bluuebunny/crossref_metadata_2025 huggingface dataset:
Controversies in Crohn’s Disease Before and After Pouch Surgery
Authors: Shaffer Seth R. , Bernstein Charles N.
Published: July 2022

BACKGROUND:

IPAA is rarely performed in patients with a known diagnosis of Crohn’s disease, although it may be done in highly selected patients with an absence of perianal disease or small bowel inflammation. Patients with a preoperative diagnosis of Crohn’s disease are, however, at increased risk of developing Crohn’s disease of the pouch. Crohn’s disease of the pouch can also occur in people with a preoperative diagnosis of ulcerative colitis; however, it is unknown whether this phenotype is similar to classic Crohn’s disease involving an intact bowel, or whether it is a distinct entity.

OBJECTIVE:

This study aimed to describe Crohn's disease of the pouch, including luminal inflammation, and fibrostenotic and perforating phenotypes, as well as management of these conditions.

RESULTS:

Crohn's disease of the pouch can present in similar ways as classic Crohn's disease, classified as either inflammatory, fibrostenotic, or penetrating. Criteria involving the diagnosis of Crohn's disease of the pouch are stringent to prevent unnecessary treatments, because a diagnosis of Crohn's disease after IPAA for presumed ulcerative colitis can cause mental anguish. Treatment of Crohn's disease of the pouch depends on the presenting phenotype, although therapies are similar to classic Crohn's disease. Endoscopic, or even surgical treatment, may be required for fibrostenotic and fistulizing diseases.

LIMITATIONS:

Crohn's disease of the pouch is a newly described disease of patients who undergo an ileoanal pouch anastomosis; and therefore, most of the evidence comes from retrospective trials in patients with an initial diagnosis of ulcerative colitis.

CONCLUSIONS:

While Crohn's disease of the pouch is controversial and perhaps a distinct disease within the spectrum of inflammatory bowel diseases, it nonetheless requires long-term medical therapy and close follow-up.
Management of Pouch Neoplasia
Authors: Sugita Akira , Koganei Kazutaka , Tatsumi Kenji
Published: July 2022

BACKGROUND:

Pouch neoplasia occurs following ileal pouch-anal anastomosis, with or without mucosectomy in ulcerative colitis and familiar adenomatous polyposis.

OBJECTIVES:

This study aimed to review available literature and make recommendations regarding pouch neoplasia.

DATA SOURCES:

Data were collected from specialty hospitals, and a literature review was conducted due to the lack of published large-scale studies. Recommendations for treatment were made based on the literature review and expert opinions.

STUDY SELECTION:

Large-scale studies of pouch neoplasia were selected.

INTERVENTION:

The intervention was studies with details of pouch neoplasia.

MAIN OUTCOME MEASURES:

We aimed to identify the management modalities for pouch neoplasia based on the type.

RESULTS:

Pouch neoplasia can occur in each component of the pouch-afferent limb, pouch body, cuff, and anal transitional zone. In patients with ulcerative colitis, pouch neoplasia is treated because colitis-associated neoplasia comprises a multifocal lesion, which most commonly involves the cuff and anal transitional zone. Close surveillance or endoscopic complete resection is optimal for low-grade dysplasia. For adenocarcinoma, high-grade dysplasia, and low-grade dysplasia with difficult complete resection, pouch excision is recommended. In familiar adenomatous polyposis patients with adenomas of the afferent limb or pouch body, endoscopic resection is optimal. Endoscopic resection is feasible for discrete adenoma in the cuff and anal transitional zone, and surgical excision is optimal for laterally spreading, extensive, large, or flat adenoma. For adenocarcinomas involving any component, pouch excision is recommended.

LIMITATIONS:

Published large-scale studies were lacking because of disease rarity.

CONCLUSION:

Pouch neoplasia occurs in each pouch component. In patients with ulcerative colitis, pouch excision is recommended for adenocarcinomas and high-grade dysplasia, whereas endoscopic intervention may be preferable to low-grade dysplasia. In familiar adenomatous polyposis patients, pouch excision is necessary for adenocarcinoma, and endoscopic resection or excisional surgery is optimal for adenoma.
Adnexal torsion: a review of diagnosis and management strategies
Authors: Chang-Patel Erica J. , Palacios-Helgeson Leslie K. , Gould Claire H.
Published: July 2022

Purpose of review

Adnexal torsion remains a diagnostic challenge heavily reliant on high clinical suspicion, with patient presentation and imaging used as adjuncts to aid in its diagnosis. This review summarizes diagnostic and management techniques of adnexal torsion to assist providers when encountering this surgical emergency.

Recent findings

Common findings of adnexal torsion include abdominal pain, nausea, vomiting, and adnexal mass or ovarian enlargement. An elevated neutrophil to lymphocyte ratio may be useful for diagnosis. A ’whirlpool’ sign, ’follicular ring’ sign, enlarged/edematous ovary, and absent Doppler flow to the ovary are highly suggestive of adnexal torsion. Intraoperative visual diagnosis of ovarian death is highly inaccurate, with only 18–20% of ovaries necrotic on pathological examination. Necrotic appearing ovaries have been shown to have follicular activity on ultrasound one year postoperatively.

Pelvic ultrasound remains the first-line imaging modality. In patients of reproductive age, we recommend performing detorsion with ovarian conservation, even in cases where the tissue appears necrotic, given poor intraoperative diagnostic rates of tissue death. Retention of ovarian function is also reliant on a timely diagnosis and intervention. We emphasize that the risk of ovarian damage/loss outweigh the risk of a diagnostic laparoscopy in patients of reproductive age.
The surgical gender gap: the impact of surgeon gender in medicine and gynecologic surgery
Authors: Galhotra Sheena , Smith Rachael B. , Norton Taylor , Mahnert Nichole D.
Published: July 2022

Purpose of review

The purpose of this review is to summarize the current literature evaluating the effect of surgeon gender on patient outcomes and satisfaction, and the impact of gender bias on female surgeons.

Recent findings

The proportion of female physicians has increased in recent years, especially in Obstetrics and Gynecology. Recent literature assessing this impact supports equivalent or superior medical and surgical outcomes for women surgeons and physicians. It also reveals superior counseling and communication styles as perceived by patients. However, women in medicine receive lower patient ratings in competence, medical knowledge, and technical skills despite the existing evidence. Additionally, female physicians experience pay inequality, limited advancement opportunities, higher prevalence of microaggressions, and higher rates of burnout.

Recognition of gender bias is essential to correcting this issue and improving the negative impact it has on female physicians, our patients, and the field of women's health.
Intraoperative dyes, fluorescence and enhanced imaging in benign gynaecologic surgery
Authors: Shibata Renae , Goldman Theodore , Acholonu Uchenna
Published: July 2022

Purpose of review

We review the literature regarding the use of dyes and fluorescence-guided visualization techniques in gynaecological surgery. We also discuss advances in imaging that may enhance surgery by incorporating real-time visual feedback through augmented reality and preoperative planning with patient-specific, three-dimensional printed surgical fields.

Recent findings

Methylene blue is one of the most commonly used dyes, while indocyanine green is the most used agent in fluorescence-guided surgery. Augmented reality and three-dimensional printing are also being increasingly used in gynaecology.

Dyes and fluorescence-based surgeries are commonly utilized to improve anatomic identification, preservation of healthy tissue and excision of disease. In addition, we explore how augmented reality and three-dimensional printing are used in gynaecology.
The role of minimally invasive gynecologic surgeons in the era of subspecialties: when to refer and consult
Authors: Shu Michael , Sosa J’Leise , Reyes Henry D. , Eddib Abeer , Eswar Alexander
Published: July 2022

Purpose of review

Minimally invasive gynecologic surgery (MIGS) is a subspecialty focus of obstetrics and gynecology with focused expertise on complex benign gynecologic disorders. To date, no formal recommendations have been made in defining a referral system for MIGS. This article reviews the evidence regarding common disorders and procedures and their outcomes, and posits a basis for MIGS referral.

Recent findings

In instances where intraoperative and perioperative features may pose clinical challenges to the surgeon and ultimately the patient, the literature suggests the following scenarios may have adverse outcomes, and therefore, benefit from the skills of MIGS subspecialists: fibroids – at least five myomas, myoma size at least 9 cm, and suspected myoma weight at least 500 g; endometriosis – presence of endometrioma(s), suspected stage III/IV endometriosis, and requirement for advanced adjunct procedures; hysterectomy – uteri at least 250 g or 12 weeks estimated size, at least three prior laparotomies, obesity, and complex surgical history with suspected adhesive disease.

A referral system for MIGS subspecialists has proven benefits for both the gynecologic surgical community as well as the patients and their outcomes. This article provides evidence for collaboration with MIGS especially as it relates to leiomyomatous uteri, endometriosis, and complex hysterectomies.
Endometriosis biomarkers of the disease: an update
Authors: Encalada Soto Diana , Rassier Sarah , Green Isabel C. , Burnett Tatnai , Khan Zaraq , Cope Adela
Published: July 2022

Purpose of review

Endometriosis is a complex benign gynaecologic condition with heterogenous presentations and a large impact on the global healthcare system and on the quality of life for millions of women. Currently, the gold standard for diagnosis involves direct visualization of lesions during surgery confirmed by histopathological diagnosis, resulting in an average delay in its initial diagnosis of 8–10 years. Therefore, the search for noninvasive diagnostic testing options has been subject to a large body of research.

Recent findings

Multiple potential biomarkers have been explored for noninvasive testing for endometriosis, including glycoproteins, inflammatory cytokines, immunological molecules, angiogenesis markers, hormones, micro RNAs (miRNAs), proteomics, metabolomics, genomics and the microbiome.

Although there are challenges to consider, areas for real promise and advancement in the noninvasive diagnosis of endometriosis are currently being explored with real promise in the area of miRNAs, proteomics, metabolomics, genomics and the microbiome.
Applications of vaginal natural orifice transluminal endoscopic surgery (vNOTES) in gynecologic surgery
Authors: Reddy Himabindu , Kim Sun Woo , Plewniak Kari
Published: July 2022

Purpose of review

Natural orifice transluminal endoscopic surgery (NOTES) is an emerging approach used across surgical disciplines. This review seeks to assess the growing body of literature on experiences and outcomes using vaginal NOTES (vNOTES) in gynecologic surgery.

Recent findings

Many limitations of vaginal surgery including lack of descensus or restricted vaginal space can be overcome with vNOTES whereas avoiding risks of abdominal incisions in traditional laparoscopy. vNOTES may have superior outcomes in pain, length of stay, and satisfaction for multiple gynecologic indications however additional data is needed to assess cost-effectiveness and long-term outcomes. Surgeons implementing this technique should have adequate experience with both traditional vaginal and laparoscopic approaches. The current body of high-quality studies is heavily influenced by single site, single surgeon studies and as such may not be fully applicable to all practices incorporating this novel technique, and adequate training should precede implementation of Vnotes.

Vaginal surgery is considered the least invasive approach, however, may not be appropriate in all cases. vNOTES presents a novel approach that combines the access and visualization afforded by endoscopy whereas avoiding the risks associated with transabdominal entry and can be considered as a feasible option in gynecologic surgery.
Female sterilization reversal in the era of in-vitro fertilization
Authors: Garg Nisha , Milad Magdy P.
Published: July 2022

Purpose of review

Regret after female sterilization is not uncommon in the United States. Prior to the development of assisted reproductive technology (ART), surgical reversal of sterilization was the only option for patients interested in fertility. First performed in 1972, this procedure has since been refined over the years by gynaecologic surgeons. With in-vitro fertilization (IVF) gaining popularity, interest in sterilization reversal has waned. However, sterilization reversal should remain an important option in patients seeking pregnancy after tubal ligation.

Recent findings

A direct comparison between IVF and sterilization reversal is challenging due to inherent differences in reporting fertility outcomes. However, sterilization reversal may optimize fertility in younger women, whereas IVF may be more effective in older women. The surgical approach to sterilization reversal can be laparotomic, laparoscopic or robotic. Clinical decision making should include consideration of the risk of ectopic pregnancy, interval from sterilization to reversal, type of sterilization procedure, planned anastomotic site and projected remaining tubal length.

In the era of IVF, sterilization reversal still has a place in the management in restoring fertility. Creating awareness of the role of sterilization reversal is the first step in improving access to adequate training in this procedure for the next generation of reproductive surgeons.
Intravaginal embryo culture: a successful alternative to standard IVF that may improve access to care
Authors: Cooper Amber R.
Published: July 2022

Purpose of review

To discuss existing literature and current use of intravaginal culture (IVC) as an option for patients seeking fertility therapies.

Recent findings

IVC is the combination of oocytes and sperm with culture media in a sealed device that is placed vaginally and left in place while fertilization and early embryo development occurs. Studies show that IVC is safe, well-tolerated, and has similar outcomes in patients as compared to standard in vitro fertilization techniques (conventional insemination and/or intracytoplasmic sperm injection). The new device, INVOcell, while recommended by the FDA for minimal stimulation and up to 72 h of culture and seven oocytes, has been used successfully with more oocytes and for 5 days (until blastocyst stage for transfer) in many centers. Live birth rates and neonatal outcomes are reassuring.

Infertility is a common disease and the vast majority of patients globally will not seek care. IVC may improve access to care, lower costs, provide an alternative for patients who have ethical or religious concerns, and be an increasingly utilized option for those seeking ART therapies. It may also ease workflow burdens in labs where space, equipment, or highly trained lab staff are scarce. More data is warranted to track cumulative outcomes and optimize the ideal patient candidate, but it is a viable alternative in the armamentarium of fertility therapies.
The longitudinal relation of inflammation to incidence of vasomotor symptoms
Authors: Gold Ellen B. , Xing Guibo , Avis Nancy E. , Harlow Sioban , Joffe Hadine , Matthews Karen , Pavlovic Jelena M. , Thurston Rebecca C. , Waetjen Elaine
Published: July 2022

Objective

Vasomotor symptoms (VMS), the most frequently reported symptoms during the menopausal transition, have been associated with inflammation. Whether inflammation is a risk factor for or a consequence of VMS remains unclear. The objectives of these analyses were to determine if elevated proinflammatory marker levels were associated with increased incident VMS in women without VMS at baseline and whether these associations varied by menopause transition stage or race/ethnicity.

Methods

We used longitudinal data on incident VMS, high-sensitivity C-reactive protein (hs-CRP; n = 1,922) and interleukin-6 (IL-6; n = 203) from 13 follow-up visits in the Study of Women's Health Across the Nation, which included five racial/ethnic groups of midlife women. We performed multivariable discrete-time survival analyses to determine adjusted hazard ratios (aHRs) for the association of these proinflammatory markers with incident VMS in women without VMS at baseline.

Results

We found no significant associations of incident VMS with dichotomized hs-CRP (>3 vs ≤3 mg/L) at baseline, concurrent or prior visit (aHRs, 1.04-2.03) or IL-6 (>1.44 vs ≤1.44 pg/mL) at visit 1, concurrent or prior visit (aHRs, 0.67-1.62), or continuous hs-CRP or IL-6 values over 13 follow-up visits (with nonsignificant adjusted increased hazards ranging from 0% to 2%).

Conclusions

Our results showed no significant association of the proinflammatory biomarkers, hs-CRP or IL-6, either concurrently or with subsequent incident VMS, indicating that inflammation was unlikely to be a risk factor for VMS. Thus, clinical treatments directed at reducing inflammation would be unlikely to reduce the occurrence of VMS.
Changes in Bronchiolitis Incidence During the Last Two Decades in Tampere, Finland: A Retrospective Study
Authors: Vihikangas Tytti , Palmu Sauli , Koivisto Anna-Maija , Heikkilä Paula
Published: July 2022

Background:

Bronchiolitis, a lower respiratory tract infection, causes a remarkable number of hospitalizations globally. The epidemiology follows the same pattern as respiratory syncytial virus (RSV), the most common pathogen in bronchiolitis. Epidemics have typically followed a biannual pattern in Nordic countries—first, a small epidemic during spring, followed by a higher peak the next autumn. The aim of this study was to evaluate whether the incidence of bronchiolitis hospitalization has changed during the last 2 decades in Tampere, Finland.

Methods:

In this retrospective register-based study, data on infants <12 months of age hospitalized with bronchiolitis in 2000–2019 were collected from electronic files of Tampere University Hospital and analyzed by monthly incidences. Additionally, data on RSV incidences were collected from the Finnish National Infectious Diseases Register for children <5 years of age and living in the study area. Poisson’s regression analysis was used to evaluate changes in the incidence rates of bronchiolitis.

Results:

Of the 1481 infants hospitalized with bronchiolitis, 82.0% had a diagnosis of RSV bronchiolitis. At first, bronchiolitis’ epidemiological pattern followed its typical biannual pattern, then shifted to annual in the middle of the study period, and thereafter occurred biannually again. The highest incidence rate ratios compared to the low-incidence months were between December (22.5), January (25.8) and February (25.5) in 2000–2006, and between February (24.7), March (25.1) and April (21.0) in 2007–2019.

Conclusions:

The epidemiological pattern of bronchiolitis changed during the study period; incidence peaks were higher and have shifted toward spring in recent years.
The Prognostic Predictors of Airway Stenting in Malignant Airway Involvement From Esophageal Carcinoma
Authors: Leelayuwatanakul Nophol , Thanthitaweewat Vorawut , Wongsrichanalai Virissorn , Lertbutsayanukul Chawalit , Prayongrat Anussara , Kitpanit Sarin , Sriprasart Thitiwat
Published: July 2022

Background:

In locoregional esophageal carcinoma (EC), airway involvement is the most common route of extraesophageal metastasis. The prognosis remains poor even with a multimodality approach. Although airway stenting is well known for restoration of the airway, the survival benefit is still lacking.

Methods:

A total of 37 of patients with airway involvement from EC who underwent airway stenting at a single institution from 2015 to 2020 were retrospectively reviewed. Survival curves after stent placement among different groups were analyzed using Kaplan-Meier method.

Results:

Of 37 patients, 34 were male, and the mean age was 58.9 years (42 to 80). EC was commonly located at midesophagus (51.4%). The site of airway involvement was left main bronchus (48.6%), trachea (32.4%), multiple sites (16.2%), and right main bronchus (2.7%). The nature of airway involvement was tumor invasion (91.9%), compression (62.2%), and fistula (37.8%). Twenty-three patients (62.2%) had airway involvement at the time of esophageal cancer diagnosis. Only 4 patients underwent esophageal stenting. The median survival time after stent placement was 97 days (5 to 539). Chemotherapy and/or radiotherapy were given before stent placement in 18 patients (48.6%). Treatment-naive before airway stenting and diagnosis of airway involvement at the same time of EC diagnosis were independent predictors for the increased survival after stent placement (P<0.05). Poststent treatment was associated with improved survival (P=0.002).

Conclusion:

In patients with malignant airway involvement from EC who underwent airway stenting, the prognostic predictors for improved survival were treatment-naive status, receiving treatment after airway stenting, and early-onset of airway involvement.
Synbiotics in the Management of Pediatric Gastrointestinal Disorders
Authors: Hojsak Iva , Kolaček Sanja , Mihatsch Walter , Mosca Alexis , Shamir Raanan , Szajewska Hania , Vandenplas Yvan ,   Working Group on Probiotics and Prebiotics of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition, van den Akker Chris H. P. , Berni Canani Roberto , Dinleyici Ener Cagri , Domellof Magnus , van Goudoever Johannes B. , Guarino Alfredo , Gutierrez‐Castrellon Pedro , Indrio Flavia , Orel Rok , Salvatore Silvia , Weizman Zvi
Published: July 2022

Background:

Synbiotics are a mixture comprising of live microorganisms and substrate(s) selectively utilized by host microorganisms that confers a health benefit on the host. There is an increasing number of studies investigating their role in different diseases and disorders.

Aim:

The purpose of this article is to provide recommendations for the use of synbiotics in the management of pediatric gastrointestinal disorders. The recommendations are developed by the ESPGHAN Special Interest Group on Gut Microbiota and Modifications.

Methods:

From existing literature databases, we searched and appraised all systematic reviews and/or meta‐analyses, and subsequently published randomized controlled trials (RCTs) that compared the use of synbiotics, in all delivery vehicles and formulations, at any dose, compared to no synbiotics. Synbiotics which are part of infant formula were not assessed. The recommendations were formulated only if at least 2 RCTs that used a well‐defined synbiotic were available.

Results:

Based on the currently available evidence, no recommendation can be formulated in favor or against the use of evaluated synbiotic combination in the treatment of acute gastroenteritis, prevention of necrotizing enterocolitis, Helicobacter pylori infection, inflammatory bowel disease, functional gastrointestinal disorders, and allergy in infants and children.

Conclusions:

There is a need for more, well‐designed RCTs on the role of synbiotics in gastrointestinal disorders with the same outcome measures to enable the inter‐studies comparisons.
SARS-CoV-2 Non-Structural Protein 1(NSP1) Mutation Virulence and Natural Selection: Evolutionary Trends in the Six Continents
Authors: Salami Ghaleh Samira , Rahimian Karim , Mahmanzar Mohammadamin , Mahdavi Bahar , Tokhanbigli Samaneh , Mollapour Sisakht Mahsa , Farhadi Amin , Mousakhan Bakhtiari Mahsa , Lee Kuehu Donna , Deng Youping
Published: July 2022

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an unsegmented positivesense single-stranded RNA virus that belongs to the β-coronavirus. This virus was the cause of a novel severe acute respiratory syndrome in 2019 (COVID-19) that emerged in Wuhan, China at the early stage of the pandemic and rapidly spread around the world. Rapid transmission and reproduction of SARS-CoV-2 threaten worldwide health with a high mortality rate from the virus. According to the significant role of non-structural protein 1 (NSP1) in inhibiting host mRNA translation, this study focuses on the link between amino acid sequences of NSP1 and alterations of them spreading around the world. The SARS-CoV-2 NSP1 protein sequences were analyzed and FASTA files were processed by Python language programming libraries. Reference sequences compared with each NSP1 sample to identify every mutation and categorize them were based on continents and frequencies. NSP1 mutations rate divided into continents were different. Based on continental studies, E87D in global vision and also in Europe notably increased. The E87D mutation has significantly risen especially in the last months of the study as the first frequent mutation observed. The remarkable mutations, H110Y and R24C, have the second and third frequencies, respectively. Based on this mutational information, despite NSP1 being a conserved sequence occurrence, these mutations change the rate of flexibility and stability of the NSP1 protein, which can eventually affect inhibiting the host translation.

IMPORTANCE

In this study, we analyzed 6,510,947 sequences of non-structural protein 1 as a conserved region of SARS-CoV-2. According to the obtained results, 93.4819% of samples had no mutant regions on their amino acid sequences. Heat map data of mutational samples demonstrated high percentages of mutations that occurred in the region of 72 to 126 amino acids indicating a hot spot region of the protein. Increased rates of E87D, H110Y, and R24C mutations in the timeline of our study were reported as significant compared to available mutant samples. Analyzing the details of replacing amino acids in the most frequent E87D mutation reveals the role of this alteration in increasing molecule flexibility and destabilizing the structure of the protein.
Trophoblast glycoprotein is required for efficient synaptic vesicle exocytosis from retinal rod bipolar cells
Authors: Wakeham Colin M , Shi Qing , Ren Gaoying , Haley Tammie L , Duvoisin Robert M , von Gersdorff Henrique , Morgans Catherine W
Published: July 2022

Rod bipolar cells (RBCs) faithfully transmit light-driven signals from rod photoreceptors in the outer retina to third order neurons in the inner retina. Recently, significant work has focused on the role of leucine-rich repeat (LRR) proteins in synaptic development and signal transduction at RBC synapses. We previously identified trophoblast glycoprotein (TPBG) as a novel transmembrane LRR protein localized to the dendrites and axon terminals of RBCs. We now examine the effects on RBC physiology and retinal processing of TPBG genetic knockout in mice using immunofluorescence and electrophysiological techniques. The scotopic electroretinogram showed a modest increase in the b-wave and a marked attenuation in oscillatory potentials in the TPBG knockout. No effect of TPBG knockout was observed on the RBC dendritic morphology, TRPM1 currents, or RBC excitability. Because scotopic oscillatory potentials primarily reflect RBC-driven rhythmic activity of the inner retina, we investigated the contribution of TPBG to downstream transmission from RBCs to third-order neurons. Using electron microscopy, we found shorter synaptic ribbons in TPBG knockout axon terminals in RBCs. Time-resolved capacitance measurements indicated that TPBG knockout reduces synaptic vesicle exocytosis and subsequent GABAergic reciprocal feedback without altering voltage-gated Ca2+currents. Thus, TPBG is required for normal synaptic ribbon development and efficient neurotransmitter release from RBCs to downstream cells. Our results highlight a novel synaptic role for TPBG at RBC ribbon synapses and support further examination into the mechanisms by which TPBG regulates RBC physiology.

Graphical abstract
A Markov constraint to uniquely identify elementary flux mode weights in unimolecular metabolic networks
Authors: Chitpin Justin G. , Perkins Theodore J.
Published: July 2022

Elementary flux modes (EFMs) are minimal, steady state pathways characterizing a flux network. Fundamentally, all steady state fluxes in a network are decomposable into a linear combination of EFMs. While there is typically no unique set of EFM weights that reconstructs these fluxes, several optimization-based methods have been proposed to constrain the solution space by enforcing some notion of parsimony. However, it has long been recognized that optimization-based approaches may fail to uniquely identify EFM weights and return different feasible solutions across objective functions and solvers. Here we show that, for flux networks only involving single molecule transformations, these problems can be avoided by imposing a Markovian constraint on EFM weights. Our Markovian constraint guarantees a unique solution to the flux decomposition problem, and that solution is arguably more biophysically plausible than other solutions. We describe an algorithm for computing Markovian EFM weights via steady state analysis of a certain discrete-time Markov chain, based on the flux network, which we call the cycle-history Markov chain. We demonstrate our method with a differential analysis of EFM activity in a lipid metabolic network comparing healthy and Alzheimer’s disease patients. Our method is the first to uniquely decompose steady state fluxes into EFM weights for any unimolecular metabolic network.
Therapeutic doses of ketamine acutely attenuate the aversive effect of losses during decision-making.
Authors: Oemisch Mariann , Seo Hyojung
Published: July 2022

The discovery of rapid-acting antidepressant, ketamine has opened a pathway to a new generation of treatments for depression, and inspired neuroscientific investigation based on a new perspective that non-adaptive changes in the intrinsic excitatory and inhibitory circuitry might underlie the pathophysiology of depression. Nevertheless, it still remains largely unknown how the hypothesized molecular and synaptic levels of changes in the circuitry might mediate behavioral and neuropsychological changes underlying depression, and how ketamine might restore adaptive behavior. Here, we used computational models to analyze behavioral changes induced by therapeutic doses of ketamine, while rhesus macaques were iteratively making decisions based on gains and losses of tokens. When administered intramuscularly or intranasally, ketamine reduced the aversiveness of undesirable outcomes such as losses of tokens without significantly affecting the evaluation of gains, behavioral perseveration, motivation and other cognitive aspects of learning such as temporal credit assignment and time scales of choice and outcome memory. Ketamine's potentially antidepressant effect was separable from other side effects such as fixation errors, which unlike outcome evaluation, was readily countered with strong motivation to avoid errors. We discuss how the acute effect of ketamine to reduce the initial impact of negative events could potentially mediate longer-term antidepressant effects through mitigating the cumulative effect of those events produced by slowly decaying memory, and how the disruption-resistant affective memory might pose challenges in treating depression. Our study also invites future investigations on ketamine's antidepressant action over diverse mood states and with affective events exerting their impacts at diverse time scales.
Rho of plant GTPase MxROP1 regulates Fe deficiency responses by targeting Zinc Ribbon 3 in apple rootstock
Authors: Li Keting , Zhai Longmei , Jiang Lizhong , Sun Qiran , Wu Ting , Zhang Xinzhong , Xu Xuefeng , Han Zhenhai , Wang Yi
Published: July 2022

Small G protein is a multifunctional molecular switch that can regulate plant growth, development and responses to the environment. However, how Rho-related GTPase of plants (ROPs) regulates the response to Fe deficiency has not been well clarified. Here, we found that Fe deficiency induced MxROP1 in Malus xiaojinensis at both the transcriptional and translational levels. The overexpression of MxROP1, MxROP1DN (inactive form) and MxROP1CA (active form) in apple roots increased the activity of ferric chelate reductase and the ability to acidify the rhizosphere, and lines that overexpressed MxROP1DN exhibited the strongest reaction to enhance Fe uptake. Yeast two-hybrid library screening indicated that MxROP1 interacted with ZR3.1, a DNL zinc finger protein that negatively regulates Fe deficiency responses. We further identified their interaction in vitro and in vivo using pull-down and bimolecular fluorescence complementation assays, respectively, and MxROP1DN-MxZR3.1 interacted the most strongly. Furthermore, MxROP1 negatively affected the stability of MxZR3.1 protein in vitro as shown by a cell semi-degradation assay, and the application of MG132 inhibited the degradation of MxZR3.1-HIS proteins. This indicated that MxROP1 caused the degradation of MxZR3.1 protein through the 26S proteasome pathway. Similar results were found in OE-MxROP1+OE-MxZR3.1 transgenic apple callus compared with those in the OE-MxZR3.1 callus. We also demonstrated that MxZR3.1 interacted with MxbHLH39, a known positive transcription factor and core component of Fe deficiency, and MxROP1 affected the interaction of MxZR3.1-MxbHLH39 using a competitive binding assay. This illuminated one MxROP1-MxZR3.1-MxbHLH39 pathway that maintains Fe homeostasis in M. xiaojinensis.
Examining the Influence of the Budget Execution Processes on the Efficiency of County Health Systems in Kenya
Authors: Musiega Anita , Tsofa Benjamin , Nyawira Lizah , Njuguna Rebecca G , Munywoki Joshua , Hanson Kara , Mulwa Andrew , Molyneux Sassy , Maina Isabel , Normand Charles , Jemutai Julie , Barasa Edwine
Published: July 2022

Public Financial Management (PFM) processes are a driver of health system efficiency. The budget execution process is the stage in the PFM cycle where health system inputs are translated into outputs and outcomes. This study examined how the budget execution process influenced the efficiency of county health systems in Kenya. We conducted a concurrent mixed methods case study using counties classified as relatively efficient (n=2) and relatively inefficient (n=2) in a related quantitative analysis as our cases. We developed a conceptual framework from a literature review to guide the development of tools and analysis. We collected qualitative data through document reviews, and in-depth interviews (n=70) with actors from health and finance sectors at the national and county level. We collected quantitative data from secondary sources, including budgets and budget reports. We analyzed qualitative data using the thematic approach and carried out descriptive analyses on quantitative data. The budget execution processes within counties in Kenya were characterized by poor budget credibility, cash disbursement delays, limited provider autonomy, and poor procurement practices. These challenges were linked to an inappropriate input mix that compromised the capacity of county health systems to deliver healthcare services, misalignment between county health needs and the use of resources, reduced staff motivation and productivity, procurement inefficiencies, and reduced county accountability for finances and performance. The efficiency of county health systems in Kenya can be enhanced by improving budget credibility, cash disbursement processes, procurement processes and improved provider autonomy.
Epigenome-wide meta-analysis of BMI in nine cohorts: examining the utility of epigenetic BMI in predicting metabolic health
Authors: Do Whitney L. , Sun Dianjianyi , Meeks Karlijn , Dugue Pierre-Antoine , Demerath Ellen , Guan Weihua , Li Shengxu , Chen Wei , Milne Roger , Adeyemo Abedowale , Agyemang Charles , Nassir Rami , Manson JoAnn , Shadyab Aladdin H , Hou Lifang , Horvath Steve , Assimes Themistocles L. , Bhatti Parveen , Jordahl Kristina , Baccarelli Andrea , Smith Alicia , Staimez Lisa R. , Stein Aryeh , Whitsel Eric A. , Venkat Narayan K.M. , Conneely Karen
Published: July 2022

This study sought to examine the association between DNA methylation and body mass index (BMI) and the potential utility of these cytosine-phosphate-guanine (CpG) sites in predicting metabolic health. We pooled summary statistics from six trans-ethnic EWAS of BMI representing nine cohorts (n=17058), replicated these findings in the Women’s Health Initiative (WHI, n=4822) and developed an epigenetic prediction score of BMI. In the pooled EWAS, 1265 CpG sites were associated with BMI (p<1E-7), and 1238 replicated in the WHI (FDR < 0.05). We performed several stratified analyses to examine whether these associations differed between individuals of European descent and individuals of African descent. We found five CpG sites had a significant interaction with BMI by race/ethnicity. To examine the utility of the significant CpG sites in predicting BMI, we used elastic net regression to predict log normalized BMI in the WHI (80% training/20% testing). This model found 397 sites could explain 32% of the variance in BMI in the WHI test set. Individuals whose methylome-predicted BMI overestimated their BMI (high epigenetic BMI) had significantly higher glucose and triglycerides, and lower HDL-cholesterol and LDL-cholesterol compared to accurately predicted BMI. Individuals whose methylome-predicted BMI underestimated their BMI (low epigenetic BMI) had significantly higher HDL-cholesterol and lower glucose and triglycerides. This study identified 553 previously identified and 685 novel CpG sites associated with BMI. Participants with high epigenetic BMI had poorer metabolic health suggesting that the overestimation may be driven in part by cardiometabolic derangements characteristic of metabolic syndrome.
Accurate sex prediction of cisgender and transgender individuals without brain size bias
Authors: Wiersch Lisa , Hamdan Sami , Hoffstaedter Felix , Votinov Mikhail , Habel Ute , Clemens Benjamin , Derntl Birgit , Eickhoff Simon B. , Patil Kaustubh R. , Weis Susanne
Published: July 2022

Brain size differs substantially between human males and females. This difference in total intracranial volume (TIV) can cause bias when employing machine-learning approaches for the investigation of sex differences in brain morphology. TIV-biased models will likely not capture actual qualitative sex differences in brain organization but rather learn to classify an individual’s sex based on brain size differences, thus leading to spurious and misleading conclusions, for example when comparing brain morphology between cisgender- and transgender individuals. Here, TIV bias in sex classification models applied to cis- and transgender individuals was systematically investigated by controlling for brain size either through featurewise confound removal or by matching training samples for TIV. Our results provide evidence that non-TIV-biased models can classify the sex of both cis- and transgender individuals with high accuracy, highlighting the importance of appropriate modelling to avoid bias in automated decision making.

Teaser

Accurate non-biased structural sex classification in cis- and transgender individuals by matching training samples for TIV
REDIRECTION: Generating drug repurposing hypotheses using link prediction with DISNET data
Authors: Ayuso Muñoz Adrián , Carro Esther Ugarte , Prieto Santamaría Lucía , Carrasco Belén Otero , Ruiz Ernestina Menasalvas , Pérez Gallardo Yuliana , Rodríguez-González Alejandro
Published: July 2022

In the recent years and due to COVID-19 pandemic, drug repurposing or repositioning has been placed in the spotlight. Giving new therapeutic uses to already existing drugs, this discipline allows to streamline the drug discovery process, reducing the costs and risks inherent to de novo development. Computational approaches have gained momentum, and emerging techniques from the machine learning domain have proved themselves as highly exploitable means for repurposing prediction. Against this backdrop, one can find that biomedical data can be represented in terms of graphs, which allow depicting in a very expressive manner the underlying structure of the information. Combining these graph data structures with deep learning models enhances the prediction of new links, such as potential disease-drug connections. In this paper, we present a new model named REDIRECTION, which aim is to predict new disease-drug links in the context of drug repurposing. It has been trained with a part of the DISNET biomedical graph, formed by diseases, symptoms, drugs, and their relationships. The reserved testing graph for the evaluation has yielded to an AUROC of 0.93 and an AUPRC of 0.90. We have performed a secondary validation of REDIRECTION using RepoDB data as the testing set, which has led to an AUROC of 0.87 and a AUPRC of 0.83. In the light of these results, we believe that REDIRECTION can be a meaningful and promising tool to generate drug repurposing hypotheses.
System-level high-amplitude co-fluctuations
Authors: Betzel Richard F. , Chumin Evgeny , Zamani Esfahlani Farnaz , Tanner Jacob , Faskowitz Joshua
Published: July 2022

Edge time series decompose interregional correlations (functional connectivity; FC) into their time-varying contributions. Previous studies have revealed that brief, high-amplitude, and globally-defined “events” contribute disproportionately to the time-averaged FC pattern. This whole-brain view prioritizes systems that occupy vast neocortical territory, possibly obscuring extremely high-amplitude co-fluctuations that are localized to smaller brain systems. Here, we investigate local events detected at the system level, assessing their independent contributions to global events and characterizing their repertoire during resting-state and movie-watching scans. We find that, as expected, global events are more likely to occur when large brain systems exhibit events. Next, we study the co-fluctuation patterns that coincide with system events–i.e. events detected locally based on the behavior of individual brain systems. We find that although each system exhibits a distinct co-fluctuation pattern that is dissimilar from those associated with global events, the patterns can nonetheless be grouped into two broad categories, corresponding to events that coincide with sensorimotor and attention systems and, separately, association systems. We then investigate system-level events during movie-watching, discovering that the timing of events in sensorimotor and attention systems decouple, yielding reductions in co-fluctuation amplitude. Next, we show that by associating each edge with its most similar system-averaged edge time series, we recover overlapping community structure, obviating the need for applying clustering algorithms to high-dimensional edge time series. Finally, we focus on cortical responses to system-level events in subcortical areas and the cerebellum. We show that these structures coincide with spatially distributed cortical co-fluctuations, centered on prefrontal and somatosensory systems. Collectively, the findings presented here help clarify the relative contributions of large and small systems to global events, as well as their independent behavior.
Distinctive chaperonopathy in skeletal muscle associated with the dominant variant inDNAJB4
Authors: Inoue Michio , Noguchi Satoru , Inoue Yukiko U. , Iida Aritoshi , Ogawa Megumu , Bengoechea Rocio , Pittman Sara K. , Hayashi Shinichiro , Watanabe Kazuki , Hosoi Yasushi , Sano Terunori , Takao Masaki , Oya Yasushi , Takahashi Yuji , Miyajima Hiroaki , Weihl Conrad C. , Inoue Takayoshi , Nishino Ichizo
Published: July 2022

DnaJ homolog, subfamily B, member 4, a member of the heat shock protein 40 chaperones encoded byDNAJB4, is highly expressed in myofibers. We identified a heterozygous c.270 T>A (p.F90L) variant inDNAJB4in a family with a dominantly inherited distal myopathy, in which affected members have specific features on muscle pathology represented by the presence of cytoplasmic inclusions and the accumulation of desmin, p62, HSP70 and DNAJB4 predominantly in type 1 fibers. Both Dnajb4- F90L knock-in and knockout mice developed muscle weakness and recapitulated the patient muscle pathology in the soleus muscle, where DNAJB4 has the highest expression. These data indicate that the identified variant is causative resulting in defective chaperone function and selective muscle degeneration in specific muscle fibers. This study demonstrates the importance of DNAJB4 in skeletal muscle proteostasis by identifying the associated chaperonopathy.
Polycomb repression during S/G2 phases restrain initiation of cell differentiation to the G1 phase of the cell cycle
Authors: Asenjo Helena G. , Alcazar-Fabra María , Espinosa Mencía , Lopez-Onieva Lourdes , Gallardo Amador , Dimitrova Emilia , Feldmann Angelika , Pachano Tomas , Martorell-Marugán Jordi , Carmona-Sáez Pedro , Sanchez-Pozo Antonio , Rada-Iglesias Álvaro , Klose Robert J. , Landeira David
Published: July 2022

The potential of pluripotent cells to respond to developmental cues and trigger cell differentiation is enhanced during the G1 phase of the cell cycle, but the molecular mechanisms involved are poorly understood. Variations in polycomb activity during interphase progression have been hypothesized to regulate the cell-cycle-phase-dependent transcriptional activation of differentiation genes during lineage transition in pluripotent cells. Here, we asked whether the Polycomb Repressive Complex 1 (PRC1) modulates the ability of mouse embryonic stem cells (ESCs) to differentially respond to developmental cues depending on the phase of the cell cycle in which they are found. We discovered that recruitment of PRC1 complexes and their associated molecular functions, ubiquitination of H2AK119 and three-dimensional chromatin interactions, are enhanced during S and G2 phases compared to the G1 phase. In agreement with the accumulation of PRC1 at target promoters upon G1 phase exit, cells in S and G2 phases show firmer transcriptional repression of developmental regulator genes that is drastically perturbed upon genetic ablation of the PRC1 catalytic subunit Ring1b. Importantly, depletion of Ring1b during retinoic acid stimulation interferes with the preference of mESCs to induce the transcriptional activation of differentiation genes in G1 phase. We propose that incremental enrolment of polycomb repressive activity during interphase progression reduces the tendency of cells to respond to developmental cues during S and G2 phases, facilitating activation of cell differentiation in the G1 phase of the pluripotent cell cycle.
Structural plasticity of Atg18 oligomers: organization of assembled tubes and scaffolds at the isolation membrane
Authors: Mann Daniel , Fromm Simon A. , Martinez-Sanchez Antonio , Gopaldass Navin , Mayer Andreas , Sachse Carsten
Published: July 2022

Autophagy-related protein 18 (Atg18) participates in the elongation of early autophagosomal structures in concert with Atg2 and Atg9 complexes. How Atg18 contributes to the structural coordination of Atg2 and Atg9 at the isolation membrane remains to be understood. Here, we determined the cryo-EM structures of Atg18 organized in helical tubes as well as soluble oligomers. The helical assembly is composed of Atg18 tetramers forming a lozenge cylindrical lattice with remarkable structural similarity to the COPII outer coat. When reconstituted with lipid membranes, using subtomogram averaging we determined tilted Atg18 dimer structures bridging two juxtaposed lipid membranes spaced apart by 80 Å. Together with an AlphaFold Atg18-Atg2 model, we propose that Atg18 oligomers form a structural scaffold coordinating the Atg2 membrane bridge. The observed structural plasticity of Atg18’s oligomeric organization and membrane binding provide a molecular framework for the positioning of downstream components of the autophagy machinery.