bluuebunny/crossref_metadata_2025 huggingface dataset:
Myostatin blockade with a form of the ActRIIB receptor has potent anti‐obesity and insulin sensitizing actions
Authors: Akpan Imo , Dhir Ravindra , Yin Xiaoyan , Lachey Jennifer , Goncalves Marcus , Ahima Rexford S
Published: June 2021

Myostatin (GDF‐8), a member of the Growth and Differentiation Factor (GDF) family, inhibits muscle growth. The cellular action of myostatin is mediated by the activin receptor type IIB (ActRIIB). Loss‐of‐function mutations of the myostatin gene or disruption of myostatin signaling increases muscle mass. Skeletal muscle is the major organ for glucose disposal, thus we hypothesized that blockade of myostatin would enhance glucose metabolism. We administered a decoy form of the activin type IIB receptor [RAP‐031 10 mg/kg] or vehicle intraperitoneally twice weekly for 10 weeks in C57BL/6J mice. RAP‐031 increased body weight and lean tissue and decreased fat content in mice fed regular chow or high‐fat (45%) diet. RAP‐031 increased the weights of soleus, gastrocnemius and tibialis anterior muscles, as well muscle fiber diameters. We assessed glucose homeostasis using hyperinsulinemic‐euglycemic clamp and radioisotopic tracer kinetics. RAP‐031 increased the glucose infusion and disposal rates by 119% and 45% respectively, and suppressed hepatic glucose production by 66%. Together, these results demonstrate that blockade of myostatin signaling by treatment with an ActRIIB‐based therapeutic is a viable approach toward increasing muscle mass, decreasing fat and improving insulin sensitivity. [This work was supported by National Institutes of Health grant R01DK062348 and an Acceleron Pharma research gift].
Endothelial control of myogenic tone in mesenteric arteries is impaired after intermittent hypoxia exposure
Authors: Jackson‐Weaver Olan , Gonzalez Bosc Laura , Kanagy Nancy
Published: June 2021

Sleep apnea (SA) is an independent risk factor for hypertension and rats exposed to intermittent hypoxia (IH) develop hypertension. Both animal and clinical studies of SA report elevated vascular contractility and decreased vasodilation but effects on myogenic tone (MT) are not well‐described. Ca2+ sparks hyperpolarize vascular smooth muscle (VSM) to inhibit MT. We reported previously that IH reduces Ca2+ spark frequency and enhances MT in small mesenteric arteries (SMA). In Sham but not IH SMA, endothelium removal enhanced MT and reduced Ca2+ spark frequency. We hypothesized that endothelial‐derived NO stimulates VSM Ca2+ sparks to inhibit MT in Sham but not IH SMA. We found that NOS inhibition (L‐NNA, 100 μM) had no effect on MT in either IH or Sham SMA (27±5 vs. 23±10 in E‐IH, 10±2 vs 10±2% in Sham). We also observed no effect of cyclooxygenase inhibition (aspirin, 10 μM) or cytochrome P450 inhibition (SKF 525A, 10 μM). However, vessel distensibility was greater in IH than in Sham SMA (0.7±0.1 vs. 0.5±0.1 p<0.05). Denuding enhanced distensibility in Sham but not IH arteries so that distensibility, like MT and spark frequency was not different between IH and Sham in denuded SMA. These results indicate that the endothelial factor(s) that augments Ca2+ spark frequency and inhibits pressure‐induced MT is lost after IH exposure and is not NO, a COX product or a CYP product. This factor may also restrict arterial distensibility.
Store‐operated Ca2+ entry (SOCE) and canonical transient receptor potential channel (TRPC) proteins are expressed in rat distal pulmonary venous smooth muscle
Authors: Peng Gongyong , Lu Wenju , Shimoda Larissa , Ran Pixin , Sylvester J , Wang Jian
Published: June 2021

Chronic hypoxia causes remodeling and alters contractile responses in both pulmonary arteries (PA) and pulmonary veins (PV). Although PA have been studied extensively in this disorder, the mechanisms by which PV respond to hypoxia and whether these responses contribute to chronic hypoxic pulmonary hypertension (CHPH) remain poorly understood. In pulmonary arterial smooth muscle, we have previously demonstrated that influx of Ca2+ through store‐operated calcium channels (SOCC) thought to be composed of TRPC proteins is likely to play an important role in development of CHPH. To determine whether this mechanism could also be operative in pulmonary venous smooth muscle, we measured intracellular Ca2+ concentration ([Ca2+]i) by fura‐2 fluorescence microscopy in primary cultures of pulmonary venous smooth muscle cells (PVSMC) isolated from rat distal PV. In cells perfused with Ca2+‐free media containing cyclopiazonic acid (10 µM) and nifedipine (5 µM) to deplete SR Ca2+ stores and block voltage‐dependent Ca2+ channels, restoration of extracellular Ca2+ caused marked increases in [Ca2+]i whereas MnCl2 (200 µM) quenched fura‐2 fluorescence, indicating SOCE. SKF‐96365 and NiCl2, antagonists of SOCC, blocked SOCE at concentrations that did not alter Ca2+ responses to 60 mM KCl. Real‐time PCR revealed mRNA expression of TRPC1, ‐4, and ‐6, and Western blotting confirmed protein expression of TRPC1, ‐4, and ‐6 in both rat de‐endolthelialized distal PV and PVSMC. Our results suggest that SOCE through Ca2+ channels composed of TRPC proteins could contribute to Ca2+ signaling in distal PVSMC.
Glycogenin protein level in muscle fiber types of stimulated rodent hind limb following changes in glycogen content
Authors: Wilson Rhonda Joanne , Yuan Zongfei , Graham Terry E
Published: June 2021

Glycogenin (GN) may be degraded, may stay bound to partly‐catabolized glycogen or may form unglycosylated GN when glycogen content decreases. Oxidative and glycolytic muscle fibers may respond differently. One hind limb (40 Female Sprague Dawley rats) was stimulated to contract for 40 min to lower glycogen content. The soleus (SOL), red (RG) and white (WG) gastrocnemius muscles from unstimulated and stimulated limbs were examined for total and unglycosylated GN protein levels. Muscle tissue (corresponding unstimulated and stimulated) was grouped (n=6) by post‐stimulation glycogen content (WGI <40; WGII <100; RGI <100, RGII >100; SOL >100 μmol▸g dry wt.−1). GN increased (P≤0.05) in WGI (66%), RGI (33%), and RGII (100%), but was unchanged in WGII and SOL. In WGII, GN decreased in a low‐spin myofibrillar pellet fraction and increased in the soluble fraction (no net change). Unglycosylated GN was detected in stimulated W and RG muscles (up to 25% of total GN) and was most abundant in WGI (lowest glycogen content). In summary, no correlation existed between GN level and glycogen content post‐stimulation either across fiber types or within a fiber type. No net degradation of GN occurred in either W or RG muscles in response to significant reduction in glycogen content; new GN was always synthesized. Pre‐existing GN is likely retained in smaller granules or as unglycosylated protein. Funded by NSERC of Canada.
The effects of combined exercise on inflammatory markers and obesity‐related hormones in obese middle aged women
Authors: Jung Hyemin , Kim Donghee , Lee Hayan , Jang Seonwoong , Baek Kyoungyeop , Yang Meehyun , Kim Hyeok , Kwon Soyoung , Kim Daeyeol , Kuk Doohong , Choi Cheolseung
Published: June 2021

The present study was conducted to know the effects of combined exercise on inflammatory markers and hormones relevant to obesity. Obese middle aged women(age: 46.4±6, BMI: 33.1±2.9, %Fat: 33.5±3.5) had done yoga for stretching, running for aerobic exercise(55‐65 %VO2max for first 1‐6 weeks and 66‐75 %VO2max for later 7‐12 weeks), and dumbbell exercise for resistant exercise(55‐65 %1RM for first 1‐6 weeks and 66‐75 %1RM for later 7‐12 weeks) for a hour per exercise, differently progressed by the day in every week. Blood plasma was extracted at the beginning of exercise, 6 weeks after beginning exercise, and 12 weeks after beginning exercise to analyse inflammatory markers(CRP, TNF‐α), obesity‐related hormones(leptin, adiponectin). One‐way ANOVA was used for data analysis. CRP, TNF‐α decreased at 12 weeks after beginning exercise, comparing to that at the beginning of exercise, but were not statistically significant. Leptin decreased and Adiponectin increased statistically significantly at 12 weeks after beginning exercise, comparing to those at the beginning of exercise(p<.05). Therefore, the combined exercise may be the preventive action against vascular diseases.
Acute effects of exercise with different impact on bone turnover in young healthy males
Authors: Lin Che‐fu , Tu Kuo‐Cheng , Yang Ai‐Lun , Lin Linda, L. , Huang Tsang‐hai
Published: June 2021

Objectives

The purpose of this study was to investigate the acute response of two types of lower‐limb exercise with different mechanical impact on bone metabolism.

Methods

Voluntary young males were recruited and randomly assigned into two exercise groups: plyometric jumping group (n=10) and resistance training (n=9). Heart rate of subjects during exercise was monitored. The subjects consumed diet provided by our laboratory throughout the experimental period. Blood samples were collected before exercise as baseline, and 5min, 15min, 1hr, 3hr, 6hr, 24hr, 48hr, and 72hr after single bout exercise. Serum tartrate‐resistant acid phosphatase (TRAP), osteocalcin (OC), calcium (Ca), phosphorous (Phos), creatine kinase (CK), and lactate (Lac) were determined by EIA methods. Data were analyzed by two‐way (group × time) ANOVA.

Results

Regarding main effects of time, serum TRAP significantly decreased at 5 min (p<0.01), OC decreased at 3 hours (p<0.05), Ca increased at 5min and 15min as compared with baseline data. Lactate reached its peak immediately after the completion of exercise and remained significantly elevated during the following 3 hours. Time and group showed significant interaction in serum CK and Phos.

Conclusions

In conclusion, exercise with different impact induced different response in muscle damage related parameters, while similar pattern of bone turnover shown between two groups. Responses of bone metabolism revealed by serum markers probably caused by a systemic regulation rather than a local mechanical impact.

This study was supported by a grant from the National Science Council (NSC‐95‐2413‐H‐006‐011‐MY2, Taiwan).
Local sensory nerve control of skin blood flow during local warming in type 2 diabetes mellitus
Authors: Strom Nicholas Alan , Sawyer Jessica R. , Roberts Shelly K. , Kingsley‐Berg Shirley M. , Charkoudian Nisha
Published: June 2021

Local warming in human skin elicits a biphasic vasodilation with a local sensory nerve component (initial peak) and nitric oxide mediated plateau. Though microvascular dysfunction in type 2 diabetes mellitus (T2DM) is well known, effects at the neural level of control in individuals with well managed T2DM are less understood. We tested the hypothesis that local sensory nerve contributions to vasodilation are less in T2DM compared to healthy controls (C). We measured skin blood flow using laser‐Doppler flowmetry (LDF) and arterial pressure using Finometer in T2DM and C subjects at baseline and during 35 minutes of local warming (LW) of the skin to 42 °C. Two LDF sites received Ringers via microdialysis throughout LW; one site was pretreated with local lidocaine (LIDO) to block local sensory innervation. Maximum cutaneous vascular conductance (CVC) was evaluated using microdialysis of nitroprusside. In preliminary studies (N = 4 T2DM, 6 C), CVC during the initial peak at the untreated site was decreased in T2DM (73 ± 4 vs. C: 85 ± 5 % max; P = 0.05), but was not different at the LIDO site (T2DM: 54 ± 9 vs. C: 66 ± 6 % max; P > 0.05). The difference between sites (sensory nerve contribution) was similar between groups (T2DM: 19 ± 7 vs. C: 18 ± 7 % max; P > 0.05), and was lower with LIDO than was previously shown with local EMLA. Our results suggest a non‐neural component which is decreased in T2DM.

Supported by NIH HL73884 and CTSA UL1 RR024150.
High salt intake exacerbates the magnitude of the increase in blood pressure in Cyp1a1‐Ren2 transgenic rats with ANG II‐dependent malignant hypertension
Authors: Williams Dustyn E , Davis Porcha D , Mitchell Kenneth D
Published: June 2021

The present study was performed to determine the effects of high‐salt diet on the magnitude of the blood pressure increase that occurs following induction of ANG II‐dependent malignant hypertension in Cyp1a1‐Ren2 transgenic rats with inducible expression of the Ren2 renin gene [TGR(Cyp1a1Ren2)]. Cyp1a1‐Ren2 rats (n=6) were fed a normal diet containing 0.3% indole‐3‐carbinol (I3C) for 10 days to induce malignant hypertension. Rats induced with I3C exhibited an increase in systolic blood pressure (SBP) from 126±11 to 172±10 mmHg (P<0.001). In a second group (n=6), rats were fed a high salt diet (8% NaCl) for 7 days and then induced with 0.3% I3C for 10 days during continued high salt intake. High salt intake alone did not alter basal SBP (126±11 vs. 128±8 mmHg); however, subsequent dietary administration of 0.3% I3C during continued high salt intake increased SBP from 128±8 to 212 ±10 mmHg (P<0.001), a substantially greater increase in SBP than that observed in rats fed a normal salt diet (88±8 vs. 46±17 mmHg, P<0.001). Chronic administration of the AT1 receptor antagonist, Losartan (100 mg/L in drinking water, n=6), markedly attenuated the I3C‐induced increase in SBP (181±8 vs. 212±12 mmHg, P<0.01) in rats induced with I3C and maintained on a high salt diet. Thus, activation of AT1 receptors contributes to the exacerbation of malignant hypertension induced by high dietary salt intake in Cyp1a1‐Ren2 transgenic rats.
Genetically engineered missense mutations in β‐propeller 1 of the low‐density‐lipoprotein receptor‐related protein 5 (LRP5) induce high bone mass and strength
Authors: Niziolek Paul Joseph , Cui Yajun , Warman Matthew L. , Robling Alexander G.
Published: June 2021

The low‐density‐lipoprotein receptor‐related protein 5 (LRP5), a co‐receptor in the Wnt signaling pathway, has been implicated as an important modulator of bone mass. Among humans, a loss of function mutation in LRP5 results in a severe osteoporotic disease, while certain missense mutations in the gene result in a high bone mass (HBM) phenotype. To explore the role of the HBM mutation in skeletal development and function, we have inserted (knocked‐in) two missense LRP5 mutations, A214V and G171V, into mice. We measured areal bone mineral density (aBMD) in vivo from 4.5 weeks to 16.5 weeks of age, and found that HBM mice had a 13‐26% greater aBMD at 4.5 weeks of age when compared to age‐matched wild‐type relatives. These gains were further increased to 28‐47% greater aBMD, compared to wild‐type, at 16.5 weeks of age. We also compared 16 wk old male HBM mice to their wild‐type relatives for bone structural differences. We found significant increases in skull thickness and vertebral trabecular bone parameters. We also found significantly increased femoral bone strength as determined by three‐point bending tests. In summary, we have created two strains of Lrp5 missense mutant mice that model the human high bone mass phenotypes. Supported by NIH AR‐53237 and Indiana CTSI.
Renal responses to potassium restriction depend on dietary sodium
Authors: Yang Li E , Riquier Anne D.M. , Kou Dow‐Ning , Nguyen Mien , McDonough Alicia Ann
Published: June 2021

Previous studies of renal responses to dietary potassium (K) restriction compared control chow containing 0.74%NaCl with and without 2% KCl.

Aim

re‐examine renal responses to K restriction with 2% NaCl chow, the % found in the average American diet. Sprague Dawley rats (n=4‐6) were fed one of these diets 6 d: control chow CKCNa= 2%KCl‐0.74%NaCl, low K chow LKCNa = 0.05%KCl‐0.74%NaCl, high Na chow CKHNa= 2%KCl‐2%NaCl, low K high Na chow LKHNa= 0.05%KCl‐2%NaCl. Rats were placed in metabolic cages overnight, anesthetized for BP, sacrificed, and kidneys removed. Plasma [K] fell from 3.8 to 2.4 mM and [Na] remained at 140 mM in both LKCNa and LKHNa. Compared to LKCNa, LKHNa gained twice as much weight (6 vs 3 g/d), had lower BP (93 vs 101 mmHg) and higher urine osmolality (500 vs 325 mOsm). In renal homogenates of LKCNa vs CKCNa, as previously reported, pool size of NHE3, HK‐ATPase(g) and HK‐ATPase(c) and NaK‐ATPase(b) were increased and pool size of ROMK, ENaC(b) and AQP2 were decreased. In LKHNa vs CKHNa pool size of ROMK and ENaC(b) were reduced but NHE3, HK‐ATPases, NaK‐ATPase, AQP2 were unchanged.

Conclusion

dietary K restriction and/or hypokalemia provoke BP to fall and decrease ROMK and ENaC abundance which are key to conserving K. The additional physiologic and transporter changes seen with lower NaCl diet may be secondary to drastically lowering total electrolytes and/or chloride. DK34316 and UKRO fellowship to LEY.
Comparative analysis of chromosomal damage at buccal cells at patients who suffer from cancer and tuberculosis
Authors: Kurteshi Kemajl , Hadjidekova Valeria , Hoxha Musa , Nefic Hilada
Published: June 2021

Chromosomal damage a evaluate by micronucleus (MN) test at buccal cells at patients of Clinics of University of Prishtina , department of Pulmology . We investigate the 60 patients from which , 20 was sicken from cnacer , 20 sicken from tuberculosis ,20 perssonel (doctors and nurses) and 30 subjects as control group . Founded high frequency at 28 patient (with cancer and tuberculosis ) compared with personel of hospital and control group but not significant .Also founded high frequency of micronucleus at patient who suffer from cancer , copmare with patient who suffer from tuberculosis , but not significant .

Statistical analysis done with software program Sigma stat 3.2 version 2004 year .
On the Road Again to Nursing's Future
Authors: Kennedy Maureen Shawn
Published: June 2021

But how do we get there from here?
Lower Risk of Ischemic Stroke and Major Bleeding Events with Direct Oral Anticoagulants vs. Warfarin
Authors: Rosenberg Karen
Published: June 2021

According to this study:

Patients with valvular atrial fibrillation who were new users of direct oral anticoagulants had lower rates of ischemic stroke or systemic embolism and major bleeding than new users of warfarin.
Creating a pronation therapy team
Authors: Holtz Louella
Published: June 2021

Prone positioning is a recommended therapy for patients with COVID-19 who develop acute respiratory distress syndrome. This article describes the creation, operation, and evolution of the pronation therapy team at the author's Veterans Affairs facility.
Shaft-only Phalloplasty: Technical Modifications to Optimize Aesthetics
Authors: Peters Blair R. , McCreary Eleanor , Putnam Carley A. , Berli Jens U.
Published: June 2021

Shaft-only phalloplasty (SOP) has been described as an alternative option for phalloplasty. Although traditional phalloplasty represents the most complete form of genital gender-affirming surgery, this variation also carries the greatest surgical risk. Patients may opt for a lower risk SOP for reasons including gender identity, gender expression, sexual function, desire for future childbearing, or minimal gender dysphoria associated with sedentary urination. Further, some patients may, due to associated co-morbidities, not be a candidate for neourethral reconstruction. Forgoing urethral reconstruction also means forgoing the presence of a distal urethral meatus and thereby compromising on one of the basic tenets of phalloplasty surgery—the aesthetic appearance. In an SOP, the flap is usually a simple tube with a purse-string suture placed at the distal end. Another concern can be the insufficient bulk of the phallus due to the absence of the volume added by the inner tube. The purpose of this article is to review our technical modifications that allow for creation of a phallic meatus as well as increasing phallic girth when needed. The most frequently described technique to create a neo-urethra is the tube-within-tube concept. We expanded on this and apply it as a short segment for distal meatal creation in an SOP. Improved aesthetics are achieved by creating the appearance of a phallic meatus and when desired, utilizing a lateral de-epithelialized strip to increase phallic bulk and girth. We hope these technical refinements can assist the surgeon in better meeting the goal of creating an aesthetically pleasing phallus.
Perceptions of Saudi Plastic Surgery Residents and Attendings of Online Education during the COVID-19 Pandemic
Authors: Kattan Abdullah E. , Mortada Hatan , Alzaidi Salman , Gelidan Adnan G.
Published: June 2021

Background:

The world has faced an unprecedented challenge in controlling the spread of COVID-19—a rapid reshaping of the healthcare system and education was inevitable. Consequently, residency programs adopted e-learning as a social distancing tool for the continuity of the learning process. In this study, we explore the opinions and perspectives of plastic surgery attending doctors and residents on the implications of e-learning.

Methods:

After obtaining ethical approval, this cross-sectional study was conducted electronically between October and December 2020 among plastic surgery residents and board-certified plastic surgeons in Saudi Arabia. Participants completed a validated, anonymous, self-administered questionnaire. The questionnaire gathered participants’ demographic data, perceptions of online webinars, and audiovisual evaluations. Finally, we compared traditional (in-person) teaching with online webinars. The analysis was performed at a 95% confidence interval using the Statistical Package for Social Sciences (SPSS), version 23.0 (IBM, Armonk, N.Y.).

Results:

A total of 61 responses were included in this study. The majority of respondents (78.7%) were comfortable during webinars, with 38 (62.3%) believing they should supplement traditional teaching methods. Overall, 50.8% were satisfied with the webinars. However, 37.7% were neutral. Most believed that the webinars increased their clinical (67.2%) and surgical skills (67.2%) to reasonable levels.

Conclusions:

Online education provided an excellent educational tool as a viable option to supplement traditional face-to-face training, with most residents being satisfied, supporting the use of this educational tool. More objective research is required to refine existing online plastic surgery teaching methods while creating novel distance e-learning approaches for the future.
The Impact of COVID-19 on the Personal Protective Equipment Practices and Preferences of Craniofacial Surgeons
Authors: Lee James C. , Ozaki Ashley , Ozaki Wayne
Published: June 2021

Background:

The COVID-19 pandemic has raised concern about healthcare worker exposure risk. Surgeons operating near the aerodigestive tract are at particularly high risk, given the respiratory spread of SARS-CoV-2. This study examines the practices and opinions of craniofacial surgeons as they adapt to a worldwide epidemic.

Methods:

An electronic survey study was conducted on practicing craniomaxillofacial surgeons regarding their preference of personal protective equipment use before, during, and after the pandemic in patients with or without COVID-19 infection, as well as demographic data. Statistical analysis was performed to compare changes in behaviors and preferences and differences across demographic groups.

Results:

Craniofacial surgeons changed their behaviors significantly during the pandemic, with 91.5% of respondents wearing N95 masks or powered air purifying respirators for operations involving exposure of the nasal or oral airways on untested patients, compared with 4.3% before the pandemic (P < 0.001). For examinations in the clinic, 100% reported wearing a mask during the pandemic compared with 40.3% before the pandemic (P < 0.001). After the pandemic is over, 31.9% of surgeons planned to continue using an N95 mask or powered air purifying respirator for craniomaxillofacial cases and 80.9% planned to continue using masks in clinic. Overall, 46.8% of respondents believed that N95 masks should be the standard for craniofacial surgery.

Conclusions:

The COVID-19 pandemic has significantly shifted the practices and opinion of craniofacial surgeons toward more protective personal protective equipment. These results indicate that this is likely to persist after the pandemic is over, which may limit surgeon exposure to airborne disease and help the field withstand future epidemic outbreaks.
Methods to assess advanced glycation end-products
Authors: Jaisson Stéphane , Gillery Philippe
Published: June 2021

Purpose of review

Advanced glycation end-products (AGEs) resulting from protein glycoxidation constitute biomarkers of interest in different pathological situations. Several methods for quantifying AGEs in biological fluids or tissues have been developed without any real consensus on a gold standard method. The aim of this review is to provide an overview of recent publications in the field helping to decide if these markers could find their place as diagnostic tools in clinical practice.

Recent findings

This update shows that new AGEs are regularly discovered and new analytical methods (especially mass spectrometry-based methods) regularly described. Skin autofluorescence measurement is increasingly performed due to the practicability of the dedicated devices, in spite of its questionable specificity. In biological fluids, carboxymethyllysine remains the most frequently measured AGE. However, to date, it is still difficult to compare results obtained from different studies because measured AGEs and modes of expression are different and because no method standardization has been initiated.

Despite their potential interest as biomarkers and the availability of unfortunately non-standardized assay methods, AGEs remain confined to clinical research studies without really being used in daily clinical practice. These challenges must be addressed in order to allow their implementation.
Consortium for the study of chronic pancreatitis, diabetes, and pancreatic cancer: achievements and future directions
Authors: Pandol Stephen J. , Forsmark Chris E.
Published: June 2021

Purpose of review

To answer several important clinical questions, the Consortium for the study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer (CPDPC) research consortium has established several ongoing clinical cohort studies focused on pancreatitis in adults and children, pancreatic cancer, and diabetes associated with pancreatic disease. These will provide a unique resource for clinical and basic science research into these hard-to-treat diseases.

Recent findings

The cause, natural history, and prognosis of acute relapsing and chronic pancreatitis in adults and children are being delineated. The mechanisms of diabetes associated with chronic pancreatitis, acute pancreatitis, and pancreatic cancer are being defined. The ability to predict the presence of early-stage pancreatic cancer, thought the presence of new-onset diabetes, is being explored as a strategy to improve survival. The CPDPC is now also turning to developing clinically useful biomarkers, and initiating clinical trials in these difficult to treat pancreatic diseases.

These large prospective patient cohorts, established and followed up by the CPDPC, provide a unique resource to improve the care of patients of all ages with pancreatitis, and to allow earlier diagnosis of pancreatic cancer.
Update on female urethral reconstruction
Authors: Gomez Reynaldo G. , Pfeifer Jessica
Published: June 2021

Purpose of review

Female urethral stricture (FUS) is not frequent but can be the cause of significant morbidity. A somewhat overlooked condition for years, it has received significant attention in recent times. In this review, we update the current evidence surrounding FUS management.

Recent findings

It is estimated that FUS is present in about 1% of all women having check-ups for lower urinary tract symptoms. Etiology is considered as idiopathic in half of the cases, iatrogenic in one-third, whereas infection/inflammation and trauma account for the rest. Symptoms presented are usually nonspecific and nondiagnostic. Pelvic examination, uroflowmetry, endoscopy, and urethrography are the most frequently employed diagnostic tools. Urodynamics/video-urodynamics can be used to document obstruction and to differentiate true anatomic strictures from functional disorders. Urethral dilation (UD) is the most frequent management procedure, sometimes followed by self-dilation, but recurrence is high, at over 50%. By contrast, reconstructive surgery is far more efficient, with overall curative rates of around 90%.

A high index of suspicion is required to identify FUS patients. UD is advised as a first approach but after one or two failed attempts, reconstruction at a referral center should be considered.
An EEG Voyage in Search of Triphasic Waves—The Sirens and Corsairs on the Encephalopathy/EEG Horizon: A Survey of Triphasic Waves
Authors: Kaplan Peter W. , Gélisse Philippe , Sutter Raoul
Published: June 2021

Generalized periodic discharges with triphasic wave (TW) morphology, long referred to as TWs, are typical of many toxic, metabolic, infectious, and cerebral structural problems, often in concert. Identifying TWs has been challenging for the electroencephalographer and clinician, as has been their cause, significance, prognosis, and treatment. This review highlights the many different patterns of TWs with commentary on their various causes and etiologies, characteristics, different morbidities, differentiation from nonconvulsive status epilepticus, and their prognosis. The articles in this Journal of Clinical Neurophysiology special issue on TWs will review the many challenges the clinician face when TWs are sighted.
It is not always about body size: evidence of Rensch's rule in a male weapon
Authors: Machado Glauco , Buzatto Bruno A. , Samia Diogo S. M.
Published: June 2021

In many species, sexual dimorphism increases with body size when males are the larger sex but decreases when females are the larger sex, a macro-evolutionary pattern known as Rensch's rule (RR). Although empirical studies usually focus exclusively on body size, Rensch's original proposal included sexual differences in other traits, such as ornaments and weapons. Here, we used a clade of harvestmen to investigate whether two traits follow RR: body size and length of the fourth pair of legs (legs IV), which are used as weapons in male–male fights. We found that males were slightly smaller than females and body size did not follow RR, whereas legs IV were much longer in males and followed RR. We propose that sexual selection might be stronger on legs IV length than on body size in males, and we discuss the potential role of condition dependence in the emergence of RR.
Clinical Significance of a combination of Biochemical Indexes and Immunity Indexes for hepatitis B disease Prediction
Authors: Zhang Wenyan , Chen Shan , Yang Junzheng
Published: June 2021

Objectives

To explore the clinical significance of the detection of biochemical indexes and immune indexes in the prediction of hepatitis B (HBV) disease.

Methods

150 patients with HBV disease who were treated in our hospital from 2018 to 2020 were selected and divided into acute HBV group (group A), chronic HBV group (group B) and Cirrhosis group (C group), every group included 50 cases, and 50 healthy people were selected as the control group. Peripheral venous blood was collected from subjects from 4 groups, and immune indexes (plasma immunoglobulin G (IgG), plasma immunoglobulin A (IgA), plasma immunoglobulin M (IgM)) of HBV were measured by immune nephelometry, and biochemical indexes (alanine aminotransferase (ALT) and amino acid transaminase (AST)) of HBV were measured by fasting rate method.

Results

Compared with the control group, the immune nephelometry results and fasting rate method showed that the expression of immune indexes (IgG, IgA and IgM) and the expression of biochemical indexes (ALT and AST)in group A, B and C patients were increased significantly (P <0.05), and both of the expression of immune indexes and the biochemical indexes in HBV patients showed an increasing trend accompanied with the aggravation of HBV patients (A<B <C) (P<0.05).

Conclusion

The detection of immune indexes and biochemical indexes has important clinical significance in prediction of HBV patients’ condition, and detect a combination of biochemical indexes and immune indexes can be used to make a comprehensive judgment to provide a reliable laboratory basis for diagnosis of HBV patients’ condition.
Using deep learning to analyze the compositeness of musculoskeletal aging reveals that spine, hip and knee age at different rates, and are associated with different genetic and non-genetic factors
Authors: Goallec Alan Le , Diai Samuel , Collin Sasha , Vincent Théo , Patel Chirag J.
Published: June 2021

With age, the musculoskeletal system undergoes significant changes, leading to diseases such as arthritis and osteoporosis. Due to the aging of the world population, the prevalence of such diseases is therefore expected to starkly increase in the coming decades. While numerous biological age predictors have been developed to assess musculoskeletal aging, it remains unclear whether these different approaches and data capture a single aging process, or if the diverse joints and bones in the body age at different rates. In the following, we leverage 42,000 full body, spine, hip and knee X-ray images and musculoskeletal biomarkers from the UK Biobank and use artificial intelligence to build the most accurate musculoskeletal aging predictor to date (RMSE=2.65±0.01 years; R-Squared=87.6±0.1%). Our predictor is composite and can be used to assess spine age, hip age and knee age, in addition to general musculoskeletal aging. We find that accelerated musculoskeletal aging is moderately correlated between these different musculoskeletal dimensions (e.g hip vs. knee: Pearson correlation=.351±.004). Musculoskeletal aging is heritable at more than 35%, and the genetic factors are partially shared between joints (e.g hip vs. knee: genetic correlation=.52±.04). We identified single nucleotide polymorphisms associated with accelerated musculoskeletal aging in approximately ten genes for each musculoskeletal dimension. General musculoskeletal aging is for example associated with a TBX15 variant linked to Cousin syndrome and acromegaloid facial appearance syndrome. Finally, we identified biomarkers, clinical phenotypes, diseases, environmental and socioeconomic variables associated with accelerated musculoskeletal aging in each dimension. We conclude that, while the aging of the different components of the musculoskeletal system is connected, each bone and joint can age at significantly different rates.
Nusinersen in adult patients with 5q spinal muscular atrophy: a multicenter observational cohorts’ study
Authors: Vázquez-Costa Juan F , Povedano Mónica , Nascimiento-Osorio Andrés E , Escribano Antonio Moreno , Garcia Solange Kapetanovic , Dominguez Raul , Exposito Jessica M , González Laura , Marco Carla , Castillo Julita Medina , Muelas Nuria , de Benito Daniel Natera , Ñungo Garzón Nancy Carolina , Castellano Inmaculada Pitarch , Sevilla Teresa , Hervás David
Published: June 2021

Objective

To assess safety and efficacy of nusinersen in adult 5q spinal muscular atrophy (SMA) patients.

Methods

Patients older than 15 years and followed at least for 6 months with one motor scale (Hammersmith Functional Motor Scale Expanded, HFMSE; Revised Upper Limb module, RULM) in five referral centers were included. Clinical and patients’ global impression of change (CGI-C and PGI-C) were recorded in treated patients at the last visit. Functional scales (Egen Klassification, EK2; Revised Amyotrophic Lateral Sclerosis Functional Rating Scale, ALSFRS-R) and the percent-predicted forced vital capacity were collected when available.

Results

Seventy-nine SMA patients (39 treated with nusinersen) were included. Compared with untreated patients, treated patients showed a significant improvement of 2 points (±0.46) in RULM (p<0.001) after six months. After a mean follow-up of 16 months, nusinersen treatment was associated with a significant improvement in HFMSE (OR=1.15, p=0.006), 6MWT (OR=1.07, p<0.001), and EK2 (OR=0.81, p=0.001).

Compared with untreated patients, more treated patients experienced clinically meaningful improvements in all scales, but these differences were statistically significant only for RULM (p=0.033), ALSFRS-R (p=0.005), and EK2 (p<0.001). According to the CGI-C and PGI-C, 64.1% and 61.5% of treated patients improved with treatment. Being non-sitter was associated with less response to treatment, while longer time of treatment was associated with better response. Most treated patients (77%) presented at least one adverse event, mostly mild.

Conclusions

Nusinersen treatment associates to some improvements in adult SMA patients. Most severely affected patients with complex spines are probably those with the most unfavorable risk-benefit ratio.
Effectiveness of Tocilizumab, Sarilumab, and Anakinra for critically ill patients with COVID-19 The REMAP-CAP COVID-19 Immune Modulation Therapy Domain Randomized Clinical Trial
Authors:   The REMAP-CAP Investigators, Derde Lennie P.G.
Published: June 2021

BACKGROUND

The interleukin-6 receptor antagonist tocilizumab improves outcomes in critically ill patients with coronavirus disease 2019 (COVID-19). However, the effectiveness of other immune modulating agents is unclear.

METHODS

We evaluated four immunomodulatory agents in an ongoing international, multifactorial, adaptive platform trial. Adult participants with COVID-19 were randomized to receive tocilizumab, sarilumab, anakinra, or standard care (control). In addition, a small group (n=21) of participants were randomized to interferon-β1a. The primary outcome was an ordinal scale combining in-hospital mortality (assigned -1) and days free of organ support to day 21. The trial used a Bayesian statistical model with pre-defined triggers for superiority, equivalence or futility.

RESULTS

Statistical triggers for equivalence between tocilizumab and sarilumab; and for inferiority of anakinra to the other active interventions were met at a planned adaptive analysis. Of the 2274 critically ill participants enrolled, 972 were assigned to tocilizumab, 485 to sarilumab, 378 to anakinra and 418 to control. Median organ support-free days were 7 (interquartile range [IQR] –1, 16), 9 (IQR –1, 17), 0 (IQR –1, 15) and 0 (IQR –1, 15) for tocilizumab, sarilumab, anakinra and control, respectively. Median adjusted odds ratios were 1.46 (95%CrI 1.13, 1.87), 1.50 (95%CrI 1.13, 2.00), and 0.99 (95%CrI 0.74, 1.35) for tocilizumab, sarilumab and anakinra, yielding 99.8%, 99.8% and 46.6% posterior probabilities of superiority, respectively, compared to control. Median adjusted odds ratios for hospital survival were 1.42 (95%CrI 1.05,1.93), 1.51 (95%CrI 1.06, 2.20) and 0.97 (95%CrI 0.66, 1.40) for tocilizumab, sarilumab and anakinra respectively, compared to control, yielding 98.8%, 98.8% and 43.6% posterior probabilities of superiority, respectively, compared to control. All treatments appeared safe.

CONCLUSIONS

In patients with severe COVID-19 receiving organ support, tocilizumab and sarilumab are similarly effective at improving survival and reducing duration of organ support. Anakinra is not effective in this population. (ClinicalTrials.gov number: NCT02735707)
Breastfeeding mother-child clinical outcomes after COVID-19 vaccination
Authors: Low Jia Ming , Lee Le Ye , Mei Ng Yvonne Peng , Zhong Youjia , Amin Zubair
Published: June 2021

This is a prospective cohort study of 88 lactating women in Singapore who received two doses of BNT162b2 vaccination (Pfizer/BioNTech), whereby outcomes of mother-child dyads within 28 days after the second vaccine dose were determined through a structured questionnaire. Minimal effects related to breastfeeding were reported in this cohort; 3 of 88 (3.4%) women had mastitis with 1 of 88 (1.1%) women experiencing breast engorgement. We report an incidence of lymphadenopathy in our cohort at 5 of 88 (5.7%). Reassuringly, there was no change in reported breastmilk supply after vaccination. The most common side effect was pain/redness/swelling at the injection site, which was experienced by 57 of 88 (64.8%) women. There were no serious adverse events of anaphylaxis and hospital admissions. No adverse symptoms were reported in 67 of 88 (76.1%) breastfed children.

What’s known on this subject

Two studies reported no serious adverse effects in both mother-child dyads after mRNA COVID-19 vaccination in mothers. Up to 61.9-67% lactating women experienced minor side effects.

What this study adds

We report an incidence of lymphadenopathy in our cohort at 5.7% as opposed to 0.3% from the Pfizer-BioNTech COVID-19 trial. Reassuringly, there was no change in reported milk supply after vaccination. Minimal effects related to breastfeeding were reported in this cohort; 3 (3.4%) women had mastitis with 1 person experiencing breast engorgement. The most common side effect was pain/redness/swelling at the injection site at 64.8%, which was experienced by 57 of 88 (65%) women. No adverse symptoms were reported in the breastfed children.
Did social factors buffer against the effect of adversities on self-harm during the COVID-19 pandemic? A longitudinal analysis of 49,227 UK adults
Authors: Paul Elise , Fancourt Daisy
Published: June 2021

Background

Little is known about which factors exacerbate and buffer the impact of COVID-19 -related adversities on changes in thinking about and engaging in self-harm over time.

Aims

To examine how changes in four social factors contribute to changes in self-harm thoughts and behaviours over time and how these factors in turn interact with adversities and worries about adversities to increase risk for these outcomes.

Method

Data from 49,227 UK adults in the UCL COVID-19 Social Study were analysed across the first 59 weeks of the pandemic. Fixed effects logistic regressions examined time-varying associations between social support quality, loneliness, number of days of face-to-face contact for ≥15 minutes, and number of days phoning/video calling for ≥15 minutes with self-harm thoughts and behaviours. We then examined how these four factors in turn interacted with the total number of adversities and worries about adversity on outcomes.

Results

Increases in the quality of social support decreased the likelihood of both outcomes, whilst greater loneliness increased their likelihood. Associations were inconsistent for telephone/video contact and face-to-face contact with outcomes. Social support buffered and loneliness exacerbated the impact of adversity experiences with self-harm behaviours. Other interactions were inconsistent, and some were in the unexpected direction.

Conclusions

These findings suggest the importance of the quality of one’s social support network, rather than the mere presence of contact, is important for reducing the likelihood of self-harm behaviours in the context of COVID-19 pandemic-related adversity and worry.
Predicting the mutational drivers of future SARS-CoV-2 variants of concern
Authors: Maher M. Cyrus , Bartha Istvan , Weaver Steven , di Iulio Julia , Ferri Elena , Soriaga Leah , Lempp Florian A. , Hie Brian L. , Bryson Bryan , Berger Bonnie , Robertson David L. , Snell Gyorgy , Corti Davide , Virgin Herbert W. , Kosakovsky Pond Sergei L. , Telenti Amalio
Published: June 2021

SARS-CoV-2 evolution threatens vaccine- and natural infection-derived immunity, and the efficacy of therapeutic antibodies. Herein we sought to predict Spike amino acid changes that could contribute to future variants of concern. We tested the importance of features comprising epidemiology, evolution, immunology, and neural network-based protein sequence modeling. This resulted in identification of the primary biological drivers of SARS-CoV-2 intra-pandemic evolution. We found evidence that resistance to population-level host immunity has increasingly shaped SARS-CoV-2 evolution over time. We identified with high accuracy mutations that will spread, at up to four months in advance, across different phases of the pandemic. Behavior of the model was consistent with a plausible causal structure wherein epidemiological variables integrate the effects of diverse and shifting drivers of viral fitness. We applied our model to forecast mutations that will spread in the future, and characterize how these mutations affect the binding of therapeutic antibodies. These findings demonstrate that it is possible to forecast the driver mutations that could appear in emerging SARS-CoV-2 variants of concern. This modeling approach may be applied to any pathogen with genomic surveillance data, and so may address other rapidly evolving pathogens such as influenza, and unknown future pandemic viruses.
Tau assemblies enter the cytosol in a cholesterol sensitive process essential to seeded aggregation
Authors: Tuck Benjamin J. , Miller Lauren V. C. , Wilson Emma L. , Katsinelos Taxiarchis , Cheng Shi , Vaysburd Marina , Knox Claire , Tredgett Lucy , Metzakopian Emmanouil , James Leo C. , McEwan William A.
Published: June 2021

Accumulating evidence supports a prion-like mechanism in the spread of assembled tau in neurodegenerative diseases. Prion-like spread is proposed to require the transit of tau assemblies to the interior of neurons in order to seed aggregation of native, cytosolic tau. This process is poorly understood and remains largely hypothetical. Here, we develop sensitive techniques to quantify the cytosolic entry of tau in real-time. We find that tau does not promote its own entry but, rather, is wholly dependent on cellular machinery. We find that entry to the widely used reporter cell line HEK293 requires clathrin whereas entry to neurons does not. Cholesterol depletion or knockdown of cholesterol transport protein Niemann-Pick type C1 in neurons renders cells highly vulnerable to cytosolic entry and seeded aggregation. Our findings establish entry as the rate-limiting step in seeded aggregation and demonstrate that dysregulated cholesterol, a feature of several neurodegenerative diseases, potentiates tau aggregation.

Graphical Abstract