What are important areas where better technology would support women's health? Findings from a priority setting partnership.

BACKGROUND: Women's health has historically lacked investment in research and development. Technologies that enhance women's health ('FemTech') could contribute to improving this. However, there has been little work to understand which priority unmet needs should be a focus for women's health technology development. The voices of clinicians and those who experience and utilise these technologies (including those used at home or encountered in clinical settings) are needed to ensure that device development aligns with need, without risking exacerbating or creating health inequities. METHOD: We undertook a priority setting partnership project exploring unmet needs in women's health and well-being where physical technologies or innovations could help. This comprised gathering feedback from: patients and clinicians using both qualitative surveys and discussions; collating and publishing these responses and asking for feedback; evidence checking unmet needs identified, and holding a partnership priority setting event to agree a top 10 and top 20 list of priorities. RESULTS: We generated a 'longlist' of 54 suggestions for areas where better kit, devices or equipment could support women's health. For three, we found evidence of existing technologies which mitigated against that need. We took the remaining 51 suggestions to a partnership priority setting meeting which brought together clinicians and service users. Through discussion as this group, we generated a list of the top 10 areas identified as priorities for technological development and improvement. These included better devices to manage examination, diagnosis and treatment of pelvic pain (including endometriosis), prolapse care, continence (treatment and prevention, related to pregnancy and beyond), menstruation, vaginal pain and vaginismus, point of care tests for common infections, and nipple care when breastfeeding. CONCLUSION: The top priorities suggest far-reaching areas of unmet need across women's life course and across multiple domains of health and well-being, and opportunities where innovation in the devices that people use themselves or encounter in health settings could potentially enhance health and healthcare experiences.

The impact of the COVID-19 pandemic on glycaemic control in people with diabetes: A systematic review and meta-analysis.

AIM: To identify, appraise and synthesize the available evidence on the impact of the coronavirus disease 2019 (COVID-19) pandemic and lockdown (LD) on glycaemic control in people with diabetes. MATERIALS AND METHODS: We searched multiple databases up to 2 February 2021 for studies reporting HbA1c, time in range (TIR), average or fasting glucose, severe hypoglycaemia and diabetic ketoacidosis. Data were pooled using random effects meta-analysis and are presented as mean difference (MD) with 95% confidence intervals (CI). This review was preregistered on PROSPERO (CRD42020179319). RESULTS: We include 59 studies; 44 (n = 15 464) were included in quantitative syntheses and 15 were narratively synthesized. Pooled data were grouped by diabetes type. Results from 28 studies (n = 5048 type 1 diabetes [T1D] and combined diabetes participants) showed that TIR increased during LD compared with before LD (MD 2.74%, 95% CI 1.80% to 3.69%). Data from 10 studies (n = 1294 T1D participants) showed that TIR increased after LD compared with before LD (MD 5.14%, 95% CI 3.12% to 7.16%). Pooled results from 12 studies (n = 4810 T1D and type 2 diabetes participants) resulted in average glucose decreasing after LD compared with before LD (MD -6.86 mg/dl, 95% CI -8.54 to -5.18). Results for other outcomes, including HbA1c, were not statistically significantly different. CONCLUSIONS: The COVID-19 pandemic was associated with small improvements across multiple outcomes of glycaemic control, although there was insufficient evidence to suggest that this led to changes in HbA1c. Most evidence came from people with access to diabetes technologies in high-income countries; more research is needed in less advantaged populations.

Signalling mechanisms driving homeostatic and inflammatory effects of interleukin-15 on tissue lymphocytes.

There is an intriguing dichotomy in the function of cytokine interleukin-15-at low levels, it is required for the homeostasis of the immune system, yet when it is upregulated in response to pathogenic infections or in autoimmunity, IL-15 drives inflammation. IL-15 associates with the IL-15Rα within both myeloid and non-haematopoietic cells, where IL-15Rα trans-presents IL-15 in a membrane-bound form to neighboring cells. Alongside homeostatic maintenance of select lymphocyte populations such as NK cells and tissue-resident T cells, when upregulated, IL-15 also promotes inflammatory outcomes by driving effector function and cytotoxicity in NK cells and T cells. As chronic over-expression of IL-15 can lead to autoimmunity, IL-15 expression is tightly regulated. Thus, blocking dysregulated IL-15 and its downstream signalling pathways are avenues for immunotherapy. In this review we discuss the molecular pathways involved in IL-15 signalling and how these pathways contribute to both homeostatic and inflammatory functions in IL-15-dependent mature lymphoid populations, focusing on innate, and innate-like lymphocytes in tissues.

Social Risk of Pregnant Women at a Community Health Center: An Application of the PRAPARE Assessment Tool.

Community health centers (CHCs) screen patients for social determinants of health (SDoH). The study's purpose was to assess the relationship between demographic factors and unmet social needs (SDoH risk) among pregnant mothers. Patient data from 345 pregnant women between January 2019-December 2020 assessed SDoH risk, using the Protocol for Responding to and Assessing Patients' Assets, Risks, and Experiences (PRAPARE) tool. Chi-square analyses explored relationships between social needs and demographic factors, and a multivariate logistic regression examined associations between these variables controlling for covariates. Hispanic patients and those who preferred to speak Spanish had 2.35 and 5.39 times the odds, respectively as non-Hispanic Whites and English speakers of having moderate/high/urgent SDoH risks. Mothers who had not completed high school had increased odds (aOR = 7.38) of SDoH risk. By identifying indicators that increase social risk level, CHCs can connect patients to essential social services, improving the downstream health of mothers and children.

Does Human Papillomavirus Play a Causative Role in Prostate Cancer? A Systematic Review Using Bradford Hill's Criteria.

Globally, prostate cancer is the fifth most common cause of cancer-related death among men, and metastatic castration-resistant prostate cancer has a high cancer-related mortality rate. However, the aetiology of this disease is not yet fully understood. While human papillomavirus (HPV) has been associated with several types of cancer, including cervical, anal, and oropharyngeal cancers, studies investigating the relationship between HPV and prostate cancer have shown mixed results. This systematic review aimed to evaluate the causative association between HPV and prostate cancer using Bradford Hill's criteria. A comprehensive search of PubMed was conducted, and 60 out of 482 studies were included in the review. The included studies were evaluated based on nine Bradford Hill criteria, and information on the identification and transmission of the virus and potential oncogenic mechanisms was also extracted. The strength of association criterion was not met, and other criteria, such as consistency and coherence, were not fulfilled. However, biological plausibility was supported, and potential oncogenic mechanisms were identified. While some studies have reported the presence of HPV in prostate cancer tissues, the overall quality of evidence remains low, and the association between HPV and prostate cancer is weak. Nevertheless, the prostate is a potential reservoir for the transmission of HPV, and the HPV E6 and E7 oncoproteins and inflammation are likely to be involved in any oncogenic mechanisms. Further studies with a higher level of evidence are needed to establish a definitive link between HPV and prostate cancer.

Diagnostic accuracy of natriuretic peptide screening for left ventricular systolic dysfunction in the community: systematic review and meta-analysis.

AIMS: Heart failure (HF) is a global health burden and new strategies to achieve timely diagnosis and early intervention are urgently needed. Natriuretic peptide (NP) testing can be used to screen for left ventricular systolic dysfunction (LVSD), but evidence on test performance is mixed, and international HF guidelines differ in their recommendations. Our aim was to summarize the evidence on diagnostic accuracy of NP screening for LVSD in general and high-risk community populations and estimate optimal screening thresholds. METHODS: We searched relevant databases up to August 2020 for studies with a screened community population of over 100 adults reporting NP performance to diagnose LVSD. Study inclusion, quality assessment, and data extraction were conducted independently and in duplicate. Diagnostic test meta-analysis used hierarchical summary receiver operating characteristic curves to obtain estimates of pooled accuracy to detect LVSD, with optimal thresholds obtained to maximize the sum of sensitivity and specificity. RESULTS: Twenty-four studies were identified, involving 26 565 participants: eight studies in high-risk populations (at least one cardiovascular risk factor), 12 studies in general populations, and four in both high-risk and general populations combined. For detecting LVSD in screened high-risk populations with N-terminal prohormone brain natriuretic peptide (NT-proBNP), the pooled sensitivity was 0.87 [95% confidence interval (CI) 0.73-0.94] and specificity 0.84 (95% CI 0.55-0.96); for BNP, sensitivity was 0.75 (95% CI 0.65-0.83) and specificity 0.78 (95% CI 0.72-0.84). Heterogeneity between studies was high with variations in positivity threshold. Due to a paucity of high-risk studies that assessed NP performance at multiple thresholds, it was not possible to calculate optimal thresholds for LVSD screening in high-risk populations alone. To provide an indication of where the positivity threshold might lie, the pooled accuracy for LVSD screening in high-risk and general community populations were combined and gave an optimal cut-off of 311 pg/mL [sensitivity 0.74 (95% CI 0.53-0.88), specificity 0.85 (95% CI 0.68-0.93)] for NT-proBNP and 49 pg/mL [sensitivity 0.68 (95% CI 0.45-0.85), specificity 0.81 (0.67-0.90)] for BNP. CONCLUSIONS: Our findings suggest that in high-risk community populations NP screening may accurately detect LVSD, potentially providing an important opportunity for diagnosis and early intervention. Our study highlights an urgent need for further prospective studies, as well as an individual participant data meta-analysis, to more precisely evaluate diagnostic accuracy and identify optimal screening thresholds in specifically defined community-based populations to inform future guideline recommendations.

Equine Odontoclastic Tooth Resorption and Hypercementosis.

Equine odontoclastic tooth resorption and hypercementosis (EOTRH) is a recently described painful and progressive condition of unknown etiology that occurs in middle-aged and geriatric equines. It predominantly affects the permanent incisor and canine teeth and, less commonly, the premolar and molar dentition. EOTRH was first reported in peer-reviewed literature in 2008, with subsequent publications of case reports, histological studies and retrospective case series. There have been few significant research developments related to this disease. The existing studies have primarily involved single case studies or small sample sizes, without control groups. This review aimed to report current information about EOTRH in terms of clinical, histopathological, diagnostic, radiological, and therapeutic aspects, by searching the available peer-reviewed scientific literature.

IL-15 and PIM kinases direct the metabolic programming of intestinal intraepithelial lymphocytes.

Intestinal intraepithelial lymphocytes (IEL) are an abundant population of tissue-resident T cells that protect and maintain the intestinal barrier. IEL respond to epithelial cell-derived IL-15, which is complexed to the IL-15 receptor α chain (IL-15/Rα). IL-15 is essential both for maintaining IEL homeostasis and inducing IEL responses to epithelial stress, which has been associated with Coeliac disease. Here, we apply quantitative mass spectrometry to IL-15/Rα-stimulated IEL to investigate how IL-15 directly regulates inflammatory functions of IEL. IL-15/Rα drives IEL activation through cell cycle regulation, upregulation of metabolic machinery and expression of a select repertoire of cell surface receptors. IL-15/Rα selectively upregulates the Ser/Thr kinases PIM1 and PIM2, which are essential for IEL to proliferate, grow and upregulate granzyme B in response to inflammatory IL-15. Notably, IEL from patients with Coeliac disease have high PIM expression. Together, these data indicate PIM kinases as important effectors of IEL responses to inflammatory IL-15.

Tissue environment, not ontogeny, defines murine intestinal intraepithelial T lymphocytes.

Tissue-resident intestinal intraepithelial T lymphocytes (T-IEL) patrol the gut and have important roles in regulating intestinal homeostasis. T-IEL include both induced T-IEL, derived from systemic antigen-experienced lymphocytes, and natural T-IEL, which are developmentally targeted to the intestine. While the processes driving T-IEL development have been elucidated, the precise roles of the different subsets and the processes driving activation and regulation of these cells remain unclear. To gain functional insights into these enigmatic cells, we used high-resolution, quantitative mass spectrometry to compare the proteomes of induced T-IEL and natural T-IEL subsets, with naive CD8+ T cells from lymph nodes. This data exposes the dominant effect of the gut environment over ontogeny on T-IEL phenotypes. Analyses of protein copy numbers of >7000 proteins in T-IEL reveal skewing of the cell surface repertoire towards epithelial interactions and checkpoint receptors; strong suppression of the metabolic machinery indicating a high energy barrier to functional activation; upregulated cholesterol and lipid metabolic pathways, leading to high cholesterol levels in T-IEL; suppression of T cell antigen receptor signalling and expression of the transcription factor TOX, reminiscent of chronically activated T cells. These novel findings illustrate how T-IEL integrate multiple tissue-specific signals to maintain their homeostasis and potentially function.

Risks of and From SARS-CoV-2 Infection and COVID-19 in People With Diabetes: A Systematic Review of Reviews.

BACKGROUND: This review was commissioned by the World Health Organization and presents a summary of the latest research evidence on the impact of coronavirus disease 2019 (COVID-19) on people with diabetes (PWD). PURPOSE: To review the evidence regarding the extent to which PWD are at increased risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and/or of suffering its complications, including associated mortality. DATA SOURCES: We searched the Cochrane COVID-19 Study Register, Embase, MEDLINE, and LitCOVID on 3 December 2020. STUDY SELECTION: Systematic reviews synthesizing data on PWD exposed to SARS-CoV-2 infection, reporting data on confirmed SARS-CoV-2 infection, admission to hospital and/or to intensive care unit (ICU) with COVID-19, and death with COVID-19 were used. DATA EXTRACTION: One reviewer appraised and extracted data; data were checked by a second. DATA SYNTHESIS: Data from 112 systematic reviews were narratively synthesized and displayed using effect direction plots. Reviews provided consistent evidence that diabetes is a risk factor for severe disease and death from COVID-19. Fewer data were available on ICU admission, but where available, these data also signaled increased risk. Within PWD, higher blood glucose levels both prior to and during COVID-19 illness were associated with worse COVID-19 outcomes. Type 1 diabetes was associated with worse outcomes than type 2 diabetes. There were no appropriate data for discerning whether diabetes was a risk factor for acquiring SARS-CoV-2 infection. LIMITATIONS: Due to the nature of the review questions, the majority of data contributing to included reviews come from retrospective observational studies. Reviews varied in the extent to which they assessed risk of bias. CONCLUSIONS: There are no data on whether diabetes predisposes to infection with SARS-CoV-2. Data consistently show that diabetes increases risk of severe COVID-19. As both diabetes and worse COVID-19 outcomes are associated with socioeconomic disadvantage, their intersection warrants particular attention.

Mechanisms of activation of innate-like intraepithelial T lymphocytes.

Intraepithelial T lymphocytes (T-IEL) contain subsets of innate-like T cells that evoke innate and adaptive immune responses to provide rapid protection at epithelial barrier sites. In the intestine, T-IEL express variable T cell antigen receptors (TCR), with unknown antigen specificities. Intriguingly, they also express multiple inhibitory receptors, many of which are normally found on exhausted or antigen-experienced T cells. This pattern suggests that T-IEL are antigen-experienced, yet it is not clear where, and in what context, T-IEL encounter TCR ligands. We review recent evidence indicating TCR antigens for intestinal innate-like T-IEL are found on thymic or intestinal epithelium, driving agonist selection of T-IEL. We explore the contributions of the TCR and various co-stimulatory and co-inhibitory receptors in activating T-IEL effector functions. The balance between inhibitory and activating signals may be key to keeping these highly cytotoxic, rapidly activated cells in check, and key to harnessing their immune surveillance potential.

Isolation, Characterization, and Culture of Intestinal Intraepithelial Lymphocytes.

Intestinal intraepithelial lymphocytes (IEL) comprise distinct groups of innate-like and memory T cells that collectively form one of the largest T cell compartments in the body. IEL are located within the intestinal epithelium and are the first immune cells in the gut to interact with the food, microbiota, and pathogens that the gut is continually exposed to. IEL can respond rapidly to external insults to protect the small intestinal epithelium but are also considered regulatory cells that are important to maintain the homeostasis of the gut. However, the mechanisms of IEL activation and their interactions within the epithelium remain largely elusive. Indeed, IEL are not commonly evaluated even in studies of gut immunology, potentially because they are perceived as being difficult to isolate and study. In this protocol, we present a simplified method to isolate IEL from the murine small intestine and provide representative data for flow cytometric analyses of the different IEL subsets. We also outline two procedures for culturing IEL, which can permit functional studies and coculture with epithelial cells. These strategies should make studies of this large but enigmatic T cell compartment more accessible and open up understanding of homeostatic mechanisms in the intestine, and tissue-associated immunity.

A Comparative Neuro-Histological Assessment of Gluteal Skin Thickness and Cutaneous Nociceptor Distribution in Horses and Humans.

The current project aims to build on knowledge of the nociceptive capability of equine skin to detect superficial acute pain, particularly in comparison to human skin. Post-mortem samples of gluteal skin were taken from men (n = 5) and women (n = 5), thoroughbreds and thoroughbred types (mares, n = 11; geldings, n = 9). Only sections that contained epidermis and dermis through to the hypodermis were analysed. Epidermal depth, dermal depth and epidermal nerve counts were conducted by a veterinary pathologist. The results revealed no significant difference between the epidermal nerve counts of humans and horses (t = 0.051, p = 0.960). There were no significant differences between epidermal thickness of humans (26.8 µm) and horses (31.6 µm) for reference (left side) samples (t = 0.117, p = 0.908). The human dermis was significantly thinner than the horse dermis (t = -2.946, p = 0.007). Epidermal samples were thicker on the right than on the left, but only significantly so for horses (t = 2.291, p = 0.023), not for humans (t = 0.694, p = 0.489). The thicker collagenous dermis of horse skin may afford some resilience versus external mechanical trauma, though as this is below the pain-detecting nerve endings, it is not considered protective from external cutaneous pain. The superficial pain-sensitive epidermal layer of horse skin is as richly innervated and is of equivalent thickness as human skin, demonstrating that humans and horses have the equivalent basic anatomic structures to detect cutaneous pain. This finding challenges assumptions about the physical capacity of horses to feel pain particularly in comparison to humans, and presents physical evidence to inform the discussion and debate regarding the ethics of whipping horses.

Generalised peritonitis from strangulated small bowel obstruction secondary to mesh erosion: a rare long-term complication of laparoscopic mesh sacrohysteropexy.

A 77-year-old woman who underwent an uncomplicated laparoscopic mesh sacrohysteropexy (LMH) in 2009 for uterovaginal prolapse, presented with features of small bowel obstruction (SBO) 9 years later. She underwent laparotomy which revealed that the sacrohysteropexy mesh had eroded into the small bowel causing complete obstruction, complicated by ischaemia and perforation. Small bowel resection and primary anastomosis was performed, and the patient had an uneventful postoperative recovery. Although rare, cases of SBO occurring secondary to the use of a synthetic mesh in LMH have been reported. This is the first reported case of SBO directly attributable to erosion of mesh into the small bowel itself. Given the increasing frequency of women undergoing surgical management of pelvic organ prolapse which involves techniques using synthetic mesh, it is important to consent patients appropriately for such life-threatening risks and to focus on the development of surgical techniques and mesh materials to minimise such complications.