomas , Feuchtinger Annette , Steiger Katja , Schlitter Anna Melissa , Weichert Wilko , Esposito Irene , Siveke Jens T. , Walch Axel
Published: December 2021

Background

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies to date. The impressively developed stroma that surrounds and modulates the behavior of cancer cells is one of the main factors regulating the PDAC growth, metastasis and therapy resistance. Here, we postulate that stromal and cancer cell compartments differentiate in protein/lipid glycosylation patterns and analyze differences in glycan fragments in those compartments with clinicopathologic correlates.

Results

We analyzed native glycan fragments in 109 human FFPE PDAC samples using high mass resolution matrix-assisted laser desorption/ionization Fourier-transform ion cyclotron resonance mass spectrometric imaging (MALDI-FT-ICR-MSI). Our method allows detection of native glycan fragments without previous digestion with PNGase or any other biochemical reaction. With this method, 8 and 18 native glycans were identified as uniquely expressed in only stromal or only cancer cell compartment, respectively. Kaplan–Meier survival model identified glycan fragments that are expressed in cancer cell or stromal compartment and significantly associated with patient outcome. Among cancer cell region-specific glycans, 10 predicted better and 6 worse patient survival. In the stroma, 1 glycan predicted good and 4 poor patient survival. Using factor analysis as a dimension reduction method, we were able to group the identified glycans in 2 factors. Multivariate analysis revealed that these factors can be used as independent survival prognostic elements with regard to the established Union for International Cancer Control (UICC) classification both in tumor and stroma regions.

Conclusion

Our method allows in situ detection of naturally occurring glycans in FFPE samples of human PDAC tissue and highlights the differences among glycans found in stromal and cancer cell compartment offering a basis for further exploration on the role of specific glycans in cancer–stroma communication.
More crime in cities? On the scaling laws of crime and the inadequacy of per capita rankings—a cross-country study
Authors: Oliveira Marcos
Published: December 2021

Crime rates per capita are used virtually everywhere to rank and compare cities. However, their usage relies on a strong linear assumption that crime increases at the same pace as the number of people in a region. In this paper, we demonstrate that using per capita rates to rank cities can produce substantially different rankings from rankings adjusted for population size. We analyze the population–crime relationship in cities across 12 countries and assess the impact of per capita measurements on crime analyses, depending on the type of offense. In most countries, we find that theft increases superlinearly with population size, whereas burglary increases linearly. Our results reveal that per capita rankings can differ from population-adjusted rankings such that they disagree in approximately half of the top 10 most dangerous cities in the data analyzed here. Hence, we advise caution when using crime rates per capita to rank cities and recommend evaluating the linear plausibility before doing so.
A case of complete atrioventricular block with extremely high blood concentration of azelnidipine
Authors: Ide Naohito , Mochizuki Ayaka , Kagawa Yoshiyuki , Ito Masaharu
Published: December 2021

Background

Azelnidipine, a dihydropyridine calcium channel blocker (CCB), has less adverse effects (e.g. hot flushes and reflex tachycardia) compared to other dihydropyridine CCBs. Azelnidipine has been reported to reduce heart rate as opposed to inducing tachycardia. No evidence of bradycardia or complete atrioventricular block (CAVB) with azelnidipine treatment has been reported.

Case presentation

In the present study, a 92-year-old woman was diagnosed with CAVB while taking azelnidipine and simvastatin for an extended period of time, and referred to our medical center. It was thought that the CAVB may have been an adverse effect of azelnidipine treatment. Specifically, it was considered that in this patient, one of the causes might be the concomitant use of simvastatin inhibiting the metabolism of azelnidipine by cytochrome P450 enzyme 3A4. Consequently, it was suggested to the patient’s physician that the patient’s serum azelnidipine levels be measured and treatment with azelnidipine and simvastatin be discontinued. The patient’s serum concentration of azelnidipine at the time of her visit to our center was 63.4 ng/mL, higher than the normal acceptable level. There was no occurrence of CAVB for 4 weeks, to present, following discontinuation of azelnidipine and simvastatin treatment.

Conclusions

Azelnidipine has a different mechanism of action that other CCBs. In very rare cases, it may cause CAVB when combined with CYP3A4 inhibitors. If a patient taking azelnidipine is diagnosed with CAVB, physicians should suspect that the condition may be an adverse effect of azelnidipine and should consider discontinuing azelnidipine. And, in the elderly, it is necessary to avoid concomitant use of CYP3A4 inhibitors.
Associations between measurements of central blood pressure and target organ damage in high-risk patients
Authors: Jeon Ki-Hyun , Kim Hack-Lyoung , Lim Woo-Hyun , Seo Jae-Bin , Kim Sang-Hyun , Zo Joo-Hee , Kim Myung-A
Published: December 2021

Background

It is not well-known which components of central blood pressure (CBP) are more influential to target organ damage (TOD). This study aimed to determine the relationship between CBP measurements and various types of TOD in high-risk patients.

Methods

A total of 148 patients who had documented atherosclerotic cardiovascular disease or its multiple risk factors were prospectively enrolled. CBP was measured by using applanation tonometry of the radial artery. The following nine TOD parameters were evaluated: left ventricular mass index, relative wall thickness, septal e′ velocity, septal E/e′, brachial-ankle pulse wave velocity, ankle-brachial index, estimated glomerular filtration rate, urine protein and obstructive coronary artery disease.

Results

The mean age of the study population was 67.1 ± 9.0 years and 108 (73 %) were male. Among four CBP measurements (systolic, diastolic, mean, and pulse pressures), central pulse pressure (CPP) was associated with the largest number of TOD parameters. As CPP increased, the number of TOD increased (P = 0.010), but this association was not observed in other CBP measurements (P > 0.05 for each).

Conclusions

CPP had a stronger correlation with TOD than other CBP measurements. Non-invasive CPP could be a useful indicator for predicting TOD in patients at high coronary risk.
Medico-legal evidence collection in child sexual assault cases: a forensic significance
Authors: Kaur Suminder , Kaur Simarpreet , Rawat Banita
Published: December 2021

Background

Every year, millions of children face sexual exploitation worldwide. In India, 109 children (National Crime Records Bureau2018) were sexually abused everyday (22% jump from the previous year). Even with advanced DNA techniques, the conviction rate remains low. The methods used for forensic DNA evidence analysis vary around the world, but the primary step of biological evidence collection plays the most vital role. Proper and timely evidence collection from the victim by a trained medical professional is important.

Main body

Dynamics of child sexual assault being massively different from an adult rape demands altogether different approach of evidence collection. A standard sexual kit employed for evidence collection needs urgent modifications considering genital development of pre- and post-pubertal victims. In the present study, parameters including systemic collection and evaluation of forensic evidences, medico-legal examination, and developmental consequences of sexual assault on pre-pubertal victims were assessed. Further suggestions for separate evidence collection kit during medico-legal examination were given for pre-pubertal victims and alleged accused in sexual assault cases in order to streamline and for better evaluation of DNA analysis in forensic laboratories.

Conclusion

The importance of expert medical practitioners plays a significant role in collection of appropriate information and evidences from the victim of sexual assault. General guidelines for evidence collection in sexual assault cases are not well suited for pre-pubertal victims. Appropriate reforms pertaining to the age and genital development of victims are required. Securing clothing as forensic evidence is essential in most cases as it turned out to be the exclusive evidence bearing material. The purpose of this article is to bring awareness about the thorough medical examination and modified sexual assault kit for pre-pubertal victims and alleged accused for a better approach in evidence collection and conviction rate.
Functional outcome in operated patients of multilevel lumbar canal stenosis and use of HRQoL role in depicting the anxiety and its correlation with the pain
Authors: Singh Ajay Kumar , Singh Prashant Raj , Pandey Tarun Kumar , Kumar Ankur , Agarwal Abhay Kumar
Published: December 2021

Background

Lumbar canal stenosis (LCS) is a degenerative spinal disease of elderly people, and it not only impairs the mechanical activity but also alters the economic and mental status of the patients indirectly.

This is single-center observational prospective study conducted for 2 years and included 30 consecutive operated patients of multilevel LCS patients and excluded the patients with single-level LCS, with primary LCS or with grade II subluxation. We analyzed the various measurement indices used for the surgical outcome assessment as ED-5D 5L and OLBPDI (Oswestry low back pain disability index). Statistical analysis was done using SPSS (Statistical Package for Social Sciences) Version 21.0 statistical Analysis Software. The independent t test, post hoc analysis, Wilcoxon signed rank statistic test and RM-ANOVA test were also applied.

Result

Most patients have improvement in pain and all the components of HRQoL (health-related quality of life) after surgery, which was further improved in mean follow-up of 1 year. Our study also suggested that the patients with higher anxiety/depression have higher pain intensity and low HRQoL, which was persistent in postoperative period (p < .001).

Conclusion

ED-5D 5L and OLBPD are good indices to assess all the components of quality of life and give valuable information overall. Anxiety has shown important correlation with the pain component in both preoperative and postoperative phase.
Privacy preserving divisible double auction with a hybridized TEE-blockchain system
Authors: Liu Bingyu , Xie Shangyu , Yang Yuanzhou , Wang Rujia , Hong Yuan
Published: December 2021

Double auction mechanisms have been designed to trade a variety of divisible resources (e.g., electricity, mobile data, and cloud resources) among distributed agents. In such divisible double auction, all the agents (both buyers and sellers) are expected to submit their bid profiles, and dynamically achieve the best responses. In practice, these agents may not trust each other without a market mediator. Fortunately, smart contract is extensively used to ensure digital agreement among mutually distrustful agents. The consensus protocol helps the smart contract execution on the blockchain to ensure strong integrity and availability. However, severe privacy risks would emerge in the divisible double auction since all the agents should disclose their sensitive data such as the bid profiles (i.e., bid amount and prices in different iterations) to other agents for resource allocation and such data are replicated on all the nodes in the network. Furthermore, the consensus requirements will bring a huge burden for the blockchain, which impacts the overall performance. To address these concerns, we propose a hybridized TEE-Blockchain system (system and auction mechanism co-design) to privately execute the divisible double auction. The designed hybridized system ensures privacy, honesty and high efficiency among distributed agents. The bid profiles are sealed for optimally allocating divisible resources while ensuring truthfulness with a Nash Equilibrium. Finally, we conduct experiments and empirical studies to validate the system and auction performance using two real-world applications.
‘Clear explanation’ in mental capacity assessment
Authors: Owen Gareth , Kane Nuala , Keene Alex Ruck
Published: December 2021

We comment on Martin Curtice's article on expert and professional reports for the Court of Protection, which highlights the importance of ‘clear explanation’ in mental capacity assessment. We put the Court in a broader context of the Mental Capacity Act and summarise recent research and education that aims to help give clinicians working in England and Wales capacity assessment guidance that is clinically grounded, multi-perspectival and legally defensible.
Orbital selectivity in the normal state of KFe(2)Se(2) superconductor
Authors: Craco Luis , Leoni Stefano
Published: December 2021

Using density functional dynamical mean-ﬁeld theory, we show how correlation eﬀects lead to pseudogap and Kondo-quasiparticle features in the electronic structure of pure and doped KFe2Se2 superconductor. Therein, correlation- and doping-induced orbital diﬀerentiation are linked to the emergence of an incoherent-coherent crossover in the normal state of KFe2Se2 superconductor. This crossover explains the puzzling temperature and doping dependent evolution of resistivity and Hall coeﬃcient, seen in experiments of alkali-metal intercalated iron-selenide superconductors. Our microscopic description emphasises the role of incoherent and coherent electronic excitations towards unconventional transport responses of strange, bad-metals.
Early-Pregnancy Intermediate Hyperglycemia and Adverse Pregnancy Outcomes Among Women Without Gestational Diabetes
Authors: Ye Yunzhen , Xiong Yu , Zhou Qiongjie , Xiao Xirong , Li Xiaotian
Published: December 2021

Context

Universal early-pregnancy screening for overt diabetes reveals intermediate hyperglycemia (fasting plasma glucose [FPG] [5.1-6.9 mM]).

Objective

We evaluated the association between early-pregnancy intermediate hyperglycemia and adverse pregnancy outcomes among women without gestational diabetes.

Methods

This retrospective cohort study was conducted at the Obstetrics and Gynecology Hospital, Shanghai, China, from 2013 to 2017. All singleton pregnancies with FPG less than or equal to 6.9 mM in early pregnancy and receiving a 75-g oral glucose tolerance test (OGTT) were included. Women with prepregnancy diabetes were excluded. Individuals with normal OGTT were analyzed. Pregnancy outcomes for FPG less than 5.1 mM and intermediate hyperglycemia were evaluated. The primary outcomes were large for gestational age (LGA) and primary cesarean delivery. Multivariate logistic regressions were conducted. Statistical significance was defined as P less than .05.

Results

In total, 24 479 deliveries were included, of which 23 450 (95.8%) had normal OGTTs later in pregnancy (NGT). There were 807 (3.4%) women who had an FPG of 5.1 to 6.9 mM in early pregnancy. Compared to the NGT group with an FPG of less than 5.1 mM in early pregnancy (N = 20692), the intermediate hyperglycemia NGT group (N = 693) had a higher age and body mass index (BMI), and significantly higher rates of LGA, primary cesarean delivery, preterm birth, preeclampsia, and neonatal distress. The rates of primary cesarean delivery (adjusted odds ratio [AOR] 1.24; 95% CI, 1.05-1.45), preterm birth (AOR 1.75; 95% CI, 1.29-2.36), and neonatal distress (AOR 3.29; 95% CI, 1.57-6.89) remained statistically significantly higher after adjustments for maternal age, BMI, and other potential confounding factors.

Conclusion

Women with intermediate hyperglycemia in early pregnancy are at an increased risk for adverse maternal-fetal outcomes, even with normal future OGTTs.
Maternal Polycystic Ovary Syndrome and Offspring Birth Weight: A Mendelian Randomization Study
Authors: Gan Yuexin , Lu Donghao , Yan Chonghuai , Zhang Jun , Zhao Jian
Published: December 2021

Context

Observational associations between maternal polycystic ovary syndrome (PCOS) and offspring birth weight (BW) have been inconsistent and the causal relationship is still uncertain.

Objective

We conducted a 2-sample Mendelian randomization (MR) study to estimate the causal effect of maternal PCOS on offspring BW.

Methods

We constructed genetic instruments for PCOS with 14 single nucleotide polymorphisms (SNPs) which were identified in a genome-wide association study (GWAS) meta-analysis including 10 074 PCOS cases and 103 164 controls of European ancestry from 7 cohorts. The genetic associations of these SNPs with the offspring BW were extracted from summary statistics estimated by the Early Growth Genetics consortium (n = 406 063 European ancestry individuals) using the weighted linear model, an approximation method of structural equation model, which separated maternal genetic effects from fetal genetic effects. We used a 2-sample MR design to examine the causal relationship between maternal PCOS and offspring BW. Sensitivity analyses were conducted to assess the robustness of the MR results.

Results

We found little evidence for a causal effect of maternal PCOS on offspring BW (–6.1 g, 95% CI –16.8 g, 4.6 g). Broadly consistent results were found in the sensitivity analyses.

Conclusion

Despite the large scale of this study, our results suggested little causal effect of maternal PCOS on offspring BW. MR studies with a larger sample size of women with PCOS or more genetic instruments that would increase the variation of PCOS explained are needed in the future.
Conventional and Bidirectional Genetic Evidence on Resting Heart Rate and Cardiometabolic Traits
Authors: Huang Tao , Wang Wenxiu , Wang Jingjia , Lv Jun , Yu Canqing , Guo Yu , Pei Pei , Huang Ninghao , Yang Ling , Millwood Iona Y , Walters Robin G , Chen Yiping , Du Huaidong , Su Jian , Chen Junshi , Chen Zhengming , Tang Yida , Li Liming
Published: December 2021

Context

Observational studies have suggested that higher resting heart rate (RHR) may be associated with increased cardiometabolic risk. However, causal associations are not fully understood.

Objective

We aimed to examine the direction, strength, and causality of the associations of RHR with cardiometabolic traits.

Methods

We assessed the strength of associations between measured RHR and cardiometabolic traits in 506 211 and 372 452 participants from China Kadoorie Biobank (CKB) and UK Biobank (UKB). Mendelian randomization (MR) analyses were used to make causal inferences in 99 228 and 371 508 participants from CKB and UKB, respectively.

Results

We identified significant directionally concordant observational associations between RHR and higher total cholesterol, triglycerides (TG), low-density lipoprotein, C-reactive protein (CRP), glucose, body mass index, waist-hip ratio (WHR), systolic blood pressure (SBP), and diastolic blood pressure (DBP) after the Bonferroni correction. MR analyses showed that 10 beat/min higher genetically predicted RHR was trans-ethnically associated with a higher DBP (beta 2.059 [95% CI 1.544, 2.574] mmHg in CKB; 2.037 [1.845, 2.229] mmHg in UKB), higher CRP (0.180 [0.057, 0.303] log mg/L in CKB; 0.154 [0.134, 0.174] log mg/L in UKB), higher TG (0.052 [−0.009, 0.113] log mmol/L in CKB; 0.020 [0.010, 0.030] log mmol/L in UKB) and higher WHR (0.218 [−0.033, 0.469] % in CKB; 0.225 [0.111, 0.339] % in UKB). In the opposite direction, higher genetically predicted SBP, TG, glucose, and WHR, and lower high-density lipoprotein, were associated with elevated RHR.

Conclusion

Our large-scale analyses provide causal evidence for associations between RHR and cardiometabolic traits, highlighting the importance of monitoring heat rate as a means of alleviating the adverse effects of metabolic disorders.
Risk Factors for and Effects of Persistent and Severe Hypophosphatemia Following Ferric Carboxymaltose
Authors: Schaefer Benedikt , Zoller Heinz , Wolf Myles
Published: December 2021

Context

Hypophosphatemia, osteomalacia, and fractures are complications of certain intravenous iron formulations.

Objective

This study investigated risk factors for incident, severe, and persistent hypophosphatemia, and associated alterations in bone and mineral biomarkers following intravenous iron treatment.

Methods

We analyzed data from the PHOSPHARE-IDA randomized clinical trials, comprising 245 patients aged 18 years or older with iron deficiency anemia at 30 outpatient clinics in the United States who received intravenous ferric carboxymaltose (FCM) or ferric derisomaltose (FDI). Outcome measures included serum phosphate, intact fibroblast growth factor-23 (iFGF23), 1,25-dihydroxyvitamin D (1,25(OH)2D), ionized calcium, parathyroid hormone (PTH), and alkaline phosphatase.

Results

FCM was the only consistent risk factor for incident hypophosphatemia (< 2.0 mg/dL; odds ratio vs FDI: 38.37; 95% CI: 16.62, 88.56; P < 0.001). Only FCM-treated patients developed severe hypophosphatemia (< 1.0 mg/dL; 11.3%; 13/115) or persistent hypophosphatemia (< 2.0 mg/dL at study end; 40.0%; 46/115). More severe hypophosphatemia associated with significantly greater increases in iFGF23, PTH, and alkaline phosphatase, and more severe decreases in 1,25(OH)2D and ionized calcium (all P < 0.05). Patients with persistent vs resolved hypophosphatemia demonstrated significantly greater changes in iFGF23, PTH, 1,25(OH)2D, and N-terminal procollagen-1 peptide levels (all P < 0.01), but alkaline phosphatase increased similarly in both groups.

Conclusion

Treatment with FCM was the only consistent risk factor for hypophosphatemia. Patients who developed severe or persistent hypophosphatemia after FCM treatment manifested more severe derangements in bone and mineral metabolism. Changes in bone biomarkers continued beyond resolution of hypophosphatemia, suggesting ongoing effects on bone that may help explain the association of FCM with osteomalacia and fractures.
Prevalence and Determinants of Transient Congenital Hypothyroidism in Children With Eutopic Gland in France: A Retrospective Cohort Study
Authors: Barry Yaya , Mandereau-Bruno Laurence , Bonaldi Christophe , Cheillan David , Coutant Régis , Léger Juliane , Regnault Nolwenn
Published: December 2021

Context

The increase in the incidence of congenital hypothyroidism (CH) reported worldwide may partly be explained by an increase in the transient form of CH.

Objective

We aimed to estimate the proportion of transient CH (TCH) in France, and to identify associated neonatal and young child characteristics.

Methods

We used probabilistic record linkage to link children with eutopic gland born between 2006 and 2012 recorded in the national French CH registry and the French national health data system (SNDS). Of the 703 children recorded, 484 (68.8%) were linked. We retrospectively examined reimbursement for oral levothyroxine (LT4) between January 1, 2006, and December 31, 2017. Children who had discontinued treatment for 6 months or more before December 31, 2017, were classified as having TCH. We used a Cox model to examine the factors associated with TCH.

Results

Among the main study sample (n = 471), 53.5% were female, 14.2% were preterm, and 13.8% had low birth weight. One-quarter (n = 111, 24.3%) had mild CH (thyroid-stimulating hormone [TSH] < 50 mU/L, serum) at diagnosis and a median LT4 dose at treatment initiation of 30 μg/day. One-third (n = 155, 32.9%) had TCH. Premature birth (adjusted hazard ratio = 2.1 [1.0–4.2]), a TSH < 50 mU/L at CH screening (7.4 [3.2–17.1]), LT4 dose received at 12 months of age (0.98 [0.97–0.99, P = 0.003]), congenital cardiac malformations (6.6 [1.5–29.0]), and year of birth (1.2 [1.1–1.4]) were all associated with TCH.

Conclusion

One-third of the children had TCH, and it was associated with several characteristics at birth and postpartum. These data are useful for CH medical management and epidemiological surveillance.
Blood Pressure Variability and the Risk of Fracture: A Nationwide Cohort Study
Authors: Yoo Jung Eun , Yoon Ji Won , Park Hyo Eun , Han Kyungdo , Shin Dong Wook
Published: December 2021

Context

Although blood pressure variability (BPV) is associated with various health outcomes, only 1 study suggested that BPV is correlated with hip fractures. As cardiovascular disease and fractures share similar pathophysiology, there might be a link between BPV and fractures.

Objective

To investigate the association between BPV and the incident fractures.

Design

Retrospective cohort study.

Setting

Population-based, using the Korean National Health Insurance System database.

Patients or Other Participants

A total of 3 256 070 participants aged ≥50 who participated in ≥3 health examinations within the previous 5 years, including the index year (2009-2010), were included. Outcome data were obtained through the end of 2016.

Exposure

BPV was calculated using variability independent of the mean. High variability was defined as the highest quartile of variability.

Main Outcome Measures

Newly diagnosed fractures.

Results

During the median follow-up of 7.0 years, there were 337 045 cases of any fracture (10.4%). After adjusting for age, sex, income, lifestyle factors, and comorbidities, a higher risk of fracture was observed with higher quartiles of BPV than the lowest quartile group: the adjusted hazard ratios (95% CIs) for incident any fracture were 1.07 (1.06-1.08) in the higher quartile of systolic BPV, 1.06 (1.05-1.07) in that of diastolic BPV, and 1.07 (1.06-1.08) in that of both systolic and diastolic BPV. Consistent results were noted for vertebral fractures and hip fractures, as well as in various subgroup analyses.

Conclusions

A positive association was noted between higher BPV and fracture incidence. BPV is an independent predictor for developing fracture.
Osteoglycin Across the Adult Lifespan
Authors: Woessner Mary N , Hiam Danielle , Smith Cassandra , Lin Xuzhu , Zarekookandeh Navabeh , Tacey Alexander , Parker Lewan , Landen Shanie , Jacques Macsue , Lewis Joshua R , Brennan-Speranza Tara , Voisin Sarah , Duque Gustavo , Eynon Nir , Levinger Itamar
Published: December 2021

Context

Osteoglycin (OGN) is a proteoglycan released from bone and muscle which has been associated with markers of metabolic health. However, it is not clear whether the levels of circulating OGN change throughout the adult lifespan or if they are associated with clinical metabolic markers or fitness.

Objective

We aimed to identify the levels of circulating OGN across the lifespan and to further explore the relationship between OGN and aerobic capacity as well as OGN’s association with glucose and HOMA-IR.

Methods

107 individuals (46 males and 61 females) aged 21-87 years were included in the study. Serum OGN levels, aerobic capacity (VO2peak), glucose, and homeostatic model assessment for insulin resistance (HOMA-IR) were assessed. T-tests were used to compare participant characteristics between sexes. Regression analyses were performed to assess the relationship between OGN and age, and OGN and fitness and metabolic markers.

Results

OGN displayed a nonlinear, weak “U-shaped” relationship with age across both sexes. Men had higher levels of OGN than women across the lifespan (β = 0.23, P = .03). Age and sex explained 16% of the variance in OGN (adjusted R2 = 0.16; P < .001). Higher OGN was associated with higher VO2peak (β = 0.02, P = .001); however, those aged <50 showed a stronger positive relationship than those aged >50. A higher OGN level was associated with a higher circulating glucose level (β = 0.17, P < .01). No association was observed between OGN and HOMA-IR.

Conclusion

OGN was characterized by a U-shaped curve across the lifespan which was similar between sexes. Those with a higher aerobic capacity or higher glucose concentration had higher OGN levels. Our data suggest an association between OGN and aerobic fitness and glucose regulation. Future studies should focus on exploring the potential of OGN as a biomarker for chronic disease.
Impact of Cortisol on Reduction in Muscle Strength and Mass: A Mendelian Randomization Study
Authors: Katsuhara Shunsuke , Yokomoto-Umakoshi Maki , Umakoshi Hironobu , Matsuda Yayoi , Iwahashi Norifusa , Kaneko Hiroki , Ogata Masatoshi , Fukumoto Tazuru , Terada Eriko , Sakamoto Ryuichi , Ogawa Yoshihiro
Published: December 2021

Context

Prolonged exposure to pathological cortisol, as in Cushing’s syndrome causes various age-related disorders, including sarcopenia. However, it is unclear whether mild cortisol excess, for example, accelerates sarcopenia due to aging or chronic stress.

Objective

We used Mendelian randomization (MR) analysis to assess whether cortisol was causally associated with muscle strength and mass.

Methods

Three single-nucleotide polymorphisms associated with plasma cortisol concentrations in the CORtisol NETwork consortium (n = 12 597) were used as instrumental variables. Summary statistics with traits of interest were obtained from relevant genome-wide association studies. For the primary analysis, we used the fixed-effects inverse-variance weighted analysis accounting for genetic correlations between variants.

Results

One SD increase in cortisol was associated with SD reduction in grip strength (estimate, −0.032; 95% CI −0.044 to −0.020; P = 3e-04), whole-body lean mass (estimate, −0.032; 95% CI, −0.046 to −0.017; P = 0.004), and appendicular lean mass (estimate, −0.031; 95% CI, −0.049 to −0.012; P = 0.001). The results were supported by the weighted-median analysis, with no evidence of pleiotropy in the MR-Egger analysis. The association of cortisol with grip strength and lean mass was observed in women but not in men. The association was attenuated after adjusting for fasting glucose in the multivariable MR analysis, which was the top mediator for the association in the MR Bayesian model averaging analysis.

Conclusion

This MR study provides evidence for the association of cortisol with reduced muscle strength and mass, suggesting the impact of cortisol on the development of sarcopenia.
Maternal and Neonatal 3-epi-25-hydroxyvitamin D Concentration and Factors Influencing Their Concentrations
Authors: Mao Di , Yuen Lai-Yuk , Ho Chung-Shun , Wang Chi-Chiu , Tam Claudia Ha-Ting , Chan Michael Ho-Ming , Lowe William L , Ma Ronald Ching-Wan , Tam Wing-Hung
Published: December 2021

Background

Little is known about the presence of 3-epi-25 hydroxyvitamin D in maternal and neonatal circulation, the extent of its contribution to total 25 hydroxyvitamin D, or factors influencing its levels.

Methods

A total of 1502 and 1321 archived maternal and umbilical cord serum samples from the Hyperglycemia and Adverse Pregnancy Outcome Study cohort from Hong Kong were assayed for 25(OH)D2, 25(OH)D3, and isomeric form of 25(OH)D3 (3-epi-25(OH)D3) by a liquid chromatography-tandem mass spectrometry method.

Results

Vitamin D deficiency (total serum 25(OH)D level < 50 nmol/L) and severe vitamin D deficiency (total serum 25(OH)D level < 25 nmol/L) occurred in 590 (39.3%) and 25 (1.7%) mothers, respectively. 3-epi-25(OH)D3 could be detected in 94.5% of maternal and 92.1% of neonatal umbilical sera, with the highest 3-epi-25(OH)D3 levels contributing to 19.9% and 15.3% of the maternal and umbilical cord sera 25(OH)D3 levels, respectively. Pregnancy with a male fetus, ambient solar radiation, and maternal glycemia and 25(OH)D3 levels were independent factors associated with maternal 3-epi-25(OH)D3 level. Advanced maternal age, multiparity, maternal gestational weight gain below the Institute of Medicine recommendation, maternal glycemic status, and earlier gestational age at delivery were significantly associated with higher umbilical cord serum 3-epi-25(OH)D3.

Conclusions

3-epi-25(OH)D3 accounted for a significant portion of total 25(OH)D in maternal and neonatal circulations. Further study is needed to determine the possible mechanism underlying this observation.
Racial Disparities in Acromegaly and Cushing’s Disease: A Referral Center Study in 241 Patients
Authors: Ioachimescu Adriana G , Goswami Neevedita , Handa Talin , Pappy Adlai , Veledar Emir , Oyesiku Nelson M
Published: December 2021

Context

Acromegaly (ACM) and Cushing’s disease (CD) are caused by functioning pituitary adenomas secreting growth hormone and ACTH respectively.

Objective

To determine the impact of race on presentation and postoperative outcomes in adults with ACM and CD, which has not yet been evaluated.

Methods

This is a retrospective study of consecutive patients operated at a large-volume pituitary center. We evaluated (1) racial distribution of patients residing in the metropolitan area (Metro, N = 124) vs 2010 US census data, and(2) presentation and postoperative outcomes in Black vs White for patients from the entire catchment area (N = 241).

Results

For Metro area (32.4% Black population), Black patients represented 16.75% ACM (P = .006) and 29.2% CD (P = .56). Among the total 112 patients with ACM, presentations with headaches or incidentaloma were more common in Black patients (76.9% vs 31% White, P = .01). Black patients had a higher prevalence of diabetes (54% vs 16% White, P = .005), significantly lower insulin-like growth factor (IGF)-1 deviation from normal (P = .03) and borderline lower median growth hormone levels (P = .09). Mean tumor diameter and proportion of tumors with cavernous sinus invasion were similar. Three-month biochemical remission (46% Black, 55% White, P = .76) and long-term IGF-1 control by multimodality therapy (92.3% Black, 80.5% White, P = .45) were similar. Among the total 129 patients with CD, Black patients had more hypopituitarism (69% vs 45% White, P = .04) and macroadenomas (33% vs 15% White, P = .05). At 3 months, remission rate was borderline higher in White (92% vs 78% Black, P = 0.08), which was attributed to macroadenomas by logistic regression.

Conclusion

We identified disparities regarding racial distribution, and clinical and biochemical characteristics in ACM, suggesting late or missed diagnosis in Black patients. Large nationwide studies are necessary to confirm our findings.
Delayed Follow-up Visits and Thyrotropin Among Patients With Levothyroxine During the COVID-19 Pandemic
Authors: Inoue Kosuke , Noh Jaeduk Yoshimura , Yoshihara Ai , Watanabe Natsuko , Matsumoto Masako , Fukushita Miho , Suzuki Nami , Hoshiyama Ayako , Mitsumatsu Takako , Suzuki Ai , Kinoshita Aya , Mikura Kentaro , Yoshimura Ran , Sugino Kiminori , Ito Koichi
Published: December 2021

Context

The indirect effects of the COVID-19 pandemic on clinical practice have received great attention, but evidence regarding thyroid disease management is lacking.

Objective

We aimed to investigate the association between delayed follow-up visits during the pandemic and their serum thyrotropin (TSH) levels among patients being treated with levothyroxine.

Methods

This study included 25 361 patients who made a follow-up visit as scheduled (n = 9063) or a delayed follow-up visit (< 30 d, n = 10 909; ≥ 30 d, n = 5389) during the pandemic (after April 2020) in Japan. We employed modified Poisson models to estimate the adjusted risk ratio (aRR) of TSH greater than 4.5 mIU/L and greater than 10 mIU/L during the pandemic according to the 3 types of follow-up visit group (ie, as scheduled, delayed < 30 d, and delayed ≥ 30 d). The models included age, sex, city of residence, TSH levels, underlying thyroid disease, dose of levothyroxine, and duration of levothyroxine prescriptions.

Results

The mean age was 52.8 years and women were 88%. Patients who were older and had a higher dose or longer duration of levothyroxine prescriptions were more likely to make a delayed follow-up visit during the pandemic. Changes in TSH were larger among the delayed-visit groups than the scheduled-visit group. We found increased risks of elevated TSH levels during the pandemic among the delayed visit groups, particularly those with delayed visit of 30 or more days (TSH > 4.5 mIU/L, aRR [95% CI] = 1.72 [1.60-1.85]; and TSH > 10 mIU/L, aRR [95% CI] = 2.38 [2.16-2.62]).

Conclusion

A delayed follow-up visit during the COVID-19 pandemic was associated with less well-controlled TSH among patients with levothyroxine.
Insulin Receptor Autoantibody–mediated Hypoglycemia in a Woman With Mixed Connective Tissue Disease
Authors: Petersen Max C , Graves Jonah M , Yao Tony , Schomburg Lutz , Minich Waldemar B , Parks Deborah L , McGill Janet B , Salam Maamoun
Published: December 2021

Autoantibodies to the insulin receptor are rare and typically cause severe insulin resistance and hyperglycemia, a condition termed type B insulin resistance. Uncommonly, antibodies to the insulin receptor can cause hypoglycemia. We present the case of a woman who developed recurrent severe hypoglycemia and myopathy, was found to have insulin receptor autoantibodies and mixed connective tissue disease, and had resolution of hypoglycemia with immunosuppression. A 55-year-old woman with a history of obesity, hypertension, and prior hemorrhagic stroke presented with recurrent severe hypoglycemia. A diagnostic fast resulted in hypoinsulinemic hypoketotic hypoglycemia. Adrenal function was intact. Progressive myopathy had developed simultaneously with her hypoglycemia, and rheumatologic evaluation revealed mixed connective tissue disease. The plasma acylcarnitine profile was normal, extensive oncologic evaluation including insulin-like growth factor 2 measurement was unrevealing, and anti-insulin antibody testing was negative. Ultimately, anti-insulin receptor antibodies were found to be present. The patient was treated with glucocorticoids and rituximab. Eight weeks after initiation of immunosuppression, the insulin receptor antibody titer had decreased and hypoglycemia had resolved. Eight months after diagnosis, the patient remained free of severe hypoglycemia despite tapering of glucocorticoids to a near-physiologic dose. Though antibodies to the insulin receptor typically cause severe insulin resistance, this patient had no evidence of insulin resistance and instead presented with recurrent severe hypoglycemia, which responded to glucocorticoids and rituximab. The diagnosis of insulin receptor antibody–mediated hypoglycemia is rare but should be considered in patients with systemic autoimmune disease, including mixed connective tissue disease, in the appropriate clinical context.
The Cross-sectional Average Inequality in Lifespan (CAL†): A Lifespan Variation Measure That Reflects the Mortality Histories of Cohorts
Authors: Nepomuceno Marília R. , Cui Qi , van Raalte Alyson , Aburto José Manuel , Canudas-Romo Vladimir
Published: December 2021

Lifespan variation is a key metric of mortality that describes both individual uncertainty about the length of life and heterogeneity in population health. We propose a novel and timely lifespan variation measure, which we call the cross-sectional average inequality in lifespan, or CAL†. This new index provides an alternative perspective on the analysis of lifespan inequality by combining the mortality histories of all cohorts present in a cross-sectional approach. We demonstrate how differences in the CAL† measure can be decomposed between populations by age and cohort to explore the compression or expansion of mortality in a cohort perspective. We apply these new methods using data from 10 low-mortality countries or regions from 1879 to 2013. CAL† reveals greater uncertainty in the timing of death than the period life table–based indices of variation indicate. Also, country rankings of lifespan inequality vary considerably between period and cross-sectional measures. These differences raise intriguing questions as to which temporal dimension is the most relevant to individuals when considering the uncertainty in the timing of death in planning their life courses.
Blood progenitor redox homeostasis through olfaction-derived systemic GABA in hematopoietic growth control in Drosophila
Authors: Goyal Manisha , Tomar Ajay , Madhwal Sukanya , Mukherjee Tina
Published: December 2021

The role of reactive oxygen species (ROS) in myeloid development is well established. However, its aberrant generation alters hematopoiesis. Thus, a comprehensive understanding of events controlling ROS homeostasis forms the central focus of this study. We show that, in homeostasis, myeloid-like blood progenitor cells of the Drosophila larvae, which reside in a specialized hematopoietic organ termed the lymph gland, use TCA to generate ROS. However, excessive ROS production leads to lymph gland growth retardation. Therefore, to moderate blood progenitor ROS, Drosophila larvae rely on olfaction and its downstream systemic GABA. GABA internalization and its breakdown into succinate by progenitor cells activates pyruvate dehydrogenase kinase (PDK), which controls inhibitory phosphorylation of pyruvate dehydrogenase (PDH). PDH is the rate-limiting enzyme that connects pyruvate to the TCA cycle and to oxidative phosphorylation. Thus, GABA metabolism via PDK activation maintains TCA activity and blood progenitor ROS homeostasis, and supports normal lymph gland growth. Consequently, animals that fail to smell also fail to sustain TCA activity and ROS homeostasis, which leads to lymph gland growth retardation. Overall, this study describes the requirement of animal odor-sensing and GABA in myeloid ROS regulation and hematopoietic growth control.
Force-induced changes of α-catenin conformation stabilize vascular junctions independently of vinculin
Authors: Duong Cao Nguyen , Brückner Randy , Schmitt Martina , Nottebaum Astrid F. , Braun Laura J. , Meyer zu Brickwedde Marika , Ipe Ute , vom Bruch Hermann , Schöler Hans R. , Trapani Giuseppe , Trappmann Britta , Ebrahimkutty Mirsana P. , Huveneers Stephan , de Rooij Johan , Ishiyama Noboru , Ikura Mitsuhiko , Vestweber Dietmar
Published: December 2021

Cadherin-mediated cell adhesion requires anchoring via the β-catenin–α-catenin complex to the actin cytoskeleton, yet, α-catenin only binds F-actin weakly. A covalent fusion of VE-cadherin to α-catenin enhances actin anchorage in endothelial cells and strongly stabilizes endothelial junctions in vivo, blocking inflammatory responses. Here, we have analyzed the underlying mechanism. We found that VE-cadherin–α-catenin constitutively recruits the actin adaptor vinculin. However, removal of the vinculin-binding region of α-catenin did not impair the ability of VE-cadherin–α-catenin to enhance junction integrity. Searching for an alternative explanation for the junction-stabilizing mechanism, we found that an antibody-defined epitope, normally buried in a short α1-helix of the actin-binding domain (ABD) of α-catenin, is openly displayed in junctional VE-cadherin–α-catenin chimera. We found that this epitope became exposed in normal α-catenin upon triggering thrombin-induced tension across the VE-cadherin complex. These results suggest that the VE-cadherin–α-catenin chimera stabilizes endothelial junctions due to conformational changes in the ABD of α-catenin that support constitutive strong binding to actin.