Trial Forge Guidance 4: a guideline for reporting the results of randomised Studies Within A Trial (SWATs).

BACKGROUND: Evidence to support decisions on trial processes is minimal. One way to generate this evidence is to use a Study Within A Trial (SWAT) to test trial processes or explore methodological uncertainties. SWAT evidence relies on replication to ensure sufficient power and broad applicability of findings. Prompt reporting is therefore essential; however, SWAT publications are often the first to be abandoned in the face of other time pressures. Reporting guidance for embedded methodology trials does exist but is not widely used. We sought therefore to build on these guidelines to develop a straightforward, concise reporting standard, which remains adherent to the CONSORT guideline. METHODS: An iterative process was used to develop the guideline. This included initial meetings with key stakeholders, development of an initial guideline, pilot testing of draft guidelines, further iteration and pilot testing, and finalisation of the guideline. RESULTS: We developed a reporting guideline applicable to randomised SWATs, including replications of previous evaluations. The guideline follows the Consolidated Standards for Reporting Trials (CONSORT) statement and provides example text to ensure ease and clarity of reporting across all domains. CONCLUSIONS: The SWAT reporting guideline will aid authors, reviewers, and journal editors to produce and review clear, structured reports of randomised SWATs, whilst also adhering to the CONSORT guideline. TRIAL REGISTRATION: EQUATOR Network - Guidelines Under Development ( https://www.equator-network.org/library/reporting-guidelines-under-development/reporting-guidelines-under-development-for-clinical-trials/#SWAT ). Registered on 25 March 2021.

Standards of Care for the Health of Transgender and Gender Diverse People, Version 8.

Background: Transgender healthcare is a rapidly evolving interdisciplinary field. In the last decade, there has been an unprecedented increase in the number and visibility of transgender and gender diverse (TGD) people seeking support and gender-affirming medical treatment in parallel with a significant rise in the scientific literature in this area. The World Professional Association for Transgender Health (WPATH) is an international, multidisciplinary, professional association whose mission is to promote evidence-based care, education, research, public policy, and respect in transgender health. One of the main functions of WPATH is to promote the highest standards of health care for TGD people through the Standards of Care (SOC). The SOC was initially developed in 1979 and the last version (SOC-7) was published in 2012. In view of the increasing scientific evidence, WPATH commissioned a new version of the Standards of Care, the SOC-8. Aim: The overall goal of SOC-8 is to provide health care professionals (HCPs) with clinical guidance to assist TGD people in accessing safe and effective pathways to achieving lasting personal comfort with their gendered selves with the aim of optimizing their overall physical health, psychological well-being, and self-fulfillment. Methods: The SOC-8 is based on the best available science and expert professional consensus in transgender health. International professionals and stakeholders were selected to serve on the SOC-8 committee. Recommendation statements were developed based on data derived from independent systematic literature reviews, where available, background reviews and expert opinions. Grading of recommendations was based on the available evidence supporting interventions, a discussion of risks and harms, as well as the feasibility and acceptability within different contexts and country settings. Results: A total of 18 chapters were developed as part of the SOC-8. They contain recommendations for health care professionals who provide care and treatment for TGD people. Each of the recommendations is followed by explanatory text with relevant references. General areas related to transgender health are covered in the chapters Terminology, Global Applicability, Population Estimates, and Education. The chapters developed for the diverse population of TGD people include Assessment of Adults, Adolescents, Children, Nonbinary, Eunuchs, and Intersex Individuals, and people living in Institutional Environments. Finally, the chapters related to gender-affirming treatment are Hormone Therapy, Surgery and Postoperative Care, Voice and Communication, Primary Care, Reproductive Health, Sexual Health, and Mental Health. Conclusions: The SOC-8 guidelines are intended to be flexible to meet the diverse health care needs of TGD people globally. While adaptable, they offer standards for promoting optimal health care and guidance for the treatment of people experiencing gender incongruence. As in all previous versions of the SOC, the criteria set forth in this document for gender-affirming medical interventions are clinical guidelines; individual health care professionals and programs may modify these in consultation with the TGD person.

Generation of Functional Gene Knockout Melanoma Cell Lines by CRISPR-Cas9 Gene Editing.

Recent advances in the treatment of metastatic melanoma have emerged only from advances in our understanding of melanoma development and progression at the cellular and molecular levels. Despite the impact that such advances have made on the clinical management of this cancer over the last decade, additional insights into factors that promote melanoma progression and therapeutic resistance are needed to combat this disease. CRISPR-Cas9 gene editing technology is a powerful tool for studying gene function in a timely and cost-effective manner, enabling the manipulation of specific DNA sequences via a targeted approach. Herein, we describe a protocol for generating functional gene knockouts in melanoma cell lines by CRISPR-Cas9 gene editing, and we present an example application of this protocol for the successful knockout of the Foxc2 transcription factor-encoding gene in the B16-F1 murine melanoma cell line.

A Flow Cytometric Assay for Investigating Melanoma Cell Adhesion to Lymphatic Endothelial Cells.

Lymph node invasion by tumor cells is an important process in the progression of melanoma and is a poor prognostic factor for patients with this cancer. Before they are able to spread to regional lymph nodes, though, melanoma cells must first adhere to lymphatic endothelium and transmigrate into the lymphatic vasculature. In order to study melanoma cell adhesion to lymphatic endothelial cells and the factors that regulate this process, we have developed an in vitro flow cytometry-based assay to measure melanoma cell attachment to lymphatic endothelial cells. This assay will be a useful tool for investigating the interactions that take place between melanoma cells and lymphatic endothelial cells during the adhesion process.

The FOXC2 Transcription Factor Promotes Melanoma Outgrowth and Regulates Expression of Genes Associated With Drug Resistance and Interferon Responsiveness.

BACKGROUND/AIM: The FOXC2 transcription factor promotes the progression of several cancer types, but has not been investigated in the context of melanoma cells. To study FOXC2's influence on melanoma progression, we generated a FOXC2-deficient murine melanoma cell line and evaluated The Cancer Genome Atlas (TCGA) patient datasets. MATERIALS AND METHODS: We compared tumor growth kinetics and RNA-seq/qRT-PCR gene expression profiles from wild-type versus FOXC2-deficient murine melanomas. We also performed Kaplan-Meier survival analysis of TCGA data to assess the influence of FOXC2 gene expression on melanoma patients' response to chemotherapy and immunotherapy. RESULTS: FOXC2 promotes melanoma progression and regulates the expression of genes associated with multiple oncogenic pathways, including the oxidative stress response, xenobiotic metabolism, and interferon responsiveness. FOXC2 expression in melanoma correlates negatively with patient response to chemotherapy and immunotherapy. CONCLUSION: FOXC2 drives a tumor-promoting gene expression program in melanoma and is a prognostic indicator of patient response to multiple cancer therapies.

The role of WhatsApp® in medical education; a scoping review and instructional design model.

BACKGROUND: Technological advances have driven huge change in educational practices though concerns exist about a lack of evidence informing this change, in particular with social media-based medical education activities. The purpose of this study was to conduct a scoping review of WhatsApp use in medical education, narratively describing how it has been used and evaluated, and the theoretical considerations in relevant articles. METHODS: A modified 5-stage scoping review model was used. We performed 2 searches from February 2009 to February 2019 in EBSCO, SCOPUS, Web of Science, EMBASE, Medline PubMed and Google Scholar) using the term "WhatsApp" in all search fields. A 3-stage process for study selection was performed. Only original articles in English presenting original data about WhatsApp in medical education were included. The Kirkpatrick model of training evaluation was used to describe learning outcomes in included studies. RESULTS: Twenty-three articles were selected for review. Three strategies for WhatsApp use were apparent; primarily educational use with a pre-defined curriculum (n = 5), primarily educational use without a curriculum (n = 11), and primarily non-educational use (n = 7). Most of the educational studies used an online moderator and were in a local hospital or university department. Studies not primarily educational were national or international and seldom included an online moderator. All 5 studies with a pre-defined curriculum reported Kirkpatrick level 2 learner knowledge outcomes. A majority of the remaining studies only reported Kirkpatrick level 1 learner attitudes. Seven studies with 647 participants reported an improvement in learners' knowledge following WhatsApp learning, though methodological weaknesses were apparent. Evidence for underlying learning theory considerations were scant throughout the studies. CONCLUSIONS: WhatsApp is popular and convenient in medical education. Current published literature suggests it may also be effective as a medical learning tool. By combining the 3 strategies for WhatsApp use and the exploration-enactment-assessment integrated learning design framework, we propose an instant messenger design model for medical education. This may address the need for theory-driven instructional design in social media learning. Further research would clarify the role of WhatsApp and our design model in this area.

Do stroke patients screened as lower-nutritional-risk still receive dietitian assessment if indicated? A retrospective evaluation of two dietetic models of care for adult stroke patients.

BACKGROUND: Dietetic models of care at Logan Hospital changed from all patients with a confirmed stroke receiving dietitian assessment (Old pathway) to only those patients screened as high-nutritional-risk (Modified pathway). However, it was unknown whether all low-nutritional-risk patients who were indicated for dietitian assessment for nutrition support actually received assessment. This pre-post retrospective study evaluated whether the Old pathway and the Modified pathway were equally effective in identifying low-nutritional-risk stroke patients who were indicated for dietitian assessment and compared the time spent providing Dietetic care. METHODS: For both pathways, medical charts were reviewed for low-nutritional-risk patients admitted between December 2012 and November 2017 with a confirmed stroke, who were given a standard food and fluid diet code and scored MST < 2 (Malnutrition Screening Tool) on admission. Data collected included demographics, anthropometrics, malnutrition assessment, dietetic intervention and time spent caring for patients. Malnutrition-related clinical indicators were used to classify patients as either Dietitian Assessment for Nutrition Support Indicated or Not Indicated. RESULTS: Low-nutritional-risk patients were similar on the Old (n = 180) and Modified (n = 206) pathways [mean (SD) 66 (13) years, 63% male, 4% malnutrition]. Those classified as Dietitian Assessment for Nutrition Support Indicated (n = 61 of 180) were older, had a longer length of stay (P < 0.05), and were all identified by the Dietitian on both pathways. Ten minutes less dietetic time per patient was required on the Modified pathway (P < 0.001). CONCLUSIONS: The Modified Nutrition Stroke pathway performed more efficiently than the Old pathway and was equally effective at ensuring that stroke patients who were determined as being low-nutritional-risk received dietitian assessment during admission if indicated.

Immune checkpoint blockade therapy for cancer: An overview of FDA-approved immune checkpoint inhibitors.

Although T lymphocytes have long been appreciated for their role in the immunosurveillance of cancer, it has been the realization that cancer cells may ultimately escape a response from tumor-reactive T cells that has ignited efforts to enhance the efficacy of anti-tumor immune responses. Recent advances in our understanding of T cell immunobiology have been particularly instrumental in informing therapeutic strategies to overcome mechanisms of tumor immune escape, and immune checkpoint blockade has emerged as one of the most promising therapeutic options for patients in the history of cancer treatment. Designed to interfere with inhibitory pathways that naturally constrain T cell reactivity, immune checkpoint blockade releases inherent limits on the activation and maintenance of T cell effector function. In the context of cancer, where negative T cell regulatory pathways are often overactive, immune checkpoint blockade has proven to be an effective strategy for enhancing the effector activity and clinical impact of anti-tumor T cells. Checkpoint inhibitors targeting CTLA-4, PD-1, and PD-L1 have yielded unprecedented and durable responses in a significant percentage of cancer patients in recent years, leading to U.S. FDA approval of six checkpoint inhibitors for numerous cancer indications since 2011. In this review, we highlight the clinical success of these FDA-approved immune checkpoint inhibitors and discuss current challenges and future strategies that must be considered going forward to maximize the efficacy of immune checkpoint blockade therapy for cancer.

Outbreak characteristics associated with identification of contributing factors to foodborne illness outbreaks.

Information on the factors that cause or amplify foodborne illness outbreaks (contributing factors), such as ill workers or cross-contamination of food by workers, is critical to outbreak prevention. However, only about half of foodborne illness outbreaks reported to the United States' Centers for Disease Control and Prevention (CDC) have an identified contributing factor, and data on outbreak characteristics that promote contributing factor identification are limited. To address these gaps, we analyzed data from 297 single-setting outbreaks reported to CDC's new outbreak surveillance system, which collects data from the environmental health component of outbreak investigations (often called environmental assessments), to identify outbreak characteristics associated with contributing factor identification. These analyses showed that outbreak contributing factors were more often identified when an outbreak etiologic agent had been identified, when the outbreak establishment prepared all meals on location and served more than 150 meals a day, when investigators contacted the establishment to schedule the environmental assessment within a day of the establishment being linked with an outbreak, and when multiple establishment visits were made to complete the environmental assessment. These findings suggest that contributing factor identification is influenced by multiple outbreak characteristics, and that timely and comprehensive environmental assessments are important to contributing factor identification. They also highlight the need for strong environmental health and food safety programs that have the capacity to complete such environmental assessments during outbreak investigations.

The EVerT2 (Effective Verruca Treatments 2) trial: a randomized controlled trial of needling vs. nonsurgical debridement for the treatment of plantar verrucae.

BACKGROUND: Verrucae are a common foot skin pathology, which can in some cases persist for many years. Plantar verrucae can be unsightly and painful. There are a range of treatment options including needling. OBJECTIVES: The EVerT2 (Effective Verruca Treatments 2) trial aimed to evaluate the clinical and cost-effectiveness of the needling procedure for the treatment of plantar verrucae, relative to callus debridement. METHODS: This single-centre randomized controlled trial recruited 60 participants (aged ≥ 18 years with a plantar verruca). Participants were randomized 1 : 1 to the intervention group (needling) or the control group (debridement of the overlying callus). The primary outcome was clearance of the index verruca at 12 weeks after randomization. Secondary outcomes included recurrence of the verruca, clearance of all verrucae, number of verrucae, size of the index verruca, pain and participant satisfaction at 12 and 24 weeks. A cost-effectiveness analysis was carried out from the National Health Service perspective over 12 weeks. RESULTS: Sixty eligible patients were randomized (needling group n = 29, 48%; debridement group n = 31, 52%) and 53 were included in the primary analysis (needling n = 28, 97%; debridement n = 25, 81%). Clearance of the index verruca occurred in eight (15%) participants (needling n = 4, 14%; debridement n = 4, 16%; P = 0·86). The needling intervention costs were on average £14·33 (95% confidence interval 5·32-23·35) more per patient than for debridement. CONCLUSIONS: There is no evidence that the needling technique is more clinically or cost-effective than callus debridement. The results show a significant improvement in pain outcomes after needling compared with the debridement treatment alone.

Contribution of Clostridium difficile infection to the development of lower gastrointestinal adverse events during autologous stem cell transplantation.

BACKGROUND: Lower gastrointestinal (GI) adverse events (LGAE) are common afflictions of patients undergoing stem cell transplantation (SCT). Unfortunately, the pathophysiology remains poorly characterized. Emerging data suggest a prominent role of intestinal microbiota; however, contributions of pathogenic gut microbiota such as Clostridium difficile are not well defined. We performed a genome-wide association study (GWAS) to investigate clinical and genetic factors associated with development of LGAE. METHODS: A total of 972 patients undergoing autologous SCT were graded for LGAE based on Common Terminology Criteria for Adverse Events (v 4.0). Germline DNA material was obtained from leukapharesis products and genotyped using Illumina(®) Whole Genome Genotyping Infinium chemistry and HumanOmni1-Quad Bead chips containing over 1.1 million single nucleotide polymorphisms (SNPs) (Illumina, San Diego, California, USA). Statistical models incorporating clinical factors, genetic factors, and a combination of clinical plus genetic factors were utilized to compare patients who developed severe LGAE (grade 2 or above) and others. RESULTS: Among 972 patients, 459 (47.2%) developed severe LGAE. Baseline hemoglobin and hematocrit, estimated glomerular filtration rate, ß2-microglobulin, protocol type, and C. difficile infection (CDI) were associated with severe LGAE on univariate analysis, Genomic comparisons between groups did not reveal any SNPs associated with severe LGAE and neither did incorporation of genetic factors into the clinical model. In addition, 11 candidate SNPs associated with upper GI mucositis were evaluated, alongside clinical factors in a multivariate model. Only CDI was found to be associated with severe LGAE in all models. CONCLUSION: CDI is a prominent factor in the development of LGAE in patients undergoing autologous SCT.

Pregnancy in women with Type 1 and Type 2 diabetes in Dublin.

INTRODUCTION: The Confidential Enquiry into Maternal and Child Health (CEMACH) reported outcomes of pregnancies in women with pre-gestational diabetes (PGDM) in the UK (n = 3,733). This study aimed to compare CEMACH outcomes with PGDM pregnancies in Dublin. METHODS: Retrospective chart review of all PGDM pregnancies. Comparison to CEMACH are shown in brackets. RESULTS: One hundred and ten PGDM women delivered in Dublin. Thirty (27%) had T2 diabetes (vs. 27%). Fifty-nine (53%) women had a booking HbA1c less than 7% (vs. 66%). Nineteen women (17.3%) had a first trimester miscarriage (vs. 8.5%). Of the 91 remaining women, 71 (78%) women underwent induction of labour (vs. 38.9%). Fifty-four women (59.3%) were delivered by caesarean section (vs. 67.4%). Two infants (2.1%) were macrosomic (vs. 5.7%). There was one intrauterine death (0.1 vs. 0.6%) and no maternal deaths (vs. five). CONCLUSION: These results serve to underline the continued importance of multidisciplinary care for pregnant women with diabetes.

An atypical case of successful resuscitation of an accidental profound hypothermia patient, occurring in a temperate climate.

Cases of accidental profound hypothermia occur most frequently in cold, northern climates. We describe an atypical case, occurring in a temperate climate, where a hypothermic cardiac-arrested patient was successfully resuscitated using extracorporeal circulation (ECC).

Low doses of estradiol partly inhibit release of GH in sheep without affecting basal levels.

Estradiol increases basal growth hormone (GH) concentrations in sheep and cattle. This study sought to determine the effects of estradiol on GH-releasing hormone (GRH)-stimulated GH release in sheep. Growth hormone secretory characteristics, the GH response to GRH, and steady-state GH mRNA concentrations were determined in castrated male lambs treated with 2 different doses of estradiol 17-beta for a 28-d experimental period. Although no differences between treatments in mean GH, basal GH, or GH pulse number were observed after 28 d of estradiol treatment, GH pulse amplitude was greater (P < 0.05) in the 2.00-cm implant-treated animals than in the control and 0.75-cm implant group. The effect of estradiol treatment on GRH-stimulated GH release revealed differences between the control and estradiol-treated animals (P < 0.05). The 15-min GH responses to 0.075 microg/kg hGRH in the control, 0.75-cm, and 2.00-cm implant groups, respectively, were 76 +/- 10, 22.6 +/- 2.1, and 43.6 +/- 15.0 ng/mL. Growth hormone mRNA content was determined for pituitary glands from the different treatment groups, and no differences in steady-state GH mRNA levels were observed. There were no differences in the mean plasma concentrations of IGF-I, cortisol, T(3), or T(4) from weekly samples. Growth hormone release from cultured ovine pituitary cells from control sheep was not affected by estradiol after 72 h or in a subsequent 3-h incubation with estradiol combined with GRH. These data suggest that estradiol has differing actions on basal and GRH-stimulated GH concentrations in plasma, but the increase in pulse amplitude does not represent an increased pituitary sensitivity to GRH.

Back to basics: assessment, communication, caring, and follow-up: a lesson from a couple's journey with multiple myeloma.

Ian was a patient with multiple myeloma. His wife, Judi, chronicled their journey and experiences with myeloma and the healthcare system. Through her own eyes, Judi provides a view of the positive and negative consequences of actions or omissions by the healthcare team. The other authors, oncology nurses affiliated with a myeloma treatment center, collaborated with Judi to tell her story and remind oncology nurses that they can and do make a difference when focus is placed on the basics: assessment, communication, caring, and follow-up.

Transition of care for hospitalized elderly patients--development of a discharge checklist for hospitalists.

BACKGROUND: Discharge from the hospital is a critical transition point in a patient's care. Incomplete handoffs at discharge can lead to adverse events for patients and result in avoidable rehospitalization. Care transitions are especially important for elderly patients and other high-risk patients who have multiple comorbidities. Standardizing the elements of the discharge process may help to address the gaps in quality and safety that occur when patients transition from the hospital to an outpatient setting. METHODS: The Society of Hospital Medicine's Hospital Quality and Patient Safety committee assembled a panel of care transition researchers, process improvement experts, and hospitalists to review the literature and develop a checklist of processes and elements required for ideal discharge of adult patients. The discharge checklist was presented at the Society of Hospital Medicine's Annual Meeting in April 2005, where it was reviewed and revised by more than 120 practicing hospitalists and hospital-based nurses, case managers, and pharmacists. The final checklist was endorsed by the Society of Hospital Medicine. RESULTS: The finalized checklist is a comprehensive list of the processes and elements considered necessary for optimal patient handoff at hospital discharge. This checklist focused on medication safety, patient education, and follow-up plans. CONCLUSIONS: The development of content and process standards for discharge is the first step in improving the handoff of care from the inpatient to the posthospital setting. Refining this checklist for patients with specific diagnoses, in specific age categories, and with specific discharge destinations may further improve information transfer and ultimately affect patient outcomes.

Changes in mitotic rate and GFAP expression in the primary olfactory axis of streptozotocin-induced diabetic rats.

Many diabetic individuals develop anosmia but the mechanism(s) causing the dysfunction in the olfactory system is (are) unknown. Glial fibrillary acidic protein expression is reduced in diabetic retinopathy and is also reduced, with unknown consequences, in other brain regions of diabetic rats. We used immunohistochemistry and immunoblotting from untreated control and streptozotocin-induced type 1 (insulin dependent) diabetic rats to investigate main olfactory epithelial mitotic rate and glial fibrillary acidic protein expression in the lamina propria of the sensory epithelium and in the olfactory bulb. Numbers of bromodeoxyuridine-positive cells were significantly lower in the diabetic sensory epithelium compared to non-diabetic controls. Immunohistochemical observations suggested a qualitative difference in glial fibrillary acidic protein expression in both regions examined especially in the olfactory bulb external plexiform layer and the lamina propria. Immunoblot analysis confirmed that the diabetic olfactory bulb and lamina propria expressed less glial fibrillary acidic protein compared to the non-diabetic control group. The lower expression levels in the olfactory bulb external plexiform layer suggested by immunohistochemistry do not reflect a change in the number of astrocytes since the numbers of S100B(+) cells were not different between the two groups.

Bowen disease of the nail bed presenting as longitudinal melanonychia: detection of human papillomavirus type 56 DNA.

A case of Bowen disease (BD) presenting as longitudinal melanonychia (LM) on the right third fingernail of a 25-year-old African American man is described. Findings from the histopathologic examination revealed full-thickness epidermal atypia, hypergranulosis, and koilocytic changes. Human papillomavirus (HPV) type 56 was identified by polymerase chain reaction. To the best of our knowledge, we describe the first case of BD of the nail unit in which HPV-56 DNA has been identified.