Inflammation dynamically regulates steroid hormone metabolism and action within macrophages in rheumatoid arthritis.

RATIONALE: In inflammatory diseases such as rheumatoid arthritis (RA), steroid metabolism is a central component mediating the actions of immuno-modulatory glucocorticoids and sex steroids. However, the regulation and function of cellular steroid metabolism within key leukocyte populations such as macrophages remain poorly defined. In this study, the inflammatory regulation of global steroid metabolism was assessed in RA macrophages. METHODS: Bulk RNA-seq data from RA synovial macrophages was used to assess transcripts encoding key enzymes in steroid metabolism and signalling. Changes in metabolism were assessed in synovial fluids, correlated to measures of disease activity and functionally validated in primary macrophage cultures. RESULTS: RNA-seq revealed a unique pattern of differentially expressed genes, including changes in genes encoding the enzymes 11ß-HSD1, SRD5A1, AKR1C2 and AKR1C3. These correlated with disease activity, favouring increased glucocorticoid and androgen levels. Synovial fluid 11ß-HSD1 activity correlated with local inflammatory mediators (TNFα, IL-6, IL-17), whilst 11ß-HSD1, SRD5A1 and AKR1C3 activity correlated with systemic measures of disease and patient pain (ESR, DAS28 ESR, global disease activity). Changes in enzyme activity were evident in inflammatory activated macrophages in vitro and revealed a novel androgen activating role for 11ß-HSD1. Together, increased glucocorticoids and androgens were able to suppress inflammation in macrophages and fibroblast-like-synoviocytes. CONCLUSIONS: This study underscores the significant increase in androgen and glucocorticoid activation within inflammatory polarized macrophages of the synovium, contributing to local suppression of inflammation. The diminished profile of inactive steroid precursors in postmenopausal women may contribute to disturbances in this process, leading to increased disease incidence and severity.

A comprehensive analysis of the pre- and postoperative responses to each of the 12 Oxford knee score questions one year following knee arthroplasty.

AIMS: To assess the pre- and postoperative responses to each of the 12 individual Oxford Knee Score (OKS) questions and percentages of those that were better, same or worse after primary knee arthroplasty (KA). METHODS: A single centre retrospective cohort study conducted over a 24-month period which included 3259 patients with completed OKS preoperatively and 1-year after KA. There were 1286 males and 1973 females, with an overall mean age of 70.0 (range 34-94). The mean scores for each question of the OKS were compared between baseline and 1-year. The percentage of patients who reported better, the same or worse postoperative symptoms for each question were calculated and represented on a heatmap. RESULTS: There were significant (p < 0.001) improvements in all 12 questions, all of which demonstrated moderate (Q2, Q7) or large effect sizes. Improvements in individual question responses varied. Symptoms of pain and limping demonstrated the greatest improvement, with 86% of patients enjoying a positive change in their symptoms. Despite this improvement 1067 (41.4%) continued to have mild to severe pain in their knee, and 442 (17.3%) patients limped often to all the time when walking postoperatively. Whereas other questions that did not improve to the same extent for example washing and drying only improved in 53% of patients but only 347 (13.5%) had moderate/extreme trouble or found it impossible to do this postoperatively. Preoperatively four questions (Q1, Q6, Q7, Q8) demonstrated floor effects, postoperatively all questions apart from question 7 (kneeling) demonstrated ceiling effects. CONCLUSION: The mean improvement and outcome at 1-year for each of the 12 questions varied according to the patient's preoperative response. As a clinical tool, the heatmap (improvement, same and worse) will enable communication to patients about their potential change in their knee specific symptoms according to their preoperative responses. LEVEL OF EVIDENCE: Retrospective study, Level III.

Total hip arthroplasty for femoral fractures other than capital physeal fractures in dogs: 14 cases (2012-2020).

OBJECTIVES: The goals of this retrospective study were to assess the clinical and radiographic outcomes in dogs with proximal femoral fractures, other than capital physeal fractures, treated via total hip arthroplasty. MATERIALS AND METHODS: Medical records as well as pre-operative, immediate post-operative and 2 to 3 months post-operative radiographs of 14 dogs with femoral head and neck fractures treated via total hip arthroplasty were reviewed. A Liverpool Osteoarthritis in Dogs questionnaire was completed by owners to assess long-term outcomes. RESULTS: Seven femoral head fractures, and seven femoral neck fractures were included. Four of the femoral head fractures were acute in nature, the three remaining femoral head fractures and all seven femoral neck fracture cases were chronic fractures. Malorientation of the femoral stem was more common in the chronic femoral fracture cases when compared to the acute femoral fracture cases. Two of the acute fracture cases and five chronic fracture cases experienced a change in femoral stem position post-operatively. One femoral fissure fracture occurred and was repaired intraoperatively. One case had a post-operative complication that resulted in implant removal. All dogs had good to excellent owner-perceived outcome. CLINICAL SIGNIFICANCE: Femoral head and neck fractures, and in particular the chronic cases, represented a challenging subset of cases presenting for total hip arthroplasty, resulting in suboptimal stem alignment in many cases. However, clinical outcomes were considered good to excellent in all dogs in the study, indicating that total hip arthroplasty is a viable treatment option for these types of fractures.

Evaluation of long-term outcome following therapeutic mammaplasty: the effect of wound complication on initiation of adjuvant therapy and subsequent oncological outcome.

INTRODUCTION: Therapeutic mammaplasty (TM) facilitates large tumour resection while maintaining optimal aesthetic outcome. It carries higher wound complication risks, which may delay adjuvant therapy initiation. Whether this delay affects oncological outcome requires evaluation. METHODS: Data were collected for consecutive patients receiving TM at the Leeds breast unit (2009-2017). A prospectively maintained database was used to determine tumour characteristics, wound complication rates, receipt of adjuvant therapy and breast cancer recurrence or death. RESULTS: In total 112 patients (median age of 54 years) underwent 114 TM procedures. The most common histological subtypes were invasive ductal carcinoma (61.4%), invasive lobular carcinoma (13.2%) and ductal carcinoma in situ (13.2%). Of the patients, 88.2% had oestrogen receptor-positive cancer and 14% had human epidermal growth factor receptor-positive cancer; 26.3% had multifocal cancer. The median tumour size was 30mm. The median Nottingham Prognostic Index was 4.2. The local recurrence rate was 3.5% (median follow-up of 8.6 years). The 5- and 10-year disease-free survival (DFS) was 88.5% and 83.5%, and the equivalent overall survival (OS) rates were 94% and 83.5%. Wound complication rate was 23.6% (n=27), the commonest being wound infection (11.4%; n=13) and T-junction wound breakdown (10.5%; n=12). The median time to adjuvant therapy was 72 days (interquartile range [IQR] 56-90) for patients with wound complications, and 51 days (IQR 42-58) for those without. However, this delay did not affect DFS or OS (log-rank test; p=0.58 and p=0.94, respectively). This was confirmed on Cox regression analysis. CONCLUSION: Our study finding demonstrates that although wound complications after TM leads to a modest delay to adjuvant therapy, the long-term oncological outcomes were comparable with those in patients without wound complications.

Returning value to the community through the All of Us Research Program Data Sandbox model.

OBJECTIVE: The All of Us Research Program aims to return value to participants by developing research capacity in communities. We describe a novel set of introductory exercises (Data Sandboxes) and specialized trainings to orient researchers to the Researcher Workbench to foster health equity research. MATERIALS AND METHODS: We developed a tailored training to familiarize researchers with the All of Us Research Program: (1) orientation, (2) tailored "data treasure hunt" using the Public Data Browser, and (3) overview of the analyses tools and platform. RESULTS: Participants' pre- and post-knowledge of the contents and structure of the All of Us dataset scores increased significantly after training. These trainings effectively engaged researchers in exploring this rich dataset. CONCLUSION: We describe ways of orienting and familiarizing a wide variety of researchers with the All of Us Research Program dataset, sparking their interest, and "jump-starting" their research.

An alien intermediate snail host in Malawi - Orientogalba viridis (Quoy and Gaimard, 1832) - A new concern for schistosomiasis transmission in Africa?

The freshwater amphibious snail Orientogalba viridis commonly occurs in eastern Asia, on certain Pacific islands and more importantly has recently dispersed into Europe. Since this snail is now considered an invasive species, its distribution is of growing parasitological interest as an alien intermediate host for various trematodes, particularly liver flukes. As part of ongoing surveillance for snail-borne diseases in Malawi, a population of O. viridis was first observed in May 2023, alongside an alarming presence of a human schistosome cercaria. This snail population later underwent detailed morphological characterisation with both snail and parasite identities confirmed upon DNA barcoding. This seminal observation triggered more extensive local snail surveys, finding 3 further populations in separated rice paddies, with further field-caught snails (n = 465) screened for infection and a selection used for repeated experimental challenges with miracidia from Schistosoma haematobium and Schistosoma mattheei. Although no field-caught (and experimentally exposed) snail was seen to shed schistosome cercariae, molecular xenomonitoring for schistosomiasis provided tangible evidence of putative transmission potential. Our first report of O. viridis here in Malawi, and more broadly in Africa, flags a need for increased vigilance for this invasive species alongside local clarification(s) of its transmission potential for trematodiases of either medical and/or veterinary importance.

A first report of Pseudosuccinea columella (Say, 1817), an alien intermediate host for liver fluke, in Malawi.

Starting in October 2021, quarterly malacological surveys have been undertaken in Malawi, with the sampling of 12 specified freshwater habitats throughout a calendar year. Each survey monitors the presence of aquatic intermediate snail hosts of medical and veterinary importance. In March 2023, the alien lymnaeid species Pseudosuccinea columella was encountered for the first time in the surveys, in Nsanje District. This species identity was later confirmed upon DNA analysis of mitochondrial ribosomal 16S sequences. In July 2023, P. columella was also noted at single sites within Mangochi and Chikwawa Districts, and again in Nsanje District, with an additional location observed. Of particular importance, our sampled location in Mangochi District was directly connected to Lake Malawi, which expands the species list of invasive molluscs in this lake. While P. columella is a well-known intermediate snail host for human and animal fascioliasis, screening collected snails for trematode cercariae, alongside molecular xenomonitoring, did not yield equivocal evidence of active fluke infection. However, the newly recognized presence of this alien intermediate snail host within Lake Malawi, and along the Shire River Valley, flags a new concern in altered local transmission potential for human and animal fascioliasis.

Surgical Management of Ebstein Anomaly: The Australia and New Zealand Experience.

BACKGROUND: Ebstein anomaly is a rare congenital anomaly of the tricuspid valve which presents challenges to cardiac surgeons due to the spectrum of the disease and the technical difficulty of valve repair. The natural history of the anomaly differs between patients presenting in the neonatal period to those presenting in adulthood. METHODS: A retrospective review of all patients >15 years of age with Ebstein anomaly, undergoing surgery on the tricuspid valve at 6 centers across Australia and New Zealand was performed. Patients from 1985 to 2019 were included in the study. RESULTS: A total of 125 patients were included in the study, 76 patients (60%) undergoing tricuspid valve repair, of which 23 patients underwent a Cone repair and 49 (40%) had a tricuspid valve replacement. The mean follow-up was 7.9 ± 7.3 years. Postoperatively, early mortality was 3 patients (2%) and 10-year survival was 91.5%. A postoperative pacemaker was required in 24 patients (19%). Reoperation was required in 21 patients (17%). There was no statistically significant difference in survival or reoperation between patients who underwent repair or replacement of the tricuspid valve; however, with a small number of patients in long-term follow-up. CONCLUSION: Older children and adult patients undergoing surgery for Ebstein anomaly in Australia and New Zealand experience good medium-term postoperative survival. Repair of the valve is achieved in a significant proportion of patients with increasing use and success with the Cone repair technique.

Evidence on delay in sexual initiation, multiple partnerships and condom use among young people: review of Caribbean HIV behavioural studies / Evidencias sobre la demora en la iniciación sexual, las parejas múltiples, y el uso del condón entre los jóvenes: revisión de estudios de conducta en relación con el VIH en el Caribe

OBJECTIVE: To develop a Caribbean regional profile of youth sexual behaviour associated with risk of HIV. DESIGN AND METHODS: A review of sexual behaviour surveys with youth aged 15-24 years was conducted as part of the Pan American Health Organization (PAHO) HIV Caribbean Office's Review and Gender Analysis of Caribbean HIV Behavioural and Seroprevalence Studies. Studies with internationally recommended indicators were prioritized. Studies were sought via database searches and contact with researchers and National AIDS Programmes. RESULTS: Inter-country comparisons and longitudinal analyses were limited by lack of uniformity in study age groups and indicators. Data were sufficient to identify the following among 15-24-year olds: * More males than females report sexual intercourse before the age of 15 years. * More than half of sexually active youth report sex before age 16 years. * First sexual encounter is usually with someone older, with age differences larger for females. * More males than females report multiple partnerships, with 20%-76% of males reporting this in the past year. * Condom use varies widely, with no clear pattern by gender. CONCLUSION: There are substantial levels of early sexual initiation, intergenerational sex among females and multiple partnerships among males, while condom use is inconsistent. Efforts to promote delay in sexual initiation, partner reduction and consistent condom use should be supplemented with initiatives against harmful gender norms, child abuse and transactional sex and skills to negotiate safe sex. Standardization of survey methods to facilitate cross-study comparisons should continue and encompass additional risk factors such as transactional sex, gender-based violence, drug use and HIV treatment adherence.

OBJETIVO: Desarrollar un perfil regional caribeño del comportamiento sexual de la juventud en relación con el riesgo de VIH. DISEÑO Y MÉTODOS: Se realizó una revisión de los estudios del comportamiento sexual de jóvenes entre 15 y 24 años, como parte del Estudio de la Oficina de VIH de la Organización Panamericana de la Salud (OPS) para el Caribe, y el Análisis de Género de los Estudios de Seroprevalencia y Conducta en relación con el VIH en el Caribe. Se le dio prioridad a los estudios con indicadores recomendados internacionalmente. Se obtuvieron estudios mediante búsquedas de bases de datos y contactos con los investigadores y los programas nacionales de SIDA. RESULTADOS: Los análisis longitudinales y las comparaciones entre países estuvieron limitados por la falta de uniformidad en los grupos etarios y los indicadores de los estudios. Los datos fueron suficientes para identificar lo siguiente entre los jóvenes de 15 a 24 años de edad: * Más varones que hembras reportaron relaciones sexuales antes de los 15 años de edad. * Más de la mitad de los jóvenes sexualmente activos reportaron relaciones sexuales antes de los 16 años. * El primer encuentro sexual suele ser con alguien de más edad, siendo las diferencias de edad mayores para las mujeres. * Más varones que hembras reportaron relaciones de parejas múltiples; 20%-76% de los hombres reportaron este tipo de relación en el último año. * El uso del condón varía ampliamente, sin un patrón claro por género. CONCLUSIÓN: Hay niveles considerables de iniciación sexual temprana, sexo intergeneracional entre las hembras, y múltiples parejas entre los varones, mientras que el uso del preservativo es inconsistente. Los esfuerzos por promover la demora en la iniciación sexual, la reducción de parejas, y el uso sistemático del condón deberían complementarse con las iniciativas contra las normas de género perjudiciales, el abuso infantil, el sexo transaccional, y las habilidades para negociar sexo seguro. La estandarización de los métodos de encuesta para facilitar las comparaciones transversales debe continuar y abarcar otros factores de riesgo, tales como el sexo transaccional, la violencia de género, el uso de drogas, y el cumplimiento con el tratamiento del VIH.

Acceptability of antenatal diagnosis for sicke-cell disease among jamaican mothers and female patients

A questionnaire on the need and acceptability of antenatal diagnosis (AND) for sickle-cell disease was given to 112 women with homozygous sickle-cell (SS) disease and 117 AS mothers for patients with SS disease, all aged 15-45 years. AND was favoured by 58% of patients and 76% of mothers, the option for termination of an affected pregnancy being the reason in 43% of patients and in 51% of mothers among this group. Fear of the procedure was the commonest reason for not selecting AND. Of the two common methods, chorionic villus samplis (first trimester) and amniocentesis (second trimester), 74% of all women selected the first trimester method, and 93% considered these tests should be available in Jamaica. Faced with the diagnosis of a foetus with SS disease, 30% of patients and 46% of mothers stated they would request termination