Development of a core outcome set for treatment studies for provoked vestibulodynia.

BACKGROUND: There is an inconsistency in treatment outcomes used in clinical trials for provoked vestibulodynia (PVD), which makes it impossible to compare the effects of different interventions. AIM: In this study, we completed the first step in creating a core outcome set (COS), defining what outcomes should be measured in clinical trials for PVD. METHODS: Identification of outcomes used in studies was done by extracting data from clinical trials in a recently published systematic review and via review of clinical trials for PVD registered on ClinicalTrials.gov. The COS process consisted of 2 rounds of Delphi surveys and a consensus meeting, during which the final COS was decided through a modified nominal group technique. OUTCOMES: Consensus on what outcomes to include in a COS for PVD. RESULTS: Forty scientific articles and 92 study protocols were reviewed for outcomes. Of those, 36 articles and 25 protocols were eligible, resulting in 402 outcomes, which were then categorized into 63 unique outcomes. Participants consisted of patients, relatives/partners of patients, health care professionals, and researchers. Out of 463 who registered for participation, 319 and 213 responded to the first and second surveys, respectively. The consensus meeting consisted of 18 members and resulted in 6 outcomes for the COS to be measured in all treatment trials regardless of intervention: insertional pain (nonsexual), insertional pain (sexual), provoked vulvar pain by pressure/contact, pain-related interference on one's life, pain interference on sexual life, and sexual function. CLINICAL IMPLICATIONS: Critical outcomes to be measured in clinical trials will allow for accurate comparison of outcomes across treatment interventions and provide solid treatment recommendations. STRENGTHS AND LIMITATIONS: The major strengths of the study are the adherence to methodological recommendations and the intentional focus on aspects of diversity of participating stakeholders (eg, status such as patients with lived experience and researchers, inclusiveness with respect to sexual identity), the latter of which will allow for broader application and relevance of the COS. Among the limitations of the study are the low rate of participants outside North America and Europe and the lower response rate (about 50%) for the second Delphi survey. CONCLUSION: In this international project, patients, health care professionals, and researchers have decided what critical outcomes are to be used in future clinical trials for PVD. Before the COS can be fully implemented, there is also a need to decide on how and preferably when the outcomes should be measured.

Core Outcome Sets (COS) related to pregnancy and childbirth: a systematic review.

BACKGROUND: Systematic reviews often conclude low confidence in the results due to heterogeneity in the reported outcomes. A Core Outcome Set (COS) is an agreed standardised collection of outcomes for a specific area of health. The outcomes included in a COS are to be measured and summarized in clinical trials as well as systematic reviews to counteract this heterogeneity. AIM: The aim is to identify, compile and assess final and ongoing studies that are prioritizing outcomes in the area of pregnancy and childbirth. METHODS: All studies which prioritized outcomes related to pregnancy and childbirth using consensus method, including Delphi surveys or consensus meetings were included. Searches were conducted in Ovid MEDLINE, EMBASE, PsycINFO, Academic Search Elite, CINAHL, SocINDEX and COMET databases up to June 2021. For all studies fulfilling the inclusion criteria, information regarding outcomes as well as population, method, and setting was extracted. In addition, reporting in the finalized studies was assessed using a modified version of the Core Outcome Set-STAndards for Reporting. RESULTS: In total, 27 finalized studies and 42 ongoing studies were assessed as relevant and were included. In the finalized studies, the number of outcomes included in the COS ranged from 6 to 51 with a median of 13 outcomes. The majority of the identified COS, both finalized as well as ongoing, were relating to physical complications during pregnancy. CONCLUSION: There is a growing number of Core Outcome Set studies related to pregnancy and childbirth. Although several of the finalized studies follow the proposed reporting, there are still some items that are not always clearly reported. Additionally, several of the identified COS contained a large number (n > 20) outcomes, something that possibly could hinder implementation. Therefore, there is a need to consider the number of outcomes which may be included in a COS to render it optimal for future research.

KNOWLEDGE GAPS IN ORAL AND MAXILLOFACIAL SURGERY: A SYSTEMATIC MAPPING.

OBJECTIVES: The aim of this study was to evaluate available knowledge and identify knowledge gaps within the field of oral and maxillofacial surgery, by systematically collecting and evaluating systematic reviews. Twelve specific domains were selected: surgical removal of teeth, antibiotic and corticosteroid prophylaxis, orofacial infections, dental and facial trauma, orthognathic surgery, reconstructive surgery, benign tumors, cysts, premalignant lesions, oral complications of treatment of malignant tumors, hyperbaric oxygen therapy, temporomandibular joint surgery, cost effectiveness of different surgical treatments, and ethics. METHODS: The literature search, covering four databases, was conducted during September 2014: PubMed, The Cochrane library, Centre for Reviews and Dissemination and EBSCO dentistry and oral science source. Retrieved systematic reviews were quality assessed by AMSTAR. RESULTS: In all, 1,778 abstracts were identified, of which 200 met the inclusion criteria. Forty-five systematic reviews were assessed as of high to moderate quality. The results disclosed some existing evidence in a few domains, such as surgical removal of teeth and implant survival after sinus lifts. However, in all domains, the search revealed a large number of knowledge gaps. Also of concern was the lack of data regarding health economics and ethics. CONCLUSIONS: In conclusion, there is a need for well-conducted clinical research in the fields of oral and maxillofacial surgery.

TOP TEN RESEARCH PRIORITIES FOR ATTENTION DEFICIT/HYPERACTIVITY DISORDER TREATMENT.

OBJECTIVES: The aim of this project was to identify the ten most important research questions for attention deficit/hyperactivity disorder (ADHD) treatment as identified by people with ADHD together with personnel involved in the treatment of ADHD in school, health, and correction services. METHODS: A working group consisting of consumers and personnel was established. The method for prioritization was primarily based on James Lind Alliance's guidebook, consisting of an interim priority setting exercise and a workshop. RESULTS: The top ten list includes the risk of drug dependency later in life when treated with methylphenidate as a child, teacher support, multimodal therapy, comparisons between atomoxetine and methylphenidate, methylphenidate treatment in substance abusers, parental support programmes, supported conversation, computer-aided working memory training, psychoeducative treatment, and melatonin. CONCLUSIONS: We have shown that consumers and personnel can reach consensus on research priorities for treatments for ADHD. We encourage researchers and funders to consider the list for future studies.

TIM23-mediated insertion of transmembrane α-helices into the mitochondrial inner membrane.

While overall hydrophobicity is generally recognized as the main characteristic of transmembrane (TM) α-helices, the only membrane system for which there are detailed quantitative data on how different amino acids contribute to the overall efficiency of membrane insertion is the endoplasmic reticulum (ER) of eukaryotic cells. Here, we provide comparable data for TIM23-mediated membrane protein insertion into the inner mitochondrial membrane of yeast cells. We find that hydrophobicity and the location of polar and aromatic residues are strong determinants of membrane insertion. These results parallel what has been found previously for the ER. However, we see striking differences between the effects elicited by charged residues flanking the TM segments when comparing the mitochondrial inner membrane and the ER, pointing to an unanticipated difference between the two insertion systems.

Dissecting stop transfer versus conservative sorting pathways for mitochondrial inner membrane proteins in vivo.

Mitochondrial inner membrane proteins that carry an N-terminal presequence are sorted by one of two pathways: stop transfer or conservative sorting. However, the sorting pathway is known for only a small number of proteins, in part due to the lack of robust experimental tools with which to study. Here we present an approach that facilitates determination of inner membrane protein sorting pathways in vivo by fusing a mitochondrial inner membrane protein to the C-terminal part of Mgm1p containing the rhomboid cleavage region. We validated the Mgm1 fusion approach using a set of proteins for which the sorting pathway is known, and determined sorting pathways of inner membrane proteins for which the sorting mode was previously uncharacterized. For Sdh4p, a multispanning membrane protein, our results suggest that both conservative sorting and stop transfer mechanisms are required for insertion. Furthermore, the sorting process of Mgm1 fusion proteins was analyzed under different growth conditions and yeast mutant strains that were defective in the import motor or the m-AAA protease function. Our results show that the sorting of mitochondrial proteins carrying moderately hydrophobic transmembrane segments is sensitive to cellular conditions, implying that mitochondrial import and membrane sorting in the physiological environment may be dynamically tuned.

Can abstract screening workload be reduced using text mining? User experiences of the tool Rayyan.

BACKGROUND: One time-consuming aspect of conducting systematic reviews is the task of sifting through abstracts to identify relevant studies. One promising approach for reducing this burden uses text mining technology to identify those abstracts that are potentially most relevant for a project, allowing those abstracts to be screened first. OBJECTIVES: To examine the effectiveness of the text mining functionality of the abstract screening tool Rayyan. User experiences were collected. METHODS: Rayyan was used to screen abstracts for 6 reviews in 2015. After screening 25%, 50%, and 75% of the abstracts, the screeners logged the relevant references identified. A survey was sent to users. RESULTS: After screening half of the search result with Rayyan, 86% to 99% of the references deemed relevant to the study were identified. Of those studies included in the final reports, 96% to 100% were already identified in the first half of the screening process. Users rated Rayyan 4.5 out of 5. DISCUSSION: The text mining function in Rayyan successfully helped reviewers identify relevant studies early in the screening process.

Charged flanking residues control the efficiency of membrane insertion of the first transmembrane segment in yeast mitochondrial Mgm1p.

Mgm1p is a nuclearly encoded GTPase important for mitochondrial fusion. Long and short isoforms of the protein are generated in a unique "alternative topogenesis" process in which the most N-terminal of two hydrophobic segments in the protein is inserted into the inner mitochondrial membrane in about half of the molecules and translocated across the inner membrane in the other half. In the latter population, the second hydrophobic segment is cleaved by the inner membrane protease Pcp1p, generating the short isoform. Here, we show that charged residues in the regions flanking the first segment critically affect the ratio between the two isoforms, providing new insight into the importance of charged residues in the insertion of proteins into the mitochondrial inner membrane.

A global topology map of the Saccharomyces cerevisiae membrane proteome.

The yeast Saccharomyces cerevisiae is, arguably, the best understood eukaryotic model organism, yet comparatively little is known about its membrane proteome. Here, we report the cloning and expression of 617 S. cerevisiae membrane proteins as fusions to a C-terminal topology reporter and present experimentally constrained topology models for 546 proteins. By homology, the experimental topology information can be extended to approximately 15,000 membrane proteins from 38 fully sequenced eukaryotic genomes.

Phenotypic effects of membrane protein overexpression in Saccharomyces cerevisiae.

Large-scale protein overexpression phenotype screens provide an important complement to the more common gene knockout screens. Here, we have targeted the so far poorly understood Saccharomyces cerevisiae membrane proteome and report growth phenotypes for a strain collection overexpressing approximately 600 C-terminally tagged integral membrane proteins grown both under normal and three different stress conditions. Although overexpression of most membrane proteins reduce the growth rate in synthetic defined medium, we identify a large number of proteins that, when overexpressed, confer specific resistance to various stress conditions. Our data suggest that regulation of glycosylphosphatidylinositol anchor biosynthesis and the Na(+)/K(+) homeostasis system constitute major downstream targets of the yeast PKA/RAS pathway and point to a possible connection between the early secretory pathway and the cells' response to oxidative stress. We also have quantified the expression levels for >550 membrane proteins, facilitating the choice of well expressing proteins for future functional and structural studies.