bluuebunny/crossref_metadata_2025 huggingface dataset:
Distinct mechanoreceptor pezo-1 isoforms modulate food intake in the nematode Caenorhabditis elegans
Authors: Hughes Kiley , Shah Ashka , Bai Xiaofei , Adams Jessica , Bauer Rosemary , Jackson Janelle , Harris Emily , Ficca Alyson , Freebairn Ploy , Mohammed Shawn , Fernández Eliana M , Bainbridge Chance , Brocco Marcela , Stein Wolfgang , Vidal-Gadea Andrés G
Published: December 2021

Two PIEZO mechanosensitive cation channels, PIEZO1 and PIEZO2, have been identified in mammals, where they are involved in numerous sensory processes. While structurally similar, PIEZO channels are expressed in distinct tissues and exhibit unique properties. How different PIEZOs transduce force, how their transduction mechanism varies, and how their unique properties match the functional needs of the tissues they are expressed in remain all-important unanswered questions. The nematode Caenorhabditis elegans has a single PIEZO ortholog (pezo-1) predicted to have 12 isoforms. These isoforms share many transmembrane domains but differ in those that distinguish PIEZO1 and PIEZO2 in mammals. We used transcriptional and translational reporters to show that putative promoter sequences immediately upstream of the start codon of long pezo-1 isoforms predominantly drive green fluorescent protein (GFP) expression in mesodermally derived tissues (such as muscle and glands). In contrast, sequences upstream of shorter pezo-1 isoforms resulted in GFP expression primarily in neurons. Putative promoters upstream of different isoforms drove GFP expression in different cells of the same organs of the digestive system. The observed unique pattern of complementary expression suggests that different isoforms could possess distinct functions within these organs. We used mutant analysis to show that pharyngeal muscles and glands require long pezo-1 isoforms to respond appropriately to the presence of food. The number of pezo-1 isoforms in C. elegans, their putative differential pattern of expression, and roles in experimentally tractable processes make this an attractive system to investigate the molecular basis for functional differences between members of the PIEZO family of mechanoreceptors.
Genetic analysis of Caenorhabditis elegans pry-1/Axin suppressors identifies genes involved in reproductive structure development, stress responses, and aging
Authors: Mallick Avijit , Jhaveri Nikita , Jeon Jihae , Chang Yvonne , Shah Krupali , Hosein Hannah , Gupta Bhagwati P
Published: December 2021

The Axin family of scaffolding proteins regulates a wide array of developmental and post-developmental processes in eukaryotes. Studies in the nematode Caenorhabditis elegans have shown that the Axin homolog PRY-1 plays essential roles in multiple tissues. To understand the genetic network of pry-1, we focused on a set of genes that are differentially expressed in the pry-1-mutant transcriptome and are linked to reproductive structure development. Knocking down eight of the genes (spp-1, clsp-1, ard-1, rpn-7, cpz-1, his-7, cdk-1, and rnr-1) via RNA interference efficiently suppressed the multivulva phenotype of pry-1 mutants. In all cases, the ectopic induction of P3.p vulval precursor cell was also inhibited. The suppressor genes are members of known gene families in eukaryotes and perform essential functions. Our genetic interaction experiments revealed that in addition to their role in vulval development, these genes participate in one or more pry-1-mediated biological events. Whereas four of them (cpz-1, his-7, cdk-1, and rnr-1) function in both stress response and aging, two (spp-1 and ard-1) are specific to stress response. Altogether, these findings demonstrate the important role of pry-1 suppressors in regulating developmental and post-developmental processes in C. elegans. Given that the genes described in this study are conserved, future investigations of their interactions with Axin and their functional specificity promises to uncover the genetic network of Axin in metazoans.
Fast neutron mutagenesis in soybean enriches for small indels and creates frameshift mutations
Authors: Wyant Skylar R , Rodriguez M Fernanda , Carter Corey K , Parrott Wayne A , Jackson Scott A , Stupar Robert M , Morrell Peter L
Published: December 2021

The mutagenic effects of ionizing radiation have been used for decades to create novel variants in experimental populations. Fast neutron (FN) bombardment as a mutagen has been especially widespread in plants, with extensive reports describing the induction of large structural variants, i.e., deletions, insertions, inversions, and translocations. However, the full spectrum of FN-induced mutations is poorly understood. We contrast small insertions and deletions (indels) observed in 27 soybean lines subject to FN irradiation with the standing indels identified in 107 diverse soybean lines. We use the same populations to contrast the nature and context (bases flanking a nucleotide change) of single-nucleotide variants. The accumulation of new single-nucleotide changes in FN lines is marginally higher than expected based on spontaneous mutation. In FN-treated lines and in standing variation, C→T transitions and the corresponding reverse complement G→A transitions are the most abundant and occur most frequently in a CpG local context. These data indicate that most SNPs identified in FN lines are likely derived from spontaneous de novo processes in generations following mutagenesis rather than from the FN irradiation mutagen. However, small indels in FN lines differ from standing variants. Short insertions, from 1 to 6 bp, are less abundant than in standing variation. Short deletions are more abundant and prone to induce frameshift mutations that should disrupt the structure and function of encoded proteins. These findings indicate that FN irradiation generates numerous small indels, increasing the abundance of loss-of-function mutations that impact single genes.
A role for synaptonemal complex in meiotic mismatch repair
Authors: Voelkel-Meiman Karen , Oke Ashwini , Feil Arden , Shames Alexander , Fung Jennifer , MacQueen Amy J
Published: December 2021

A large subset of meiotic recombination intermediates form within the physical context of synaptonemal complex (SC), but the functional relationship between SC structure and homologous recombination remains obscure. Our prior analysis of strains deficient for SC central element proteins demonstrated that tripartite SC is dispensable for interhomolog recombination in Saccharomyces cerevisiae. Here, we report that while dispensable for recombination per se, SC proteins promote efficient mismatch repair at interhomolog recombination sites. Failure to repair mismatches within heteroduplex-containing meiotic recombination intermediates leads to genotypically sectored colonies (postmeiotic segregation events). We discovered increased postmeiotic segregation at THR1 in cells lacking Ecm11 or Gmc2, or in the SC-deficient but recombination-proficient zip1[Δ21-163] mutant. High-throughput sequencing of octad meiotic products furthermore revealed a genome-wide increase in recombination events with unrepaired mismatches in ecm11 mutants relative to wildtype. Meiotic cells missing Ecm11 display longer gene conversion tracts, but tract length alone does not account for the higher frequency of unrepaired mismatches. Interestingly, the per-nucleotide mismatch frequency is elevated in ecm11 when analyzing all gene conversion tracts, but is similar between wildtype and ecm11 if considering only those events with unrepaired mismatches. Thus, in both wildtype and ecm11 strains a subset of recombination events is susceptible to a similar degree of inefficient mismatch repair, but in ecm11 mutants a larger fraction of events fall into this inefficient repair category. Finally, we observe elevated postmeiotic segregation at THR1 in mutants with a dual deficiency in MutSγ crossover recombination and SC assembly, but not in the mlh3 mutant, which lacks MutSγ crossovers but has abundant SC. We propose that SC structure promotes efficient mismatch repair of joint molecule recombination intermediates, and that absence of SC is the molecular basis for elevated postmeiotic segregation in both MutSγ crossover-proficient (ecm11, gmc2) and MutSγ crossover-deficient (msh4, zip3) strains.
CLOCK Genetic Variations Are Associated With Age-Related Changes in Sleep Duration and Brain Volume
Authors: Kim Song E , Kim Soriul , Kim Hyeon-Jin , Kim Regina Eun-Young , Kim Sol-Ah , Shin Chol , Lee Hyang Woon
Published: December 2021

Background

Although a connection between sleep disruption and brain aging has been documented, biological mechanisms need to be further clarified. Intriguingly, aging is associated with circadian rhythm and/or sleep dysfunction in a key gene regulating circadian rhythm, Circadian Locomotor Output Cycles Kaput (CLOCK), has been linked to both aging-related sleep disturbances and neurodegenerative diseases. This study aims to investigate how CLOCK genetic variation associates with sleep duration changes and/or volumetric brain alteration.

Methods

This population-based cross-sectional study used data from the Korean Genome Epidemiology Study and analyzed sleep characteristics and genetic and brain imaging data in 2 221 participants (mean 58.8 ± 6.8 years, 50.2% male). Eleven single-nucleotide polymorphisms (SNPs) in CLOCK were analyzed using PLINK software v1.09 to test for their association with sleep duration and brain volume. Haplotype analysis was performed by using pair-wise linkage disequilibrium of CLOCK polymorphisms, and multivariate analysis of covariance was for statistical analysis.

Results

Decreased sleep duration was associated with several SNPs in CLOCK intronic regions, with the highest significance for rs10002541 (p = 1.58 × 10−5). Five SNPs with the highest significance (rs10002541, rs6850524, rs4580704, rs3805151, rs3749474) revealed that CGTCT was the most prevalent. In the major CGTCT haplotype, decreased sleep duration over time was associated with lower cortical volumes predominantly in frontal and parietal regions. Less common haplotypes (GCCTC/CGTTC) had shorter sleep duration and more decreases in sleep duration over 8 years, which revealed smaller total and gray matter volumes, especially in frontal and temporal regions of the left hemisphere.

Conclusion

CLOCK genetic variations could be involved in age-related sleep and brain volume changes.
Creatinine to Cystatin C Ratio, a Biomarker of Sarcopenia Measures and Falls Risk in Community-Dwelling Older Women
Authors: Sim Marc , Dalla Via Jack , Scott David , Lim Wai H , Hodgson Jonathan M , Zhu Kun , Daly Robin M , Duque Gustavo , Prince Richard L , Lewis Joshua R
Published: December 2021

Background

The ratio of creatinine to cystatin C (Cr:Cyc) has been proposed as a biomarker of sarcopenia, as greater Cr:Cyc is typically associated with greater muscle mass. We examined the relationship between Cr:Cyc with individual sarcopenia measures, 5-year self-reported falls, and 12-year fall-related hospitalizations in a prospective cohort study of 1 118 community-dwelling older women (mean age 75.2 ± 2.7 years).

Methods

Serum Cr:Cyc, hand grip strength, and timed-up-and-go performance were assessed at baseline (1998), while dual-energy x-ray absorptiometry-derived appendicular lean mass (ALM)/height2 (m) was obtained in a subset of women at baseline and 1 year (n = 334). Incident 5-year self-reported falls and 12-year falls-related hospitalizations were considered.

Results

In a multivariable-adjusted model, women with the lowest Cr:Cyc (Quartile [Q] 1) had 5% (1.0 kg) weaker grip strength, as well as 3.7% (0.22 kg/m2) and 5.5% (0.031) lower ALM adjusted for height2 or body mass index, respectively, compared to women in Q4 (all p < .05). 329 women reported an incident fall over 5 years, and 326 fall-related hospitalizations were recorded over 12 years. Women in Q1 of Cr:Cyc had a greater relative hazard for a fall over 5 years (hazard ratio [HR] 1.50; 95% confidence interval [CI] 1.11–2.01) and fall-related hospitalization over 12 years (HR 1.53; 95% CI 1.13–2.07) compared to Q4 in the multivariable-adjusted model.

Conclusion

These findings support further investigation into the use of Cr:Cyc as a muscle biomarker to help clinicians identify individuals at risk of falls for early inclusion into evidence-based primary prevention programs targeting improvements to diet and exercise.
Association Between Ambient Fine Particulate Matter and Physical Functioning in Middle-Aged and Older Chinese Adults: A Nationwide Longitudinal Study
Authors: Wang Huiyu , Liu Hengyi , Guo Fuyu , Li Jiajianghui , Li Pengfei , Guan Tianjia , Yao Yao , Lv Xiaozhen , Xue Tao
Published: December 2021

Background

Exposure to air pollution is associated with several chronic diseases and subclinical processes that could subsequently contribute to physical disability. However, whether and to what extent air pollution exposure is associated with objective measures of physical functioning remains understudied.

Methods

We used longitudinal data from the China Health and Retirement Longitudinal Study (CHARLS) and included 10 823 participants who were surveyed at least twice. Annual average exposure to fine particulate matter (PM2.5) was assessed using a state-of-the-art estimator. Physical functioning was assessed with 4 objective tests covering hand-grip strength, balance, repeated chair stands, and gait speed. Mixed-effects models with participants as a random term were used to estimate associations with multiple adjustments.

Results

We found a significant and robust association between exposure to increased PM2.5 and the reduction in hand-grip strength and balance ability. Each 10 μg/m3 increase in annual averaged concentrations of PM2.5 was associated with a 220-g (95% confidence interval [CI]: 127, 312 g) reduction in hand-grip strength per 60 kg of body weight and a 5% risk (95% CI: 2, 7) of reduced balance ability. The estimated effect of each 10 μg/m3 increase in PM2.5 on hand-grip strength and balance ability was equivalent to the effect of aging (1.12 [95% CI: 0.76, 1.48] and 0.98 [95% CI: 0.50, 1.50] years, respectively).

Conclusions

PM2.5 may be differentially associated with various dimensions of physical functioning. Improving air quality can prevent physical disability.
Perceived Physical Fatigability Predicts All-Cause Mortality in Older Adults
Authors: Glynn Nancy W , Gmelin Theresa , Renner Sharon W , Qiao Yujia (Susanna) , Boudreau Robert M , Feitosa Mary F , Wojczynski Mary K , Cosentino Stephanie , Andersen Stacy L , Christensen Kaare , Newman Anne B
Published: December 2021

Background

Perceived physical fatigability is highly prevalent in older adults and associated with mobility decline and other health consequences. We examined the prognostic value of perceived physical fatigability as an independent predictor of risk of death among older adults.

Methods

Participants (N = 2 906), mean age 73.5 [SD, 10.4] years, 54.2% women, 99.7% white enrolled in the Long Life Family Study, were assessed at Visit 2 (2014–2017) with 2.7 [SD, 1.0] years follow-up. The Pittsburgh Fatigability Scale (PFS), a 10-item, self-administered validated questionnaire (score range 0–50, higher = greater fatigability) measured perceived physical fatigability at Visit 2. Deaths post-Visit 2 through December 31, 2019 were identified by family members notifying field centers, reporting during another family member’s annual phone follow-up, an obituary, or Civil Registration System (Denmark). We censored all other participants at their last contact. Cox proportional hazard models predicted mortality by fatigability severity, adjusted for family relatedness and other covariates.

Results

Age-adjusted PFS Physical scores were higher for those who died (19.1 [SE, 0.8]) compared with alive (12.2, [SE, 0.4]) overall, as well as across age strata (p < .001), except for those 60–69 years (p = .79). Participants with the most severe fatigability (PFS Physical scores ≥ 25) were over twice as likely to die (hazard ratio, 2.33 [95% CI, 1.65–3.28]) compared with those who had less severe fatigability (PFS Physical scores < 25) after adjustment.

Conclusions

Our work underscores the utility of the PFS as a novel patient-reported prognostic indicator of phenotypic aging that captures both overt and underlying disease burden that predicts death.
Effects of Physical and Cognitive Training on Falls and Concern About Falling in Older Adults: Results From a Randomized Controlled Trial
Authors: Turunen Katri M , Tirkkonen Anna , Savikangas Tiina , Hänninen Tuomo , Alen Markku , Fielding Roger A , Kivipelto Miia , Stigsdotter Neely Anna , Törmäkangas Timo , Sipilä Sarianna
Published: December 2021

Background

The aim of this study is to investigate whether combined cognitive and physical training provides additional benefits to fall prevention when compared with physical training (PT) alone in older adults.

Methods

This is a prespecified secondary analysis of a single-blind, randomized controlled trial involving community-dwelling men and women aged 70–85 years who did not meet the physical activity guidelines. The participants were randomized into combined physical and cognitive training (PTCT, n = 155) and PT (n = 159) groups. PT included supervised and home-based physical exercises following the physical activity recommendations. PTCT included PT and computer-based cognitive training. The outcome was the rate of falls over the 12-month intervention (PTCT, n = 151 and PT, n = 155) and 12-month postintervention follow-up (PTCT, n = 143 and PT, n = 148). Falls were ascertained from monthly diaries. Exploratory outcomes included the rate of injurious falls, faller/recurrent faller/fall-related fracture status, and concern about falling.

Results

Estimated incidence rates of falls per person-year were 0.8 (95% confidence interval [CI] 0.7–1.1) in the PTCT and 1.1 (95% CI 0.9–1.3) in the PT during the intervention and 0.8 (95% CI 0.7–1.0) versus 1.0 (95% CI 0.8–1.1), respectively, during the postintervention follow-up. There was no significant difference in the rate of falls during the intervention (incidence rate ratio [IRR] = 0.78; 95% CI 0.56–1.10, p = .152) or in the follow-up (IRR = 0.83; 95% CI 0.59–1.15, p = .263). No significant between-group differences were observed in any exploratory outcomes.

Conclusion

A yearlong PTCT intervention did not result in a significantly lower rate of falls or concern about falling than PT alone in older community-dwelling adults.

Clinical Trial Registration

ISRCTN52388040
Establishing a Framework for Gathering Structural and Social Determinants of Health in Alzheimer’s Disease Research Centers
Authors: Stites Shana D , Midgett Sharnita , Mechanic-Hamilton Dawn , Zuelsdorff Megan , Glover Crystal M , Marquez David X , Balls-Berry Joyce E , Streitz Marissa L , Babulal Ganesh , Trani Jean-Francois , Henderson J Neil , Barnes Lisa L , Karlawish Jason , Wolk Dave A
Published: December 2021

Structural and social determinants of health (SSDoH) are environmental conditions in which individuals are born, live, learn, work, play, worship, and age that affect health, functioning, and quality-of-life outcomes across the life course. Growing evidence suggests that SSDoH can help to explain heterogeneity in outcomes in Alzheimer’s disease and Alzheimer’s disease and related dementias (AD/ADRD) research and clinical practice. The National Institute on Aging has prioritized collecting SSDoH data to elucidate disease mechanisms and aid discovery of disease-modifying treatments. However, a major nexus of AD/ADRD research, the national network of Alzheimer’s Disease Research Centers (ADRCs), collects few SSDoH data. We describe a framework for feasibly gathering and modeling SSDoH data across ADRCs. We lay out key constructs, their measures, and empirical evidence for their importance in elucidating disease and prevention mechanisms. Toward a goal of translation, the framework proposes a modular structure with a core set of measures and options for adjunctive modules. We describe considerations for measuring SSDoH in existing geographically and culturally diverse research cohorts. We also outline a rationale for universal implementation of a set of SSDoH measures and juxtapose the approach with alternatives aimed at collecting SSDoH data.
Transcatheter aortic valve replacement in obese patients: procedural vascular complications with the trans-femoral and trans-carotid access routes
Authors: Alperi Alberto , McInerney Angela , Modine Thomas , Chamandi Chekrallah , Tafur-Soto Jose D , Barbanti Marco , Lopez Diego , Campelo-Parada Francisco , Cheema Asim N , Toggweiler Stefan , Saia Francesco , Amat-Santos Ignacio , Oteo Juan F , Serra Viçent , Dabrowski Maciej , Abi-Akar Ramzi , Echavarria Natalia Giraldo , Valvo Roberto , Lopez-Pais Javier , Matta Anthony , Arif Mobeena , Moccetti Federico , Compagnone Miriam , Mohammadi Siamak , Nombela-Franco Luis , Rodés-Cabau Josep
Published: December 2021

OBJECTIVES

Obesity may increase the risk of vascular complications in transfemoral (TF) transcatheter aortic valve replacement (TAVR) procedures. The transcarotid (TC) approach has recently emerged as an alternative access in TAVR. We sought to compare vascular complications and early clinical outcomes in obese patients undergoing TAVR either by TF or TC vascular access.

METHODS

Multicentre registry including obese patients undergoing TF- or TC-TAVR in 15 tertiary centres. All patients received newer-generation transcatheter heart valves. For patients exhibiting unfavourable ileo-femoral anatomic characteristics, the TC approach was favoured in 3 centres with experience with it. A propensity score analysis was performed for overcoming unbalanced baseline covariates. The primary end point was the occurrence of in-hospital vascular complications (Valve Academic Research Consortium-2 criteria).

RESULTS

A total of 539 patients were included, 454 (84.2%) and 85 (15.8%) had a TF and TC access, respectively. In the propensity-adjusted cohort (TF: 442 patients; TC: 85 patients), both baseline and procedural valve-related characteristics were well-balanced between groups. A significant decrease in vascular complications was observed in the TC group (3.5% vs 12% in the TF group, odds ratio: 0.26, 95% CI: 0.07–0.95, P = 0.037). There were no statistically significant differences between groups regarding in-hospital mortality (TC: 2.8%, TF: 1.5%), stroke (TC: 1.2%, TF: 0.4%) and life-threatening/major bleeding events (TC: 2.8%, TF: 3.8%).

CONCLUSIONS

In patients with obesity undergoing TAVR with newer-generation devices, the TC access was associated with a lower rate of vascular complications. Larger randomized studies are warranted to further assess the better approach for TAVR in obese patients.
Problems With Understanding Chlamydia trachomatis Immunology
Authors: Brunham Robert C
Published: December 2021

The payoff for understanding Chlamydia trachomatis immunology is the development of a vaccine. Two lines of research have contributed to our current understanding of C. trachomatis immunology. The first is the Grayston model of type-specific immunity and genus-specific pathology, which was elaborated by Caldwell and Morrison as the major outer membrane protein and heat shock protein 60 paradigm. The second is the murine model of Chlamydia muridarum infection, which established the essential role of major histocompatibility complex class II and CD4 T cells in immunity. However, neither approach has yielded a vaccine. I review these 2 lines of research and conclude with 6 problem areas in human C. trachomatis immunology whose resolution may result in a vaccine.
Productivity, efficiency and gender equity of community mobilisation approaches in trichiasis campaigns: analysis of programmatic data from seven sub-Saharan African countries
Authors: ul Hassan Ehtisham , Kelly Michaela , Waititu Titus , Olobio Nicholas , Kabona George , Mkocha Harran , Kivumbi Peter , Mwale Consity , Mubangizi Alfred , Mugume Francis , Baayenda Gilbert , Mayeku Robert , Massangaie Marilia , Mbofana Mariamo Abdala , Cumaio Mércia , Sisay Alemayehu , Mersha Tolossa , Courtright Paul
Published: December 2021

Background

Achieving elimination of trachoma as a public health problem in trichiasis-endemic districts requires a systematic approach to trichiasis case finding and outreach.

Methods

Programme monitoring data from seven countries for 2017–2019 were used to explore the efficiency of different community mobilisation approaches and uptake of trichiasis surgical services.

Results

Three countries (Ethiopia, Kenya and Mozambique) using broad-based community mobilisation strategies had large numbers of people presenting at outreach but only 2.9% of them had trichiasis, while in four countries (Nigeria, Tanzania, Uganda and Zambia) using house-to-house case finding, 37.5% of outreach attendees had trichiasis. Countries using house-to-house case finding have proportionally more women attending outreach compared with countries using broad-based mobilisation. Among trichiasis cases offered surgery 86% accepted, which was similar for men and women.

Conclusions

In these settings, house-to-house case finding appears to be a more effective and efficient approach to ensure that trichiasis cases, particularly in women, obtain access to surgical services.
Applicability of a General Analytical Approach for Detection of Genetically Modified Organisms: Collaborative Trial
Authors: Wang Chenguang , Huang Chunmeng , Zhu Pengyu , Du Zhixin , Wei Shuang , Fu Wei
Published: December 2021

Background

With the commercialization of genetically modified organisms (GMOs) in the market, laboratories have undergone a significantly increased workload. A universal analytical approach was designed to achieve cost-efficient and high-throughput GMOs screening with high specificity and accuracy. The approach provides accurate qualification of authorized and unauthorized GMOs.

Objective

This article describes the assessment of this analytical approach developed to detect the majority of commercialized GMOs over the world.

Method

Seven elements and three events were detected by qPCR in a single laboratory to detect 59 commercialized GMOs. Certificated reference materials and food/feed samples from the Chinese market were also evaluated for the specificity, conformity, and robustness of this approach and were challenged in the interlaboratory study.

Results

The results showed that elements and events selected can best detect GMO presence with good specificity and sensitivity. The results showed a concordance between 97.5 and 99.56% and the variance between 0.65 and 12.88%, which is in line with the minimum requirement of analytical methods of GMO testing.

Conclusions

The approach validated here can be used to manipulate GMO presence in food and feed and showed the capacity to manipulate GMO trace in the trade and domestic agriculture market in China.

Highlights

A universal analytical approach used to track GMO presence was evaluated for its specificity, sensitivity, and robustness.
Low-dose mepolizumab is effective as an add-on therapy for treating long-lasting peripheral neuropathy in patients with eosinophilic granulomatosis with polyangiitis
Authors: Nakamura Yuto , Fukutomi Yuma , Sekiya Kiyoshi , Kajiwara Keiichi , Kawasaki Yuichiro , Fujita Norihiro , Nagayama Kisako , Iwata Maki , Iwamoto Keisuke , Yano Koichi , Hamada Yuto , Watai Kentaro , Ryu Kai , Hayashi Hiroaki , Kamide Yosuke , Taniguchi Masami
Published: December 2021

Objective

To assess the effectiveness of low-dose mepolizumab as an add-on therapy for treating peripheral neurological symptoms in eosinophilic granulomatosis with polyangiitis (EGPA).

Methods

We prospectively studied 13 EGPA patients with conventional treatment-resistant peripheral neuropathy. Their symptoms (pain, numbness, and muscle weakness) were assessed on a visual analogue scale (VAS) before and after 12 months of mepolizumab therapy (100 mg every 4 weeks). Peripheral eosinophil levels and several biomarkers including urinary levels of eosinophil-derived neurotoxin (EDN) were measured before and after therapy.

Results

VAS scores for pain and numbness significantly improved after 12 months of mepolizumab therapy (from 67.0 to 48.0, P = 0.012, and from 67.0 to 51.0, P = 0.017, respectively). However, the VAS score for muscle weakness did not improve (P = 0.36). There were significant correlations between treatment-related changes in urinary EDN levels from baseline to 6 months later and percent changes in the VAS scores of pain and numbness (r = 0.75, P = 0.020; r = 0.88, P = 0.002).

Conclusions

Treatment-resistant peripheral neuropathy in EGPA was significantly improved by low-dose mepolizumab, and effectiveness was correlated with decreased urinary EDN. Because the possibility of a placebo effect cannot be formally excluded, placebo-controlled studies will be required in the future.
Efficacy of once-weekly teriparatide for primary prevention of glucocorticoid-induced osteoporosis: A post hoc analysis of the TOWER-GO study
Authors: Tanaka Ikuko , Tanaka Yoshiya , Soen Satoshi , Oshima Hisaji
Published: December 2021

Objectives

A post hoc analysis of the Teriparatide Once-Weekly Efficacy Research for Glucocorticoid-induced Osteoporosis (TOWER-GO) study was performed to examine the effect of once-weekly administration of 56.5 μg teriparatide on primary prevention of glucocorticoid-induced osteoporosis (GIOP).

Methods

Of the subjects of the TOWER-GO study, 73 were included. The percentage changes from baseline in lumbar spine bone mineral density (BMD) and bone turnover markers were evaluated over 72 weeks with once-weekly teriparatide and once-weekly alendronate.

Results

The percentage change of lumbar spine BMD from baseline at 72 weeks was significantly increased in both groups. Bone formation markers were significantly increased by teriparatide administration, although they were slightly decreased by alendronate administration. Bone resorption markers were gradually decreased by teriparatide, whereas alendronate markedly decreased them within 4 weeks. No major safety concerns arose.

Conclusions

In this primary prevention study of GIOP, comparable increases in BMD were observed between alendronate and once-weekly teriparatide. More desirable changes in bone markers were observed with teriparatide administration. These data suggest that once-weekly teriparatide is effective in primary prevention of GIOP.
Negative effect of anger on chronic pain intensity is modified by multiple mood states other than anger: A large population-based cross-sectional study in Japan
Authors: Yamada Keiko , Fujii Tomoko , Kubota Yasuhiko , Wakaizumi Kenta , Oka Hiroyuki , Matsudaira Ko
Published: December 2021

Objectives

To investigate whether mood states other than anger can modify the association between anger and pain intensity in individuals with chronic pain.

Methods

We analysed 22,059 participants with chronic pain, including 214 participants with rheumatoid arthritis (RA), who completed a questionnaire. The Profile of Mood States short form (POMS-SF) was used to assess six dimensions of mood states (anger-hostility, tension-anxiety, depression-dejection, confusion, fatigue, and vigour). A numerical rating scale (NRS) assessed pain intensity. We examined the association between anger-hostility and the NRS and the relationship between POMS-SF components. Moderation analyses were used to investigate whether the five mood states other than anger-hostility modified the effect of anger-hostility on the NRS.

Results

Anger-hostility contributed to pain intensity. Although increased mood states other than vigour were associated with increased pain intensity, these increased mood states appeared to suppress the effect of anger-hostility on pain intensity. Increased vigour was associated with decreased pain intensity and increased the effect of anger-hostility on pain intensity.

Conclusions

Mood states other than anger may influence the association between anger and pain intensity in individuals with chronic pain. It is important to focus on complicated mood states and anger in individuals with chronic pain, including RA.
Trends in actual medication use for child-onset systemic lupus erythematosus using the Japanese health insurance database 2009–18
Authors: Kishi Takayuki , Sakai Ryoko , Tani Yumi , Nagata Satoru , Katsumata Yasuhiro , Miyamae Takako , Harigai Masayoshi
Published: December 2021

Objectives

Immunosuppressive therapy is the mainstay of treatment for child-onset systemic lupus erythematosus (cSLE). Since epidemiological data on Japanese cSLE patients are not available, we evaluated the trends in how treatment choices have changed over time in Japan.

Methods

Using the Japanese health insurance database provided by Medical Data Vision Co., Ltd, we identified cSLE patients and evaluated changes in the use of corticosteroids and immunosuppressive medications and maximum daily doses of prednisolone from 2009 to 2018.

Results

Of 182 cSLE patients, 86% were female, and the median age was 14 years. Oral prednisolone was used in more than 97% of cSLE patients during the study period, and the median of the maximum daily dose in each patient decreased over time. Intravenous cyclophosphamide was used less frequently after 2016, while mycophenolate mofetil and hydroxychloroquine were used frequently after 2016. The use of mizoribine reduced after 2014, whereas the other immunosuppressive medications showed no significant change over time; the use of biological agents was very limited.

Conclusions

Oral prednisolone was the mainstay of treatment for cSLE, and the maximum daily dose has reduced over the past decade. The most frequently prescribed immunosuppressive therapy has shifted to mycophenolate mofetil over time.
Evaluation of locomotive syndrome in patients receiving surgical treatment for degenerative musculoskeletal diseases: A multicentre prospective study using the new criteria
Authors: Kato Satoshi , Demura Satoru , Kabata Tamon , Matsubara Hidenori , Kurokawa Yuki , Kajino Yoshitomo , Okamoto Yoshiyuki , Kuroda Kazunari , Kimura Hiroaki , Shinmura Kazuya , Yokogawa Noriaki , Shimizu Takaki , Igarashi Kentaro , Inoue Daisuke , Tsuchiya Hiroyuki
Published: December 2021

Objectives

This study aimed to evaluate the condition of patients with locomotive syndrome (LS) and their improvement after undergoing surgery for degenerative musculoskeletal diseases using the new criteria, including stage 3.

Methods

In total, 435 patients aged ≥40 years (167 middle-aged and 268 older) were divided into four groups based on the disease location: the lumbar (n = 118), hip (n = 191), knee (n = 80), and foot and ankle (n = 46) groups. Patients were evaluated by pre- and 1 year postoperative LS risk tests, including the stand-up test, two-step test, and 25-Question Geriatric Locomotive Function Scale.

Results

The pre- and postoperative prevalence of LS stage 3 were 78% and 29%, respectively. The postoperative LS stage improved in 62% of patients (77% and 53% in the middle-aged and older groups, respectively). Overall, the knee group showed the worst results, and the foot and ankle groups showed the best pre- and postoperative results. The pre- and postoperative prevalence of LS stage 3 according to the 25-Question Geriatric Locomotive Function Scale were comparable to those based on the total assessment.

Conclusions

The new LS stage criteria are appropriate, and the 25-Question Geriatric Locomotive Function Scale is a good option for evaluating patients requiring surgery.
Coxiella burnetii Infection Associated With Thromboangiitis Obliterans–like Phenomena With Digital Autoamputation: A Case Report and Review of Q Fever–Associated Autoimmunity
Authors: Shepard Zachary , Skorupa Tara , Espinoza Leigh , Erlandson Kristine , Damioli Laura
Published: December 2021

We present a case of a patient with chronic Q fever who presented with digital necrosis, autoamputations, and positive anticentromere antibody, mimicking a scleroderma vasculopathy or thromboangiitis obliterans. Coxiella burnetii infection has long been associated with the presence of autoantibodies and autoimmune phenomena including vasculitis. Clinicians should consider Q fever testing in patients with new-onset autoimmune diseases or autoantibodies and appropriate exposure histories.
The Voices of Samizdat and Magnitizdat
Authors: Komaromi Ann
Published: December 2021

This chapter treats “samizdat” (self-publishing) and “magnitizdat” (audio tape self-publishing) in the late Soviet Union via the concept of the “voice.” Komaromi discusses a select set of examples including guitar poetry; Boris Pasternak’s Doctor Zhivago; Aleksandr Solzhenitsyn’s Gulag Archipelago, Evgeniia Ginzburg’s camp memoirs; poetry at Maiakovskii Square; and the texts of Leningrad second culture. These examples facilitate exploration of the way samizdat and magnitizdat related to official culture, even as they expanded the range of late Soviet culture far beyond what was allowed in print. They also make it possible to analyze the way samizdat and magnitizdat voices mediated between silence and speech, matter and spirit, presence and absence, and the individual and the collective, creating new ways for Soviet citizens to express themselves and be heard by one another.
Predictive Performance of Next Generation Physiologically Based Kinetic (PBK) Model Predictions in Rats Based on In Vitro and In Silico Input Data
Authors: Punt Ans , Louisse Jochem , Pinckaers Nicole , Fabian Eric , van Ravenzwaay Bennard
Published: December 2021

The goal of the present study was to assess the predictive performance of a minimal generic rat physiologically based kinetic (PBK) model based on in vitro and in silico input data to predict peak plasma concentrations (Cmax) upon single oral dosing. To this purpose, a dataset was generated of 3960 Cmax predictions for 44 compounds, applying different combinations of in vitro and in silico approaches for chemical parameterization, and comparison of the predictions to reported in vivo data. Best performance was obtained when (1) the hepatic clearance was parameterized based on in vitro measured intrinsic clearance values, (2) the method of Rodgers and Rowland for calculating partition coefficients, and (3) in silico calculated fraction unbound plasma and Papp values (the latter especially for very lipophilic compounds). Based on these input data, the median Cmax of 32 compounds could be predicted within 10-fold of the observed Cmax, with 22 out of these 32 compounds being predicted within 5-fold, and 8 compounds within 2-fold. Overestimations of more than 10-fold were observed for 12 compounds, whereas no underestimations of more than 10-fold occurred. Median Cmax predictions were frequently found to be within 10-fold of the observed Cmax when the scaled unbound hepatic intrinsic clearance (Clint,u) was either higher than 20 l/h or lower than 1 l/h. Similar findings were obtained with a test set of 5 in-house BASF compounds. Overall, this study provides relevant insights in the predictive performance of a minimal PBK model based on in vitro and in silico input data.
Preoperative Considerations for the Frail Patient
Authors: McCarthy Laura , Haran Emma , Ahern Daniel P. , McDonnell Jake M. , Butler Joseph S.
Published: December 2021

Frailty is a common geriatric syndrome, the relevance of which is becoming increasingly apparent in the clinical setting. It is often accompanied by varying degrees of sarcopenia and/or osteoporosis, leading to a decline in physical function, decreased levels of physical activity, and overall poorer health outcomes in older adults. Identifying this cohort of patients before stressor events such as spinal surgery can prove paramount to improving the postoperative outcomes of these patients. This review provides a pertinent descriptive analysis to aid identification of frailty in a clinical setting, in addition to outlining methods of preoperative intervention that may improve postoperative outcomes.
Prospective, Noninterventional Study of Nivolumab in Real-world Patients With Locally Advanced or Metastatic Non–small Cell Lung Cancer After Prior Chemotherapy (ENLARGE-Lung)
Authors: Sebastian Martin , Gröschel Andreas , Gütz Sylvia , Schulz Holger , Müller-Huesmann Harald , Liersch Rüdiger , von der Heyde Eyck , Wiegand Jörg , Ukena Dieter , Bargon Joachim , Schütte Wolfgang , Riera-Knorrenschild Jorge , Fischer Jürgen R. , Griesinger Frank , Allan Victoria , Waldenberger Daniela , Schumann Christian
Published: December 2021

Nivolumab was the first immune checkpoint inhibitor approved for use in advanced non–small cell lung cancer (NSCLC). This noninterventional, prospective cohort study investigates real-world effectiveness of nivolumab in pretreated NSCLC patients in Germany (Enlarge-Lung/CA209-580). Patients with squamous (SQ) or nonsquamous (NSQ) NSCLC previously treated for locally advanced or metastatic (stage IIIB/IV) disease received nivolumab according to the current Summary of Product Characteristics. Overall survival (OS) was the primary endpoint. Of 907 patients enrolled, 660 patients who were followed for at least 12 months across 79 study centers in Germany, were analyzed. Median OS was 11.2 months [95% confidence interval (CI), 9.1–12.9]; outcomes for the 418 patients with NSQ histology [13.1 mo (95% CI, 10.6-15.6)] were more favorable than outcomes for the 242 patients with SQ histology [8.9 mo (95% CI, 6.4-11.3)]. Patients’ age, presence of distant or brain metastases, or line of therapy did not affect outcomes; however, patients with poor performance status (ECOG-PS ≥2, n=80) had shorter median OS [4.7 mo (95% CI, 3.1–5.4)]. This study represents one of the largest real-world cohorts providing outcomes of nivolumab in pretreated NSCLC. The results match well with the published evidence from pivotal clinical trials and demonstrate clinical effectiveness of nivolumab in advanced NSCLC.
Building Capacity for Community Pediatric Autism Diagnosis: A Systemic Review of Physician Training Programs
Authors: Guan Xiaoning , Zwaigenbaum Lonnie , Sonnenberg Lyn K.
Published: December 2021

Objectives:

Training primary care providers to provide diagnostic assessments for autism spectrum disorder (ASD) decreases wait times and improves diagnostic access. Outcomes related to the quality of these assessments and the impacts on system capacity have not been systematically examined. This systematic review identifies and summarizes published studies that included ASD diagnostic training for primary care providers (PCPs) and aims to guide future training and evaluation methods.

Methods:

Systematic searches of electronic databases, reference lists, and journals identified 6 studies that met 3 inclusion criteria: training for PCPs, community setting, and training outcome(s) reported. These studies were critically reviewed to characterize (1) study design, (2) training model, and (3) outcomes.

Results:

All studies were either pre-post design or nonrandomized trials with a relatively small number of participants. There was considerable heterogeneity among studies regarding the training provided and the program evaluation process. The most evaluated outcomes were access to autism diagnosis and accuracy of diagnosis.

Conclusion:

Training PCPs to make ASD diagnoses can yield high diagnostic agreement with specialty teams' assessments and reduce diagnostic wait times. Current data are limited by small sample size, poor to fair quality study methodology, and heterogenous study designs and outcome evaluations. Evidence is insufficient to draw conclusions about the overall effects of training PCPs for ASD diagnostic assessments. Since further research is still needed, this review highlights which outcomes are relevant to consider when evaluating the quality of ASD assessments across the continuum of approaches.
Gestational Diabetes in Twin Versus Singleton Pregnancies With Normal Weight or Overweight Pre-Pregnancy Body Mass Index
Authors: Dimitris Michelle C. , Kaufman Jay S. , Bodnar Lisa M. , Platt Robert W. , Himes Katherine P. , Hutcheon Jennifer A.
Published: December 2021

Background:

Gestational diabetes might be more common in twin versus singleton pregnancies, yet the reasons for this are unclear. We evaluated the extent to which this relationship is explained by higher mid-pregnancy weight gain within normal weight and overweight pre-pregnancy body mass index (BMI) strata.

Methods:

We analyzed serial weights and glucose screening and diagnostic data abstracted from medical charts for twin (n = 1397) and singleton (n = 3117) pregnancies with normal or overweight pre-pregnancy BMI delivered from 1998 to 2013 at Magee-Womens Hospital in Pennsylvania. We used causal mediation analyses to estimate the total effect of twin versus singleton pregnancy on gestational diabetes, as well as those mediated (natural indirect effect) and not mediated (natural and controlled direct effects) by pathways involving mid-pregnancy weight gain.

Results:

Odds of gestational diabetes were higher among twin pregnancies [odds ratios (ORs) for total effect = 2.83 (95% CI = 1.54, 5.19) for normal weight and 2.09 (95% CI = 1.16, 3.75) for overweight pre pregnancy BMI], yet there was limited evidence that this relationship was mediated by mid-pregnancy weight gain [ORs for natural indirect effect = 1.21 (95% CI = 0.90, 1.24) for normal weight and 1.06 (95% CI = 0.92, 1.21) for overweight pre-pregnancy BMI] and more evidence of mediation via other pathways [ORs for natural direct effect = 2.34 (95% CI = 1.24, 4.40) for normal weight and 1.97 (95% CI = 1.08, 3.60) for overweight pre-pregnancy BMI].

Conclusions:

While twin pregnancies with normal weight or overweight pre-pregnancy BMI experienced higher odds of gestational diabetes versus singletons, most of this effect was explained by pathways not involving mid-pregnancy weight gain.
Placental Development and Pregnancy-Associated Diseases
Authors: Yu Xin , Wu Hongyu , Yang Yun , Wang Feiyang , Wang Yan-Ling , Shao Xuan
Published: December 2021

Serving as the interface between the fetal and maternal environments during gestation, the placenta plays critical roles in the protection of the developing fetus and the maintenance of maternal health. The placenta is primarily derived from the embryonic trophectoderm which differentiates into various subtypes of trophoblast cells through villous and extravillous pathways. The interactions among trophoblasts and multiple decidual cells and immune cells at the maternal-fetal interface fundamentally form the functional units of the placenta, which are responsible for blood perfusion and maternal-fetal material exchange, immune tolerance, and the regulation of pregnancy adaptation. Defects in placental development and functional maintenance are in tight association with adverse pregnancy outcomes such as preeclampsia. In this article, we review recent advances on human trophoblast cell differentiation and the construction of placental functional units and discuss the placental and maternal factors that may contribute to the occurrence of preeclampsia.