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Background: Antidepressants' effects are established in randomised controlled trials (RCTs), but not in the real world., Aims: To investigate real-world comparative effects of antidepressants for depression and compare them with RCTs., Method: We performed a cohort study based on the QResearch database. We included people with a newly recorded diagnosis of depression, exposed to licensed antidepressants in the UK. We assessed all-cause dropouts (acceptability), dropouts for adverse events (tolerability), occurrence of at least one adverse event (safety), and response and remission on the Patient Health Questionnaire (PHQ)-9 (effectiveness) at 2 and 12 months. Logistic regressions were used to compute adjusted-odds ratio (aOR) with 99% CIs, assessing the associations between exposure to each antidepressant against fluoxetine (comparator) and outcomes of interest. We compared estimates from the real world with RCTs using ratio-of-odds ratio (ROR) with 95% CI., Results: A total of 673 177 depressed people were studied: females 57.1%, mean age 42.8 (s.d. 17.7) years, mean baseline PHQ-9 17.1 (s.d. 5.0) (moderately severe depression). At 2 months, antidepressant acceptability was 61.4%, tolerability 94.4%, safety 54.5%, PHQ-9 decreased to 12.3 (s.d. 6.5). At 12 months, acceptability was 12.3%, tolerability 87.5%, safety 28.8%, PHQ-9 12.9 (s.d. 6.8). In the short and long term, tricyclics, mirtazapine and trazodone were worse than fluoxetine for most outcomes; citalopram had better acceptability than fluoxetine (aOR 0.95; 99% CI 0.92, 0.97), sertraline had lower tolerability (aOR 1.12; 99% CI 1.06, 1.18), and both citalopram and sertraline had lower safety (aOR 1.17 and 1.25, respectively). In the long term, citalopram had better acceptability (aOR 0.78; 99% CI 0.76, 0.81) and effectiveness (aOR 1.12 for both response and remission), but worse tolerability (aOR 1.09; 99% CI 1.06, 1.13) and safety (aOR 1.12; 99% CI 1.08, 1.16). Observational and randomised data were similar for citalopram and sertraline, while there was some difference for drugs less prescribed in the real world., Conclusions: Antidepressants showed low acceptability, moderate-to-high tolerability and safety, and small-to-moderate effectiveness in the real world. Real-world and RCT estimates showed similar findings only when the analyses were carried out using large datasets; otherwise, the results diverged.

Introduction/aims: Expanded access (EA) is a Food and Drug Administration-regulated pathway to provide access to investigational products (IPs) to individuals with serious diseases who are ineligible for clinical trials. The aim of this report is to share the design and operations of a multicenter, multidrug EA program for amyotrophic lateral sclerosis (ALS) across nine US centers., Methods: A central coordination center was established to design and conduct the program. Templated documents and processes were developed to streamline study design, regulatory submissions, and clinical operations across protocols. The program included three protocols and provided access to IPs that were being tested in respective regimens of the HEALEY ALS Platform Trial (verdiperstat, CNM-Au8, and pridopidine). Clinical and safety data were collected in all EA protocols (EAPs). The program cohorts comprised participants who were not eligible for the platform trial, including participants at advanced stages of disease progression and with long disease duration., Results: A total of 85 participants were screened across the 3 EAPs from July 2021 to September 2022. The screen failure rate was 3.5%. Enrollment for the regimens of the platform trial was completed as planned and results informed the duration of the corresponding EAP. The verdiperstat EAP was concluded in December 2022. Mean duration of participation in the verdiperstat EAP was 5.8 ± 4.1 months. The CNM-Au8 and pridopidine EAPs are ongoing., Discussion: Multicenter EAPs conducted in parallel to randomized clinical trials for ALS can successfully enroll participants who do not qualify for clinical trials., (© 2024 The Author(s). Muscle & Nerve published by Wiley Periodicals LLC.)

Background: During the first epidemic wave, COVID-19 surveillance focused on quantifying the magnitude and the escalation of a growing global health crisis. The scientific community first assessed risk through basic indicators, such as the number of cases or rates of new cases and deaths, and later began using other direct impact indicators to conduct more detailed analyses. We aimed at synthesizing the scientific community's contribution to assessing the direct impact of the COVID-19 pandemic on population health through indicators reported in research papers., Methods: We conducted a rapid scoping review to identify and describe health indicators included in articles published between January 2020 and June 2021, using one strategy to search PubMed, EMBASE and WHO COVID-19 databases. Sixteen experts from European public health institutions screened papers and retrieved indicator characteristics. We also asked in an online survey how the health indicators were added to and used in policy documents in Europe., Results: After reviewing 3891 records, we selected a final sample of 67 articles and 233 indicators. We identified 52 (22.3%) morbidity indicators from 33 articles, 105 severity indicators (45.1%, 27 articles) and 68 mortality indicators (29.2%, 51). Respondents from 22 countries completed 31 questionnaires, and the majority reported morbidity indicators (29, 93.5%), followed by mortality indicators (26, 83.9%)., Conclusions: The indicators collated here might be useful to assess the impact of future pandemics. Therefore, their measurement should be standardized to allow for comparisons between settings, countries and different populations., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Public Health Association.)

In response to COVID-19 pandemic, we have launched a vaccine development program against SARS-CoV-2. Here we report the safety, tolerability, and immunogenicity of a recombinant protein RBD fusion heterodimeric vaccine against SARS-CoV-2 (PHH-1V) evaluated in a phase 1-2a dose-escalation, randomized clinical trial conducted in Catalonia, Spain. 30 young healthy adults were enrolled and received two intramuscular doses, 21 days apart of PHH-1V vaccine formulations [10 µg (n = 5), 20 µg (n = 10), 40 µg (n = 10)] or control [BNT162b2 (n = 5)]. Each PHH-1V group had one safety sentinel and the remaining participants were randomly assigned. The primary endpoint was solicited events within 7 days and unsolicited events within 28 days after each vaccination. Secondary endpoints were humoral and cellular immunogenicity against the variants of concern (VOCs) alpha, beta, delta and gamma. All formulations were safe and well tolerated, with tenderness and pain at the site of injection being the most frequently reported solicited events. Throughout the study, all participants reported having at least one mild to moderate unsolicited event. Two unrelated severe adverse events (AE) were reported and fully resolved. No AE of special interest was reported. Fourteen days after the second vaccine dose, all participants had a >4-fold change in total binding antibodies from baseline. PHH-1V induced robust humoral responses with neutralizing activities against all VOCs assessed (geometric mean fold rise at 35 days p < 0.0001). The specific T-cell response assessed by ELISpot was moderate. This initial evaluation has contributed significantly to the further development of PHH-1V, which is now included in the European vaccine portfolio.ClinicalTrials.gov Identifier NCT05007509EudraCT No. 2021-001411-82., (© 2023. Springer Nature Limited.)

The continuing high global incidence of COVID-19 and the undervaccinated status of billions of persons strongly motivate the development of a new generation of efficacious vaccines. We have developed an adjuvanted vaccine candidate, PHH-1V, based on a protein comprising the receptor binding domain (RBD) of the Beta variant of SARS-CoV-2 fused in tandem with the equivalent domain of the Alpha variant, with its immunogenicity, safety and efficacy previously demonstrated in mouse models. In the present study, we immunized pigs with different doses of PHH-1V in a prime-and-boost scheme showing PHH-1V to exhibit an excellent safety profile in pigs and to produce a solid RBD-specific humoral response with neutralising antibodies to 7 distinct SARS-CoV-2 variants of concern, with the induction of a significant IFNγ + T-cell response. We conclude that PHH-1V is safe and elicits a robust immune response to SARS-CoV-2 in pigs, a large animal preclinical model., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Edward Pradenas reports a relationship with Gilead Sciences Inc that includes: travel reimbursement. Julia Blanco reports a relationship with Gilead Sciences Inc that includes: speaking and lecture fees and travel reimbursement. Julia Blanco reports a relationship with Merck Sharp & Dohme UK Ltd that includes: consulting or advisory and funding grants. Julia Blanco reports a relationship with Albajuna Therapeutics that includes: equity or stocks. Julia Blanco reports a relationship with Grifols SA that includes: funding grants. Julia Blanco reports a relationship with Nesapor that includes: funding grants. Paula Cebollada Rica reports a relationship with Laboratorios HIPRA S.A. that includes: funding grants. Marta Sistere reports a relationship with Laboratorios HIPRA S.A. that includes: funding grants. Andreas Meyerhans reports a relationship with Laboratorios HIPRA S.A. that includes: funding grants. Alexandra Moros reports a relationship with Laboratorios HIPRA S.A. that includes: employment. Antonio Prefaneta reports a relationship with Laboratorios HIPRA S.A. that includes: employment. Antonio Barreiro reports a relationship with Laboratorios HIPRA S.A. that includes: employment. Eva Perozo reports a relationship with Laboratorios HIPRA S.A. that includes: employment. Alex Fernandez reports a relationship with Laboratorios HIPRA S.A. that includes: employment. Manuel Canete reports a relationship with Laboratorios HIPRA S.A. that includes: employment. Luis Gonzalez reports a relationship with Laboratorios HIPRA S.A. that includes: employment. Carme Garriga reports a relationship with Laboratorios HIPRA S.A. that includes: employment. Teresa Prat Cabanas reports a relationship with Laboratorios HIPRA S.A. that includes: employment. Ricard March reports a relationship with Laboratorios HIPRA S.A. that includes: employment. Laura Ferrer reports a relationship with Laboratorios HIPRA S.A. that includes: employment., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Cognitive decline in Huntington's disease (HD) begins early in the disease course, however the reported prevalence and severity of cognitive impairment varies based on diagnostic approach. A Movement Disorders Society Task Force recently endorsed the use of standardized DSM-5-based criteria to diagnose neurocognitive disorder (NCD) in Huntington's disease., Objectives: To determine the prevalence and severity of cognitive impairment across different stages of HD by applying NCD criteria (mild and major) to participant data from the Enroll-HD database., Methods: Enroll-HD participants were triaged into either premanifest (preHD), manifest or control groups. PreHD was further dichotomized into preHD near or preHD far based on predicted time to diagnosis using the scaled CAG-age product score (CAPs). Embedded cognitive performance and functional independence measures were used to determine prevalence of NCD (mild and major) for all groups., Results: Prevalence of NCD-mild was 25.2%-38.4% for manifest HD, 22.8%-47.3% for preHD near, 11.5%-25.1% for preHD far, and 8.8%-19.1% for controls. Prevalence of NCD-major was 21.1%-57.7% for manifest HD, 0.5%-16.3% for preHD near, 0.0%-4.5% for preHD far, and 0.0%-3.0% for controls., Conclusion: The prevalence of NCD in HD is elevated in preHD and demonstrates a sharp rise prior to diagnosis. In manifest HD, the vast majority of participants meet criteria for NCD. These findings are important for optimizing clinical care and/or anticipating the need for supportive services., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Sierra, Ullman, Baselga-Garriga, Pandeya, Frank and Laganiere.)

SARS-CoV-2 emerged in December 2019 and quickly spread worldwide, continuously striking with an unpredictable evolution. Despite the success in vaccine production and mass vaccination programs, the situation is not still completely controlled, and therefore accessible second-generation vaccines are required to mitigate the pandemic. We previously developed an adjuvanted vaccine candidate coded PHH-1V, based on a heterodimer fusion protein comprising the RBD domain of two SARS-CoV-2 variants. Here, we report data on the efficacy, safety, and immunogenicity of PHH-1V in cynomolgus macaques. PHH-1V prime-boost vaccination induces high levels of RBD-specific IgG binding and neutralizing antibodies against several SARS-CoV-2 variants, as well as a balanced Th1/Th2 cellular immune response. Remarkably, PHH-1V vaccination prevents SARS-CoV-2 replication in the lower respiratory tract and significantly reduces viral load in the upper respiratory tract after an experimental infection. These results highlight the potential use of the PHH-1V vaccine in humans, currently undergoing Phase III clinical trials., Competing Interests: Authors indicated as “1” are employees of HIPRA, a private pharmaceutical company that develops and manufactures biological medicines such as vaccines. IrsiCaixa, UPF, Cynbiose, CIRI, VirNext, and CReSA have received financial support from HIPRA. Several patent applications have been filed by HIPRA Scientific S.L.U. and Laboratorios HIPRA, S.A. on different SARS-CoV-2 vaccine candidates and SARS-CoV-2 subunit vaccines, including the novel recombinant RBD fusion heterodimer PHH-1V. A.B., A.P., L.G., L.F., E.P., J.P., T.P., and C.G. are the inventors of these patent applications., (© 2023 The Authors.)

Background: A SARS-CoV-2 protein-based heterodimer vaccine, PHH-1V, has been shown to be safe and well-tolerated in healthy young adults in a first-in-human, Phase I/IIa study dose-escalation trial. Here, we report the interim results of the Phase IIb HH-2, where the immunogenicity and safety of a heterologous booster with PHH-1V is assessed versus a homologous booster with BNT162b2 at 14, 28 and 98 days after vaccine administration., Methods: The HH-2 study is an ongoing multicentre, randomised, active-controlled, double-blind, non-inferiority Phase IIb trial, where participants 18 years or older who had received two doses of BNT162b2 were randomly assigned in a 2:1 ratio to receive a booster dose of vaccine-either heterologous (PHH-1V group) or homologous (BNT162b2 group)-in 10 centres in Spain. Eligible subjects were allocated to treatment stratified by age group (18-64 versus ≥65 years) with approximately 10% of the sample enrolled in the older age group. The primary endpoints were humoral immunogenicity measured by changes in levels of neutralizing antibodies (PBNA) against the ancestral Wuhan-Hu-1 strain after the PHH-1V or the BNT162b2 boost, and the safety and tolerability of PHH-1V as a boost. The secondary endpoints were to compare changes in levels of neutralizing antibodies against different variants of SARS-CoV-2 and the T-cell responses towards the SARS-CoV-2 spike glycoprotein peptides. The exploratory endpoint was to assess the number of subjects with SARS-CoV-2 infections ≥14 days after PHH-1V booster. This study is ongoing and is registered with ClinicalTrials.gov, NCT05142553., Findings: From 15 November 2021, 782 adults were randomly assigned to PHH-1V (n = 522) or BNT162b2 (n = 260) boost vaccine groups. The geometric mean titre (GMT) ratio of neutralizing antibodies on days 14, 28 and 98, shown as BNT162b2 active control versus PHH-1V, was, respectively, 1.68 (p < 0.0001), 1.31 (p = 0.0007) and 0.86 (p = 0.40) for the ancestral Wuhan-Hu-1 strain; 0.62 (p < 0.0001), 0.65 (p < 0.0001) and 0.56 (p = 0.003) for the Beta variant; 1.01 (p = 0.92), 0.88 (p = 0.11) and 0.52 (p = 0.0003) for the Delta variant; and 0.59 (p ≤ 0.0001), 0.66 (p < 0.0001) and 0.57 (p = 0.0028) for the Omicron BA.1 variant. Additionally, PHH-1V as a booster dose induced a significant increase of CD4 + and CD8 + T-cells expressing IFN-γ on day 14. There were 458 participants who experienced at least one adverse event (89.3%) in the PHH-1V and 238 (94.4%) in the BNT162b2 group. The most frequent adverse events were injection site pain (79.7% and 89.3%), fatigue (27.5% and 42.1%) and headache (31.2 and 40.1%) for the PHH-1V and the BNT162b2 groups, respectively. A total of 52 COVID-19 cases occurred from day 14 post-vaccination (10.14%) for the PHH-1V group and 30 (11.90%) for the BNT162b2 group (p = 0.45), and none of the subjects developed severe COVID-19., Interpretation: Our interim results from the Phase IIb HH-2 trial show that PHH-1V as a heterologous booster vaccine, when compared to BNT162b2, although it does not reach a non-inferior neutralizing antibody response against the Wuhan-Hu-1 strain at days 14 and 28 after vaccination, it does so at day 98. PHH-1V as a heterologous booster elicits a superior neutralizing antibody response against the previous circulating Beta and the currently circulating Omicron BA.1 SARS-CoV-2 variants in all time points assessed, and for the Delta variant on day 98 as well. Moreover, the PHH-1V boost also induces a strong and balanced T-cell response. Concerning the safety profile, subjects in the PHH-1V group report significantly fewer adverse events than those in the BNT162b2 group, most of mild intensity, and both vaccine groups present comparable COVID-19 breakthrough cases, none of them severe., Funding: HIPRA SCIENTIFIC, S.L.U., Competing Interests: The authors of this manuscript declare: J Blanco has received institutional grants from HIPRA, 10.13039/501100016387Grifols, and MSD, royalties for licensed patent from AlbaJuna, honoraria for lectures from FLS Science and CIBER, supporting for meeting and/or travel from 10.13039/100016016Gilead Sciences, and unpaid independent COVID-19 monitoring from GMCSC (Multidisciplinary Collaborative Group for the Scientific Monitoring of COVID-19) and unpaid participation in COVID-19 advisory group for CCAC (Comitè Científic Assessor de la COVID-19). Outside of this work, J Blanco is the CEO, founder and shareholder of AlbaJuna Therapeutics, S.L. J Corominas, C Garriga, A Barreiro, L González-González, L Madrenas, I Güell, D Raïch-Regué, J G Prado, T Prat, E Torroella, B Trinité, L Ferrer, M Cañete and A Prenafeta have received funding from HIPRA. The funding from HIPRA to R Ramos was paid to his institution. A Soriano has received grants from 10.13039/100004319Pfizer and 10.13039/100005564Gilead Sciences, consulting fees from 10.13039/100004319Pfizer, MSD and 10.13039/501100005612Shionogi, and honoraria for lectures for 10.13039/100004319Pfizer, MSD, 10.13039/100005564Gilead Sciences, 10.13039/501100005612Shionogi, 10.13039/501100006546Angelini, and Menarini. B Trinité declares royalties by an institutional agreement and consulting fees for HIPRA, and is an unpaid member in advisory board for the Health Department of the 10.13039/501100002809Generalitat de Catalunya. N Izquierdo-Useros, D Raïch-Regué and M Gallemí declare institutional grants from HIPRA, Pharma Mar, 10.13039/501100016387Grifols, Dentaid, Palobiofarma, Mynorix and Amassence. N Izquierdo-Useros and M Gallemí have received speaking honoraria from FLS Science. JR Arribas has received consulting fees and payment for participating in advisory board from 10.13039/100005564Gilead Sciences, MSD, GSK, Eli Lilly, 10.13039/100004337Roche, 10.13039/100004319Pfizer and Sobi, honoraria for lectures and support for meetings and/or travel from MSD. A Borobia has received grants from GSK, Moderna and Janssen, speaking honoraria for Janssen, 10.13039/100005564Gilead Sciences and 10.13039/100004319Pfizer, and payment for participating in advisory board for 10.13039/100004319Pfizer, Janssen and MDI. PM García has received consulting fees and speaking honoraria from 10.13039/100005564Gilead Sciences, Mundipharma and 10.13039/100004319Pfizer, payment for expert testimony and participated in advisory board for 10.13039/100005564Gilead Sciences and received support for meeting and/or travel from 10.13039/100004319Pfizer. S Otero-Romero has received speaking honoraria from Genzyme, Biogen-Idec, Novartis, Roche, and MSD. Julia G Prado declares institutional grants from 10.13039/501100016387Grifols. J Corominas, C Garriga, A Prenafeta, A Moros, M Cañete, A Barreiro, L González-González, L Madrenas, I Güell, T Prat, E Torroella and L Ferrer are employees of HIPRA. Some of these authors may have stocks of HIPRA. Several patent applications have been filed by HIPRA SCIENTIFIC S.L.U. and Laboratorios HIPRA, S.A. on different SARS-CoV-2 vaccine candidates and SARS-CoV-2 subunit vaccines, including the novel recombinant RBD fusion heterodimer PHH-1V. A Barreiro, J Corominas, A Prenafeta, L González-González, L Madrenas, L Ferrer, E Torroella, T Prat and C Garriga are the inventors of these patent applications. N Izquierdo-Useros is a patent inventor with no economical compensation for Pharma Mar and Mynorix. The other authors have no relevant conflicts of interest to declare., (© 2023 The Author(s).)

Current COVID-19 vaccines have been associated with a decline in infection rates, prevention of severe disease, and a decrease in mortality rates. However, SARS-CoV-2 variants are continuously evolving, and development of new accessible COVID-19 vaccines is essential to mitigate the pandemic. Here, we present data on preclinical studies in mice of a receptor-binding domain (RBD)-based recombinant protein vaccine (PHH-1V) consisting of an RBD fusion heterodimer comprising the B.1.351 and B.1.1.7 SARS-CoV-2 variants formulated in SQBA adjuvant, an oil-in-water emulsion. A prime-boost immunisation with PHH-1V in BALB/c and K18-hACE2 mice induced a CD4 + and CD8 + T cell response and RBD-binding antibodies with neutralizing activity against several variants, and also showed a good tolerability profile. Significantly, RBD fusion heterodimer vaccination conferred 100% efficacy, preventing mortality in SARS-CoV-2 infected K18-hACE2 mice, but also reducing Beta, Delta and Omicron infection in lower respiratory airways. These findings demonstrate the feasibility of this recombinant vaccine strategy., Competing Interests: Authors indicated as “1” are employees of HIPRA, a private pharmaceutical company that develops and manufactures vaccines. CReSA, IrsiCaixa, CMCiB-IGTP, UPF, and ICREA have received financial support from HIPRA. Two patent applications have been filed by HIPRA Scientific S.L.U. and Laboratorios HIPRA, S.A., on different SARS-CoV-2 vaccine candidates and SARS-CoV-2 subunit vaccines, including the recombinant RBD fusion heterodimer PHH-1V. Antonio Barreiro, Antoni Prenafeta, Luis González, Laura Ferrer, Ester Puigvert, Jordi Palmada, Teresa Prat, and Carme Garriga are the inventors of these patent applications., (© 2023 The Author(s).)

Objectives: Uptake of influenza, pneumococcal and shingles vaccines in older adults vary across regions and socioeconomic backgrounds. In this study, we study the coverage and factors associated with vaccination uptake, as well as refusal in the unvaccinated population and their associations with ethnicity, deprivation, household size and health conditions., Design, Setting and Participants: This is a cross-sectional study of adults aged 65 years or older in England, using a large primary care database. Associations of vaccine uptake and refusal in the unvaccinated with ethnicity, deprivation, household size and health conditions were modelled using multivariable logistic regression., Outcome Measure: Influenza, pneumococcal and shingles vaccine uptake and refusal (in the unvaccinated)., Results: This study included 2 054 463 patients from 1318 general practices. 1 711 465 (83.3%) received at least one influenza vaccine, 1 391 228 (67.7%) pneumococcal vaccine and 690 783 (53.4%) shingles vaccine. Compared with White ethnicity, influenza vaccine uptake was lower in Chinese (OR 0.49; 95% CI 0.45 to 0.53), 'Other ethnic' groups (0.63; 95% CI 0.60 to 0.65), black Caribbean (0.68; 95% CI 0.64 to 0.71) and black African (0.72; 95% CI 0.68 to 0.77). There was generally lower vaccination uptake among more deprived individuals, people living in larger household sizes (three or more persons) and those with fewer health conditions. Among those who were unvaccinated, higher odds of refusal were associated with the black Caribbean ethnic group and marginally with increased deprivation, but not associated with higher refusal in those living in large households or those with lesser health conditions., Conclusion: Certain ethnic minority groups, deprived populations, large households and 'healthier' individuals were less likely to receive a vaccine, although higher refusal was only associated with ethnicity and deprivation but not larger households nor healthier individuals. Understanding these may inform tailored public health messaging to different communities for equitable implementation of vaccination programmes., Competing Interests: Competing interests: PST reports previous consultation with AstraZeneca and Duke-NUS outside the submitted work. KK is a Member of the Scientific Advisory Group for Emergencies (SAGE), Member of Independent SAGE, Director of the University of Leicester Centre for Black Minority Health and Trustee of the south Asian Health Foundation. JH-C is a member of several SAGE committees and chair of the risk stratification subgroup of the NERVTAG. She is an unpaid director of QResearch and founder and former medical director of ClinRisk Ltd (outside the submitted work). MP, AKC, HD-M, DS, TAR, FZ, BRS, SJG, CC, CG have no interests to declare., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Objective: Prior studies identified clinical factors associated with increased risk of pancreatic ductal adenocarcinoma (PDAC). However, little is known regarding their time-varying nature, which could inform earlier diagnosis. This study assessed temporality of body mass index (BMI), blood-based markers, comorbidities and medication use with PDAC risk ., Design: We performed a population-based nested case-control study of 28 137 PDAC cases and 261 219 matched-controls in England. We described the associations of biomarkers with risk of PDAC using fractional polynomials and 5-year time trends using joinpoint regression. Associations with comorbidities and medication use were evaluated using conditional logistic regression., Results: Risk of PDAC increased with raised HbA1c, liver markers, white blood cell and platelets, while following a U-shaped relationship for BMI and haemoglobin. Five-year trends showed biphasic BMI decrease and HbA1c increase prior to PDAC; early-gradual changes 2-3 years prior, followed by late-rapid changes 1-2 years prior. Liver markers and blood counts (white blood cell, platelets) showed monophasic rapid-increase approximately 1 year prior. Recent diagnosis of pancreatic cyst, pancreatitis, type 2 diabetes and initiation of certain glucose-lowering and acid-regulating therapies were associated with highest risk of PDAC., Conclusion: Risk of PDAC increased with raised HbA1c, liver markers, white blood cell and platelets, while followed a U-shaped relationship for BMI and haemoglobin. BMI and HbA1c derange biphasically approximately 3 years prior while liver markers and blood counts (white blood cell, platelets) derange monophasically approximately 1 year prior to PDAC. Profiling these in combination with their temporality could inform earlier PDAC diagnosis., Competing Interests: Competing interests: JH-C reports grants from National Institute for Health Research (NIHR) Biomedical Research Centre, Oxford, grants from John Fell Oxford University Press Research Fund, grants from Cancer Research UK (CR-UK) grant number C5255/A18085, through the Cancer Research UK Oxford Centre, grants from the Oxford Wellcome Institutional Strategic Support Fund (204826/Z/16/Z) and other research councils, during the conduct of the study. JH-C is an unpaid director of QResearch, a not-for-profit organisation which is a partnership between the University of Oxford and EMIS Health who supply the QResearch database used for this work. JH-C is a founder and shareholder of ClinRisk ltd and was its medical director until 31st May 2019. ClinRisk Ltd produces open and closed source software to implement clinical risk algorithms (outside this work) into clinical computer systems. AC reports consulting fees from Mendelian, outside the scope of the current work. RB-R is a cofounder of Alchemab Therapeutics and consultant for Alchemab Therapeutics and GSK. PST reports previous consultation with AstraZeneca and Duke-NUS outside the current work., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Background: Guidelines recommend that GPs give patients lifestyle advice to manage hypertension and diabetes. Increasing evidence shows that this is an effective and practical treatment for these conditions, but it is unclear whether GPs offer this support., Aim: To investigate trends in the percentage of patients with hypertension/diabetes receiving lifestyle advice versus medication., Design and Setting: This was a trend analysis of self-reported data from the annual Health Survey for England (HSE) (2003-2017) and GP-recorded data from the QResearch database (2002-2016)., Method: The percentage of patients with hypertension or diabetes who received lifestyle advice or medication was calculated in each year. Associations between likelihood of receiving lifestyle advice and characteristics were assessed using multivariable logistic regression., Results: The percentage of patients receiving lifestyle advice was consistently lower than those receiving medication in both self-reported and medical records. There was consistent evidence of increasing trends in the percentage of patients with hypertension receiving lifestyle advice (HSE 13.8% to 20.1%; P trend <0.001; QResearch 11.0% to 22.7%; P trend <0.001). For diabetes, there was a non-significant decline in self-reported receipt of lifestyle advice (45.0% to 27.9%; P trend = 0.111) and a significant increase in medically recorded delivery of this advice (20.7% to 40.5%; P trend <0.001). Patients with hypertension who were overweight or obese were more likely to receive lifestyle advice than those of a healthy weight, whereas the opposite was true for diabetes., Conclusion: Only a minority of patients with diabetes or hypertension report receiving lifestyle advice or have this recorded in their medical records. Interventions beyond guidelines are needed to increase the delivery of behavioural interventions to treat these conditions., (© The Authors.)

Objective: To identify patients at risk of mid-late term revision of hip replacement to inform targeted follow-up., Design: Analysis of linked national data sets from primary and secondary care (Clinical Practice Research Datalink (CPRD-GOLD); National Joint Registry (NJR); English Hospital Episode Statistics (HES); Patient-Reported Outcome Measures (PROMs))., Participants: Primary elective total hip replacement (THR) aged≥18., Event of Interest: Revision surgery≥5 years (mid-late term) after primary THR., Statistical Methods: Cox regression modelling to ascertain risk factors of mid-late term revision. HR and 95% CI assessed association of sociodemographic factors, comorbidities, medication, surgical variables and PROMs with mid-late term revision., Results: NJR-HES-PROMs data were available from 2008 to 2011 on 142 275 THR; mean age 70.0 years and 61.9% female. CPRD GOLD-HES data covered 1995-2011 on 17 047 THR; mean age 68.4 years, 61.8% female. Patients had minimum 5 years postprimary surgery to end 2016. In NJR-HES-PROMS data, there were 3582 (2.5%) revisions, median time-to-revision after primary surgery 1.9 years (range 0.01-8.7), with 598 (0.4%) mid-late term revisions; in CPRD GOLD, 982 (5.8%) revisions, median time-to-revision 5.3 years (range 0-20), with 520 (3.1%) mid-late term revisions.Reduced risk of mid-late term revision was associated with older age at primary surgery (HR: 0.96; 95% CI: 0.95 to 0.96); better 6-month postoperative pain/function scores (HR: 0.35; 95% CI: 0.27 to 0.46); use of ceramic-on-ceramic (HR: 0.73; 95% CI: 0.56 to 0.95) or ceramic-on-polyethylene (HR: 0.76; 95% CI: 0.58 to 1.00) bearing surfaces.Increased risk of mid-late term revision was associated with the use of antidepressants (HR: 1.32; 95% CI: 1.09 to 1.59), glucocorticoid injections (HR: 1.33; 95% CI: 1.06 to 1.67) and femoral head size≥44 mm (HR: 2.56; 95% CI: 1.09 to 6.02)No association of gender, obesity or Index of Multiple Deprivation was observed., Conclusion: The risk of mid-late term THR is associated with age at primary surgery, 6-month postoperative pain and function and implant factors. Further work is needed to explore the associations with prescription medications observed in our data., Competing Interests: Competing interests: LS reports grants from National Institute for Health Research during the conduct of the study. AJ reports grants from National Institute for Health Research and has received consultancy fees from Freshfields Bruckhaus Derringer and Anthera Pharmaceuticals LTD unrelated to this work. AJ was supported by the NIHR Biomedical Research Centre at University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol. NKA reports grants from Merck, personal fees from Pfizer/Lilly, unrelated to the submitted work. SRK, MS and PGC were supported in part by the NIHR Leeds Biomedical Research Centre., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To identify patients at risk of mid-late term revision of knee replacement (KR) to inform targeted follow-up., Design: Analysis of linked national datasets from primary and secondary care (Clinical Practice Research Datalink (CPRD GOLD), National Joint Registry (NJR), English Hospital Episode Statistics (HES) and Patient Reported Outcome Measures (PROMs))., Participants: Primary elective KRs aged ≥18 years., Event of Interest: Revision surgery ≥5 years (mid-late term) postprimary KR., Statistical Methods: Cox regression modelling to ascertain risk factors of mid-late term revision. HRs and 95% CIs assessed association of sociodemographic factors, comorbidities, medication, surgical variables and PROMs with mid-late term revision., Results: NJR-HES-PROMs data were available from 2008 to 2011 on 188 509 KR. CPRD GOLD-HES data covered 1995-2011 on 17 378 KR. Patients had minimum 5 years postprimary surgery to end 2016. Age and gender distribution were similar across datasets; mean age 70 years, 57% female. In NJR, there were 8607 (4.6%) revisions, median time-to-revision postprimary surgery 1.8 years (range 0-8.8), with 1055 (0.6%) mid-late term revisions; in CPRD GOLD, 877 (5.1%) revisions, median time-to-revision 4.2 years (range 0.02-18.3), with 352 (2.0%) mid-late term revisions.Reduced risk of revision after 5 years was associated with older age (HR: 0.95; 95% CI 0.95 to 0.96), obesity (0.70; 0.56 to 0.88), living in deprived areas (0.71; 0.58 to 0.87), non-white ethnicity (0.58; 0.43 to 0.78), better preoperative pain and functional limitation (0.42; 0.33 to 0.53), better 6-month postoperative pain and function (0.33; 0.26 to 0.41) or moderate anxiety/depression (0.73; 0.63 to 0.83) at primary surgery.Increased risk was associated with male gender (1.32; 1.04 to 1.67); when anticonvulsants (gabapentin and pregabalin) (1.58; 1.01 to 2.47) or opioids (1.36; 1.08 to 1.71) were required prior to primary surgery.No implant factors were identified., Conclusion: The risk of mid-late term KR revision is very low. Increased risk of revision is associated with patient case-mix factors, and there is evidence of sociodemographic inequality., Competing Interests: Competing interests: LS reports grants from NIHR during the conduct of the study. AJ reports grants from NIHR and has received consultancy fees from Freshfields Bruckhaus Derringer and Anthera Pharmaceuticals LTD unrelated to this work. AJ was supported by the NIHR Biomedical Research Centre at University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol. NA reports grants from Merck, personal fees from Pfizer/Lilly, unrelated to the submitted work. SRK, MS and PGC were supported in part by the NIHR Leeds Biomedical Research Centre., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Objective: To estimate the costs of primary hip and knee replacement in individuals with osteoarthritis up to 2 years postsurgery, compare costs before and after the surgery, and identify predictors of hospital costs., Methods: Patients age ≥18 years with primary planned hip or knee replacements and osteoarthritis in England between 2008 and 2016 were identified from the National Joint Registry and linked with Hospital Episode Statistics data containing inpatient episodes. Primary care data linked with hospital outpatient records were also used to identify patients age ≥18 years with primary hip or knee replacements between 2008 and 2016. All health care resource use was valued using 2016/2017 costs, and nonparametric censoring methods were used to estimate total 1-year and 2-year costs., Results: We identified 854,866 individuals undergoing hip or knee replacement. The mean censor-adjusted 1-year hospitalization costs for hip and knee replacement were £7,827 (95% confidence interval [95% CI] 7,813, 7,842) and £7,805 (95% CI 7,790, 7,818), respectively. Complications and revisions were associated with up to a 3-fold increase in 1-year hospitalization costs. The censor-adjusted 2-year costs were £9,258 (95% CI 9,233, 9,280) and £9,452 (95% CI 9,430, 9,475) for hip and knee replacement, respectively. Adding primary and outpatient care, the mean total hip and knee replacement 2-year costs were £11,987 and £12,578, respectively., Conclusion: There are significant costs following joint replacement. Revisions and complications accounted for considerable costs and there is a significant incentive to identify best approaches to reduce these., (© 2020 American College of Rheumatology.)

Importance: Although children mainly experience mild COVID-19 disease, hospitalization rates are increasing, with limited understanding of underlying factors. There is an established association between race and severe COVID-19 outcomes in adults in England; however, whether a similar association exists in children is unclear., Objective: To investigate the association between race and childhood COVID-19 testing and hospital outcomes., Design, Setting, Participants: In this cohort study, children (0-18 years of age) from participating family practices in England were identified in the QResearch database between January 24 and November 30, 2020. The QResearch database has individually linked patients with national SARS-CoV-2 testing, hospital admission, and mortality data., Exposures: The main characteristic of interest is self-reported race. Other exposures were age, sex, deprivation level, geographic region, household size, and comorbidities (asthma; diabetes; and cardiac, neurologic, and hematologic conditions)., Main Outcomes and Measures: The primary outcome was hospital admission with confirmed COVID-19. Secondary outcomes were SARS-CoV-2-positive test result and any hospital attendance with confirmed COVID-19 and intensive care admission., Results: Of 2 576 353 children (mean [SD] age, 9.23 [5.24] years; 48.8% female), 410 726 (15.9%) were tested for SARS-CoV-2 and 26 322 (6.4%) tested positive. A total of 1853 children (0.07%) with confirmed COVID-19 attended hospital, 343 (0.01%) were admitted to the hospital, and 73 (0.002%) required intensive care. Testing varied across race. White children had the highest proportion of SARS-CoV-2 tests (223 701/1 311 041 [17.1%]), whereas Asian children (33 213/243 545 [13.6%]), Black children (7727/93 620 [8.3%]), and children of mixed or other races (18 971/147 529 [12.9%]) had lower proportions. Compared with White children, Asian children were more likely to have COVID-19 hospital admissions (adjusted odds ratio [OR], 1.62; 95% CI, 1.12-2.36), whereas Black children (adjusted OR, 1.44; 95% CI, 0.90-2.31) and children of mixed or other races (adjusted OR, 1.40; 95% CI, 0.93-2.10) had comparable hospital admissions. Asian children were more likely to be admitted to intensive care (adjusted OR, 2.11; 95% CI, 1.07-4.14), and Black children (adjusted OR, 2.31; 95% CI, 1.08-4.94) and children of mixed or other races (adjusted OR, 2.14; 95% CI, 1.25-3.65) had longer hospital admissions (≥36 hours)., Conclusions and Relevance: In this large population-based study exploring the association between race and childhood COVID-19 testing and hospital outcomes, several race-specific disparities were observed in severe COVID-19 outcomes. However, ascertainment bias and residual confounding in this cohort study should be considered before drawing any further conclusions. Overall, findings of this study have important public health implications internationally.

Background: The NHS Health Check cardiovascular prevention programme is now 10 years old., Aim: To describe NHS Heath Check attendance, new diagnoses, and treatment in relation to equity indicators., Design and Setting: A nationally representative database derived from 1500 general practices from 2009-2017., Method: The authors compared NHS Health Check attendance and new diagnoses and treatments by age, sex, ethnic group, and deprivation., Results: In 2013-2017, 590 218 (16.9%) eligible people aged 40-74 years attended an NHS Health Check and 2 902 598 (83.1%) did not attend. South Asian ethnic groups were most likely to attend compared to others, and females more than males. New diagnoses were more likely in attendees than non-attendees: hypertension 25/1000 in attendees versus 9/1000 in non-attendees; type 2 diabetes 8/1000 versus 3/1000; and chronic kidney disease (CKD) 7/1000 versus 4/1000. In people aged ≥65 years, atrial fibrillation was newly diagnosed in 5/1000 attendees and 3/1000 non-attendees, and for dementia 2/1000 versus 1/1000, respectively. Type 2 diabetes, hypertension, and CKD were more likely in more deprived groups, and in South Asian, Black African, and Black Caribbean ethnic groups. Attendees were more likely to be prescribed statins (26/1000) than non-attendees (8/1000), and antihypertensive medicines (25/1000 versus 13/1000 non-attendees). However, of the 117 963 people with ≥10% CVD risk who were eligible for statins, only 9785 (8.3%) were prescribed them., Conclusion: Uptake of NHS Health Checks remains low. Attendees were more likely than non-attendees to be diagnosed with type 2 diabetes, hypertension, and CKD, and to receive treatment with statins and antihypertensives. Most attendees received neither treatment nor referral. Of those eligible for statins, <10% were treated. Policy reviews should consider a targeted approach prioritising those at highest CVD risk for face-to-face contact and consider other options for those at lower CVD risk., (© The Authors.)

Background: Joint injury is a major risk factor for osteoarthritis and provides an opportunity to prospectively examine early processes associated with osteoarthritis. We investigated whether predefined baseline demographic and clinical factors, and protein analytes in knee synovial fluid and in plasma or serum, were associated with clinically relevant outcomes at 2 years after knee injury., Methods: This longitudinal cohort study recruited individuals aged 16-50 years between Nov 1, 2010, and Nov 28, 2014, across six hospitals and clinics in London, UK. Participants were recruited within 8 weeks of having a clinically significant acute knee injury (effusion and structural injury on MRI), which was typically treated surgically. We measured several predefined clinical variables at baseline (eg, time from injury to sampling, extent and type of joint injury, synovial fluid blood staining, presence of effusion, self-reported sex, age, and BMI), and measured 12 synovial fluid and four plasma or serum biomarkers by immunoassay at baseline and 3 months. The primary outcome was Knee Injury and Osteoarthritis Outcome Score (KOOS 4 ) at 2 years, adjusted for baseline score, assessed in all patients. Linear and logistic regression models adjusting for predefined covariates were used to assess associations between baseline variables and 2-year KOOS 4 . This study is registered with ClinicalTrials.gov, number NCT02667756., Findings: We enrolled 150 patients at a median of 17 days (range 1-59, IQR 9-26) after knee injury. 123 (82%) were male, with a median age of 25 years (range 16-50, IQR 21-30). 98 (65%) of 150 participants completed a KOOS 4 at 2 (or 3) years after enrolment (50 participants were lost to follow-up and two were withdrawn due to adverse events unrelated to study participation); 77 (51%) participants had all necessary variables available and were included in the core variable adjusted analysis. In the 2-year dataset mean KOOS 4 improved from 38 (SD 18) at baseline to 79 (18) at 2 years. Baseline KOOS 4, medium-to-large knee effusion, and moderate-to-severe synovial blood staining and their interaction significantly predicted 2-year KOOS 4 (n=77; coefficient -20·5, 95% CI -34·8 to -6·18; p=0·0060). The only predefined biomarkers that showed independent associations with 2-year KOOS 4 were synovial fluid MCP-1 (n=77; -0·015, 0·027 to -0·004 per change in 1 pg/mL units; p=0·011) and IL-6 (n=77; -0·0005, -0·0009 to -0·0001 per change in 1 pg/mL units; p=0·017). These biomarkers, combined with the interaction of effusion and blood staining, accounted for 39% of outcome variability. Two adverse events occurred that were linked to study participation, both at the time of blood sampling (one presyncopal episode, one tenderness and pain at the site of venepuncture)., Interpretation: The combination of effusion and haemarthrosis was significantly associated with symptomatic outcomes after acute knee injury. The synovial fluid molecular protein response to acute knee injury (best represented by MCP-1 and IL-6) was independently associated with symptomatic outcomes but not with structural outcomes, with the biomarkers overall playing a minor role relative to clinical predictors. The relationship between symptoms and structure after acute knee injury and their apparent dissociation early in this process need to be better understood to make clinical progress., Funding: Versus Arthritis, Kennedy Trust for Rheumatology Research, and NIHR Oxford Biomedical Research Centre., Competing Interests: TLV reports consultancy fees from GlaxoSmithKline, UCB, and Mundipharma and has also received research grants from Galapagos, Fidia, and Samumed. NKA reports consultancy fees from Pfizer/Lilly and received a grant in a related area of research from Merck. AJ reports consultancy fees from Freshfields Bruckhaus Deringer and from Anthera Pharmaceuticals. AW is a board member and holds stock in Fortius Clinic, has received research grants from Smith and Nephew, is a board member and shareholder in Innovate Orthopaedics, and a shareholder in DocComs. FEW has received clinical study grants from Pfizer and Astellas Pharma, reports consultancy fees from Pfizer, and is part of a consortium receiving some of its research funding from Galapagos, Fidia, and Samumed. All other authors report no competing interests., (© 2021 The Authors. Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license.)

Objectives: To examine the effect of occupation on knee osteoarthritis (OA) and total knee replacement (TKR) in working-aged adults., Methods: We used longitudinal data from the Chingford, Osteoarthritis Initiative (OAI) and Multicentre Osteoarthritis (MOST) studies. Participants with musculoskeletal disorders and/or a history of knee-related surgery were excluded. Participants were followed for up to 19-years (Chingford), 96-months (OAI) and 60-months (MOST) for incident outcomes including radiographic knee OA (RKOA), symptomatic RKOA and TKR. In those with baseline RKOA, progression was defined as the time from RKOA incidence to primary TKR. Occupational job categories and work-place physical activities were assigned to levels of workload. Logistic regression was used to examine the relationship between workload and incident outcomes with survival analyses used to assess progression (reference group: sedentary occupations)., Results: Heavy manual occupations were associated with a 2-fold increased risk (OR: 2.07, 95% CI 1.03 to 4.15) of incident RKOA in the OAI only. Men working in heavy manual occupations in MOST (2.7, 95% CI 1.17 to 6.26) and light manual occupations in OAI (2.00, 95% CI 1.09 to 3.68) had a 2-fold increased risk of incident RKOA. No association was observed among women. Increasing workload was associated with an increased risk of symptomatic RKOA in the OAI and MOST. Light work may be associated with a decreased risk of incident TKR and disease progression., Conclusion: Heavy manual work carries an increased risk of incident knee OA; particularly among men. Workload may influence the occurrence of TKR and disease progression., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Few studies have compared aspirin with direct oral anticoagulants (DOACs) (DOACs = direct thrombin inhibitors and factor Xa inhibitors) for venous thromboembolism (VTE) prophylaxis after total hip arthroplasty (THA) and total knee arthroplasty (TKA). We assessed the efficacy and safety of aspirin compared with DOACs for VTE prophylaxis after THA and TKA using the world's largest joint arthroplasty registry., Methods: We studied the National Joint Registry linked to English hospital inpatient episodes for 218,650 THA and TKA patients. Patients receiving aspirin were matched separately to patients receiving direct thrombin inhibitors and factor Xa inhibitors using propensity scores. Outcomes assessed at 90 days included VTE, length of stay, and adverse events., Results: After THA, there was a significantly lower risk of VTE associated with the use of direct thrombin inhibitors (0.44%; odds ratio [OR], 0.69; 95% confidence interval [95% CI], 0.55-0.87; P = .002) and factor Xa inhibitors (0.37%; OR, 0.63; 95% CI, 0.47-0.85; P = .003) compared with aspirin (0.63%). After THA, direct thrombin inhibitors (coefficient, -0.37 days; 95% CI, -0.43 to -0.31; P < .001) and factor Xa inhibitors (coefficient, -0.80 days; 95% CI, -0.87 to -0.74; P < .001) were associated with a reduced length of stay compared with aspirin. Similar findings for both outcomes were observed after TKA. Compared with aspirin, DOACs were not associated with an increase in the risk of short-term revision surgery, reoperation, major hemorrhage, wound disruption, surgical site infection, and mortality., Conclusion: After THA and TKA, DOACs were associated with a reduced risk of VTE compared with aspirin. DOACs were associated with a reduced length of stay, and DOACs were not associated with an increase in the risk of further surgery, wound problems, bleeding complications, or mortality compared with aspirin., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: Clinical guidelines recommend antidepressants as the first line of treatment for adults with moderate-to-severe depression. Randomised trials provide the best evidence on the comparative effectiveness of antidepressants for depression, but are limited by a short follow-up and a highly selected population. We aim to conduct a cohort study on a large database to assess acceptability, efficacy, safety and tolerability of antidepressant monotherapy in people with depressive disorder in primary care., Methods and Analysis: This is a protocol for a cohort study using data from the QResearch primary care research database, which is the largest general practice research database in the UK. We will include patients registered for at least 1 year from 1 January 1998, diagnosed with a new episode of depression and on antidepressant and a comparison group not on antidepressant. The exposure of interest will be treatment with antidepressant medications. Our outcomes will be acceptability (treatment discontinuation due to any cause), efficacy (clinical response and remission); safety (adverse events (AEs) and all-cause mortality); and tolerability (dropouts due to any AE) measured at 2 months, 6 months and 1 year. For each outcome, we will estimate the absolute risks for all antidepressants, and relative effects between antidepressants using Cox's proportion hazards models. We will calculate HRs and 99.9% CIs for each outcome of interest., Discussion: The main limitation is the observational nature of our study, while the major strengths include the large representative population contained in QResearch and the possibly high generalisability., Competing Interests: Competing interests: AC has received research and consultancy fees from INCiPiT (Italian Network for Paediatric Trials) and Angelini Pharma. He has also organised a workshop about digital mental health sponsored by Angelini Pharma., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Psychological distress includes a broader range of experiences, varying from less severe symptoms of depression and anxiety to severe psychiatric disease. Global estimates for depression and anxiety in 2017 were 3.4% and 3.8%, respectively. While for people living with HIV, global estimates were 16% and 33%, respectively., Objective: We aimed to determine the prevalence of psychological distress by gender and associated characteristics in patients living with HIV., Methods: A cross-sectional study was conducted within the Spanish HIV Research Network CoRIS. Participants were interviewed by telephone between 2010 and 2014 about their psychological distress, sociodemographics, drug consumption, self-perceived health and combined antiretroviral therapy (cART) adherence. Laboratory tests and medical history details were collected from CoRIS. Logistic regression was used to identify characteristics associated with psychological distress., Findings: We interviewed 99 women and 464 men, both living with HIV. A greater proportion of women (51, 51.5%) reported psychological distress than men (179, 38.6%; p<0.01). Non-adherence to cART (OR 4.6 and 2.3, 95% CI 1.4‒15.1 and 1.3‒4.2) and non-use of cART (8.4 and 1.8, 2.2‒32.4 and 1.1‒2.8) were related to psychological distress in women and men, respectively. Spending little time in leisure-based physical activity was related to psychological distress in women (3.1, 1.1‒9.0). Living alone (2.0, 1.3‒3.0) and being unemployed (2.3, 1.4‒3.6) were related to psychological distress in men., Conclusions and Clinical Implications: As people living with HIV have a high prevalence of psychological distress, their regular screening appointments should include psychological assessment. A gendered approach is needed to detect and manage psychological distress., Competing Interests: Competing interests: Dr Garriga, Ms Gutiérrez-Trujillo, Dr Culqui Levano, Dr del Romero, Dr Gómez-Sirvent, Dr Peña-Monje and Dr Rodríguez-Arenas declare that they have no conflicts of interest. Mrs Montero reports personal fees outside the submitted work from Bristol-Myers Squibb, ViiV Healthcare, Merck, Abbvie, Gilead Sciences, Janssen, Abbott Laboratories and Pfizer. Dr Pérez-Elías reports personal fees from Bristol-Myers Squibb and grants and personal fees from ViiV Healthcare, Janssen and Gilead Sciences, outside the submitted work. Dr Gutiérrez reports personal fees from Gilead Sciences, Janssen Cilag and ViiV Healthcare, outside the submitted work. Dr Blanco has carried out consulting work for Abbvie, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck and ViiV Healthcare; received compensation for lectures from Abbvie, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck and ViiV Healthcare; and received grants and payments for the development of educational presentations from Gilead Sciences, Bristol-Myers Squibb and ViiV Healthcare, outside the submitted work., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Regional anesthesia is increasingly used in enhanced recovery programs following total hip replacement (THR) and total knee replacement (TKR). However, debate remains about its potential benefit over general anesthesia given that complications following surgery are rare. We assessed the risk of complications in THR and TKR patients receiving regional anesthesia compared with general anesthesia using the world's largest joint replacement registry., Methods: We studied the National Joint Registry for England, Wales, Northern Ireland and the Isle of Man linked to English hospital inpatient episodes for 779,491 patients undergoing THR and TKR. Patients received either regional anesthesia (n = 544,620, 70%) or general anesthesia (n = 234,871, 30%). Outcomes assessed at 90 days included length of stay, readmissions, and complications. Regression models were adjusted for patient and surgical factors to determine the effect of anesthesia on outcomes., Results: Length of stay was reduced with regional anesthesia compared with general anesthesia (THR = -0.49 days, 95% confidence interval [CI] = -0.51 to -0.47 days, P < .001; TKR = -0.47 days, CI = -0.49 to -0.45 days, P < .001). Regional anesthesia also had a reduced risk of readmission (THR odds ratio [OR] = 0.93, CI = 0.90-0.96; TKA OR = 0.91, CI = 0.89-0.93), any complication (THR OR = 0.88, CI = 0.85-0.91; TKA OR = 0.90, CI = 0.87-0.93), urinary tract infection (THR OR = 0.85, CI = 0.77-0.94; TKR OR = 0.87, CI = 0.79-0.96), and surgical site infection (THR OR = 0.87, CI = 0.80-0.95; TKR OR = 0.84, CI = 0.78-0.89). Anesthesia type did not affect the risk of revision surgery or mortality., Conclusion: Regional anesthesia was associated with reduced length of stay, readmissions, and complications following THR and TKR when compared with general anesthesia. We recommend regional anesthesia should be considered the reference standard for patients undergoing THR and TKR., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Formation of a specialized wound epidermis is required to initiate salamander limb regeneration. Yet little is known about the roles of the early wound epidermis during the initiation of regeneration and the mechanisms governing its development into the apical epithelial cap (AEC), a signaling structure necessary for outgrowth and patterning of the regenerate. Here, we elucidate the functions of the early wound epidermis, and further reveal midkine ( mk ) as a dual regulator of both AEC development and inflammation during the initiation of axolotl limb regeneration. Through loss- and gain-of-function experiments, we demonstrate that mk acts as both a critical survival signal to control the expansion and function of the early wound epidermis and an anti-inflammatory cytokine to resolve early injury-induced inflammation. Altogether, these findings unveil one of the first identified regulators of AEC development and provide fundamental insights into early wound epidermis function, development, and the initiation of limb regeneration., Competing Interests: ST, CB, DM No competing interests declared, (© 2020, Tsai et al.)

Objective: To develop and internally validate risk models and a clinical risk score tool to predict incident radiographic knee osteoarthritis (RKOA) in middle-aged women., Methods: We analyzed 649 women in the Chingford 1,000 Women study. The outcome was incident RKOA, defined as Kellgren/Lawrence grade 0-1 at baseline and ≥2 at year 5. We estimated predictors' effects on the outcome using logistic regression models. Two models were generated. The clinical model considered patient characteristics, medication, biomarkers, and knee symptoms. The radiographic model considered the same factors, plus radiographic factors (e.g., angle between the acetabular roof and the ilium's vertical cortex [hip α-angle]). The models were internally validated. Model performance was assessed using calibration and discrimination (area under the receiver characteristic curve [AUC])., Results: The clinical model contained age, quadriceps circumference, and a cartilage degradation marker (C-terminal telopeptide of type II collagen) as predictors (AUC = 0.692). The radiographic model contained older age, greater quadriceps circumference, knee pain, knee baseline Kellgren/Lawrence grade 1 (versus 0), greater hip α-angle, greater spinal bone mineral density, and contralateral RKOA at baseline as predictors (AUC = 0.797). Calibration tests showed good agreement between the observed and predicted incident RKOA. A clinical risk score tool was developed from the clinical model., Conclusion: Two models predicting incident RKOA within 4 years were developed, including radiographic variables that improved model performance. First-time predictor hip α-angle and contralateral RKOA suggest OA origins beyond the knee. The clinical tool has the potential to help physicians identify patients at risk of RKOA in routine practice, but the tool should be externally validated., (© 2019, American College of Rheumatology.)

Importance: Little is known about variation in outcomes of surgery or about the factors associated with such variation., Objectives: To evaluate variation in patient outcomes and costs for primary hip and knee replacement across health areas in England and to identify whether patient, surgical, or hospital factors are associated with such variation., Design, Setting, and Participants: This cohort study used data from the National Joint Registry, linked to English Hospital Episode Statistics and Patient Reported Outcome Measures data sets, for 383 382 adult patients who underwent primary total hip replacement (THR) or primary total and unicompartmental knee replacement (TKR) surgical procedures from January 2014 to December 2016. Geographical Information Systems were used to display maps describing adjusted estimates of variation in outcomes across health areas. Data analysis took place from January 2018 to August 2019., Exposures: Patient characteristics (eg, age, sex, body mass index [BMI], and socioeconomic deprivation), surgical factors (eg, surgeon volume and grade), and hospital organizational factors (eg, number of operating theaters, number of specialist consultants, and hospital volume)., Main Outcomes and Measures: Length of stay (LOS), bed-day costs, change in Oxford hip or knee scores 6 months after surgery, and complications 6 months after surgery., Results: A total of 173 107 patients (mean [SD] age, 69.3 [10.7] years; mean [SD] BMI, 28.9 [5.2]) underwent primary THR and 210 275 patients (mean [SD] age 69.7 [9.4] years; mean [SD] BMI, 31.1 [5.5]) underwent primary TKR, nested in 207 health areas. A number of factors were associated with longer LOS, higher bed-day costs, smaller changes in Oxford hip or knee scores, and a higher percentage of complications, including a workforce with a higher number of less experienced physicians (eg, LOS for less experienced surgeons, THR: regression coefficient, 0.02; 95% CI, 0.01 to 0.03; P < .001; TKR: regression coefficient, 0.01; 95% CI, 0.01 to 0.02; P < .001), public hospitals (eg, bed-day costs for private hospitals, THR: regression coefficient, -0.15; 95% CI, -0.15 to -0.14; P < .001; TKR: regression coefficient, -0.19; 95% CI, -0.19 to -0.19; P < .001), low volume of surgical procedures per surgeon (eg, change in Oxford hip or knee scores for lead surgeon with ≤10 vs >150 surgical procedures per year, THR: regression coefficient, -1.03; 95% CI, -1.47 to -0.58; P < .001; TKR: regression coefficient, -0.54; 95% CI, -1.01 to -0.06), and low volume of surgical procedures per hospital (eg, percentage of complications for hospitals with ≤200 vs ≥500 surgical procedures per year, THR: regression coefficient, 0.12; 95% CI, 0.04 to 0.21; P < .001; TKR: regression coefficient, 0.09; 95% CI, 0.01 to 0.18; P = .03). Although these factors did not attenuate the magnitude of variation across health areas, they had ecological correlations with the observed geographical variations in outcomes of surgery by health area. For example, the percentage of public and private hospitals was ecologically correlated at the health area level with longer and shorter stays, respectively (public hospital, THR: ρ, 0.41; public hospital, TKR: ρ, 0.44; private hospital, THR: ρ, -0.37; private hospital, THR: ρ, -0.38). Across health areas, estimated mean length of stay ranged from 3 to 7 days, and associated bed-day costs ranged from £4727 ($5827) to £8800 ($10 848) for both total hip and knee replacement. The absolute estimated mean change in Oxford hip score varied from 18.7 to 24.6 points and, for Oxford knee score, from 13.1 to 18.8. Estimated 6-month complications ranged from 2.9% to 5.8% for both THR and TKR., Conclusions and Relevance: In this study, models indicated that higher surgical volume by surgeon and by hospital as well as private hospitals were associated with better patient outcomes, which could be explained by the changing case mix of public hospitals treating an increasing number of more complex patients. A higher proportion of less experienced physicians was associated with poorer outcomes. This variation was observed geographically.

The objective of this study is to describe the impact of the Advanced Practice Nurse role on the clinical practice and patient benefit, as well as to provide reasons for its implementation and expansion in Spain. Through the scoping review method, this study has been carried out according to five thematic blocks: life quality, cost-effectiveness, health results, satisfaction, and accessibility. The critical appraisal was performed with the Critical Appraisal Skills Programme (CASP) tool and the level of evidence and strength of recommendation have been analysed following the Oxford Centre for Evidence-Based Medicine (OCEBM) system. The results show that it is possible to formally implement advanced practice nursing in the Spanish context. The analysis of the Spanish regulatory framework reveals that the generalisation of the Case Manager Nurse is the starting point for the development of advanced practice nursing in Spain. This implementation would have a positive impact on patients in terms of health results, satisfaction, and life quality, given that the advanced practice nurse performs a more effective follow-up of chronic patients with a better control of risk factors, symptoms and health outcomes, and an earlier detection of complications. Considering these results, regional governments should promote the role of the Advanced Practice Nurse to contribute to its expansion.

Blastema formation, a hallmark of limb regeneration, requires proliferation and migration of progenitors to the amputation plane. Although blastema formation has been well described, the transcriptional programs that drive blastemal progenitors remain unknown. We transcriptionally profiled dividing and non-dividing cells in regenerating stump tissues, as well as the wound epidermis, during early axolotl limb regeneration. Our analysis revealed unique transcriptional signatures of early dividing cells and, unexpectedly, repression of several core developmental signaling pathways in early regenerating stump tissues. We further identify an immunomodulatory role for blastemal progenitors through interleukin 8 (IL-8), a highly expressed cytokine in subpopulations of early blastemal progenitors. Ectopic il-8 expression in non-regenerating limbs induced myeloid cell recruitment, while IL-8 knockdown resulted in defective myeloid cell retention during late wound healing, delaying regeneration. Furthermore, the il-8 receptor cxcr-1/2 was expressed in myeloid cells, and inhibition of CXCR-1/2 signaling during early stages of limb regeneration prevented regeneration. Altogether, our findings suggest that blastemal progenitors are active early mediators of immune support, and identify CXCR-1/2 signaling as an important immunomodulatory pathway during the initiation of regeneration., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2019. Published by The Company of Biologists Ltd.)

The purpose of this cross-sectional study is to examine the relationship between surgical treatments for sleep-disordered breathing (SDB) and composite measure of surgical complications in a nationally representative sample of hospital discharges among U.S. adults. We performed secondary analyses of 33,679 hospital discharges from the 2002-2012 Nationwide Inpatient Sample that corresponded to U.S. adults (≥18 years) who were free of head-and-neck neoplasms, were diagnosed with SDB and had undergone at least one of seven procedures. Multivariate logistic regression models were constructed to estimate adjusted odds ratios (aOR) and 95% confidence intervals (CI), controlling for age, sex, race/ethnicity, obstructive sleep apnea (OSA) and obesity diagnoses. Positive associations were found between composite measure of surgical complications and specific procedures: palatal procedure (aOR = 12.69, 95% CI: 11.91,13.53), nasal surgery (aOR = 6.47, 95% CI: 5.99,6.99), transoral robotic assist (aOR = 5.06, 95% CI: 4.34-5.88), tongue base/hypopharynx (aOR = 4.24, 95% CI: 3.88,4.62), maxillomandibular advancement (MMA) (aOR = 3.24, 95% CI: 2.74,3.84), supraglottoplasty (aOR = 2.75, 95% CI: 1.81,4.19). By contrast, a negative association was found between composite measures of surgical complications and tracheostomy (aOR = 0.033, 95% CI: 0.031,0.035). In conclusion, most procedures for SDB, except tracheostomy, were positively associated with complications, whereby palatal procedures exhibited the strongest and supraglottoplasty exhibited the weakest association., (Published by Elsevier Ltd.)

We aimed to develop a predictive model for non-satisfaction following primary total knee replacement (TKR) and to assess its transportability to another health care system. Data for model development were obtained from two UK tertiary hospitals. Model transportation data were collected from Geneva University Hospitals in Switzerland. Participants were individuals undergoing primary TKR with non-satisfaction with surgery after one year the outcome of interest. Multiple imputation and logistic regression modelling with bootstrap backward selection were used to identify predictors of outcome. Model performance was assessed by discrimination and calibration. 64 (14.2%) patients in the UK and 157 (19.9%) in Geneva were non-satisfied with their TKR. Predictors in the UK cohort were worse pre-operative pain and function, current smoking, treatment for anxiety and not having been treated with injected corticosteroids (corrected AUC = 0.65). Transportation to the Geneva cohort showed an AUC of 0.55. Importantly, two UK predictors (treated for anxiety, injected corticosteroids) were not predictive in Geneva. A better model fit was obtained when coefficients were re-estimated in the Geneva sample (AUC = 0.64). The model did not perform well when transported to a different country, but improved when it was re-estimated. This emphasises the need to re-validate the model for each setting/country.

The aims of this study were to describe the evolution of acute hepatitis C virus (HCV) infections since 2004 and to determine its associated factors. Acute HCV infections diagnosed in Barcelona from 2004 to 2015 were included. Incidence ratios (IR) were then estimated for sex and age groups. Cases were grouped between 2004-2005, 2006-2011 and 2012-2015, and their incidence rate ratios (IRR) were calculated. In addition, risk factors for acute HCV infection were identified using multinomial logistic regression for complete, available and multiple imputed data. 204 new HCV cases were identified. Two peaks of higher IR of acute HCV infection in 2005 and 2013 were observed. Men and those aged 35-54 had higher IR. IRR for men was 2.9 times greater than in women (95% confidence intervals (CI): 1.8 ‒ 4.7). Factors related to the period 2012-2015 (versus 2006-2011) were: a) sexual risk factor for transmission versus nosocomial (relative-risk ratio (RRR): 13.0; 95% CI: 2.3 ‒ 72.1), b) higher educated versus lower (RRR: 5.4; 95% CI: 1.6 ‒ 18.7), and c) HIV co-infected versus not HIV-infected (RRR: 53.1; 95% CI: 5.7 ‒ 492.6). This is one of the few studies showing IR and RRRs of acute HCV infections and the first focused on a large city in Spain. Sexual risk for transmission between men, higher educational level and HIV co-infection are important factors for understanding current HCV epidemic. There has been a partial shift in the pattern of the risk factor for transmission from nosocomial to sexual.

Introduction: Rheumatoid arthritis is a systemic inflammatory disease, and classical disease-modifying antirheumatic drugs (cDMARDs) have proven efficacy. It is unknown what impact cDMARDs might have on dementia as an outcome., Methods: Incident diagnoses of rheumatoid arthritis in persons over 18 years from 1995 to 2011 were identified from the UK Clinical Practice Research Datalink. There were 3876 cDMARD users and were propensity score matched to 1938 nonusers, on a wide range of confounders. Impact on dementia was assessed using survival models., Results: cDMARD users were at reduced risk of dementia (hazard ratio: 0.60; 95% confidence interval: 0.42-0.85). The effect was strongest in methotrexate users (hazard ratio: 0.52; 95% confidence interval; 0.34-0.82)., Discussion: The strong effect of cDMARD use on halving of dementia risk requires replication in a trial and may provide an important therapeutic pharmacological treatment.

Neuroligins are post-synaptic, cellular adhesion molecules implicated in synaptic formation and function. NLGN2 is strongly linked to inhibitory, GABAergic signaling and is crucial for maintaining the excitation-inhibition balance in the brain. Disruption of the excitation-inhibition balance is associated with neuropsychiatric disease. In animal models, altered NLGN2 expression causes anxiety, developmental delay, motor discoordination, social impairment, aggression, and sensory processing defects. In humans, mutations in NLGN3 and NLGN4 are linked to autism and schizophrenia; NLGN2 missense variants are implicated in schizophrenia. Copy number variants encompassing NLGN2 on 17p13.1 are associated with autism, intellectual disability, metabolic syndrome, diabetes, and dysmorphic features, but an isolated NLGN2 nonsense variant has not yet been described in humans. Here, we describe a 15-year-old male with severe anxiety, obsessive-compulsive behaviors, developmental delay, autism, obesity, macrocephaly, and some dysmorphic features. Exome sequencing identified a heterozygous, de novo, c.441C>A p.(Tyr147Ter) variant in NLGN2 that is predicted to cause loss of normal protein function. This is the first report of an NLGN2 nonsense variant in humans, adding to the accumulating evidence that links synaptic proteins with a spectrum of neurodevelopmental phenotypes. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Introduction: Antiretroviral therapy has led to a decrease in HIV-related mortality and to the emergence of non-AIDS defining diseases as competing causes of death. This study estimates the HIV mortality rate and their risk factors with regard to different causes in a large city from January 2001 to June 2013., Materials and Methods: We followed-up 3137 newly diagnosed HIV non-AIDS cases. Causes of death were classified as HIV-related, non-HIV-related and external. We examined the effect of risk factors on survival using mortality rates, Kaplan-Meier plots and Cox models. Finally, we estimated survival for each main cause of death groups through Fine and Gray models., Mortality Results: 182 deaths were found [14.0/1000 person-years of follow-up (py); 95% confidence interval (CI):12.0-16.1/1000 py], 81.3% of them had a known cause of death. Mortality rate by HIV-related causes and non-HIV-related causes was the same (4.9/1000 py; CI:3.7-6.1/1000 py), external was lower [1.7/1000 py; (1.0-2.4/1000 py)]., Survival Results: Kaplan-Meier estimate showed worse survival in intravenous drug user (IDU) and heterosexuals than in men having sex with men (MSM). Factors associated with HIV-related causes of death include: IDU male (subHazard Ratio (sHR):3.2; CI:1.5-7.0) and <200 CD4 at diagnosis (sHR:2.7; CI:1.3-5.7) versus ≥500 CD4. Factors associated with non-HIV-related causes of death include: ageing (sHR:1.5; CI:1.4-1.7) and heterosexual female (sHR:2.8; CI:1.1-7.3) versus MSM. Factors associated with external causes of death were IDU male (sHR:28.7; CI:6.7-123.2) and heterosexual male (sHR:11.8; CI:2.5-56.4) versus MSM., Conclusion and Recommendation: There are important differences in survival among transmission groups. Improved treatment is especially necessary in IDUs and heterosexual males.

Purpose: To describe lifetime differences in clinical characteristics of women with endometriosis between the USA and Puerto Rico., Methods: A descriptive study using self-administered demographic and clinical questionnaires was undertaken. Women with self-reported surgically diagnosed endometriosis who completed questionnaires from the Endometriosis Association (EA), Wisconsin, USA (n = 4358) and the Endometriosis Research Program (ERP) in Puerto Rico (n = 878), were included in this study. We compared demographic, gynecological and clinical history, frequency of endometriosis-associated symptoms and co-morbidities., Results: Although both groups have similar symptomatology, EA respondents had significantly higher rates of chronic pelvic pain and incapacitating pain than ERP participants. EA respondents were significantly more likely to report a history of problems getting pregnant, heavy bleeding, and hysterectomy than ERP respondents. Miscarriages were more frequently reported by the ERP group. Co-morbidities such as allergies, chronic fatigue syndrome, and fibromyalgia were more prevalent in EA respondents, whereas asthma was significantly more frequent in participants from ERP., Conclusions: Overall, women with endometriosis from the USA and Puerto Rico reported high rates of pain and infertility and a similar spectrum of symptoms. Those from the EA reported longer time to diagnosis, and diagnostic delays than those from the ERP, which may explain the observed increased in rates of endometriosis-related symptoms and co-morbidities in EA as compared to ERP.

Introduction: Breast cancer (BC) and endometriosis are important reproductive health diseases for women. Although endometriosis is not a malignant condition, some of its characteristics mimic that of a malignancy. Endometriosis is associated with increased risk of certain cancers; however, whether it alters BC risk is unclear. This study evaluates the association of endometriosis and BC and explores whether DNA repair capacity (DRC) plays a role in such a relationship., Materials and Methods: A case-control study of 991 women (385 with BC and 606 controls, all recruited over 5 years) was undertaken in Puerto Rico. Eighty participants with self-reported surgically diagnosed endometriosis were identified, 20 of whom also had a diagnosis of BC. Data from a structured questionnaire and DRC measurements were assessed to determine the association between BC, DRC, and endometriosis., Results: Participants with BC cases were 50% less likely to have history of endometriosis (OR = 0.5 95%CI: 0.3, 0.9, p = 0.038) than women without BC controls. Findings that did not reach statistical significance included the following: women with history of endometriosis had a slightly higher DRC level than those without it; BC cases and history of endometriosis were less likely to have had endometriosis diagnosis before age 38 as compared to controls with endometriosis., Discussion: Here we report an inverse association between endometriosis and BC, the former possibly conferring a protective effect on the latter. Although the mechanisms involved are unknown they may include protection provided by higher DRC and or hormonal treatments for endometriosis. A larger sample of endometriosis cases is necessary to confirm these results and answer the question of whether a higher DRC capacity may contribute to this potential protection, and to identify other factors at play.

Background: Breast cancer (BC) is the most common cancer afflicting Puerto Rican women and accounts for more cancer-related deaths in this population than any other cancer., Methods: Demographic, anthropometric, family history, and lifestyle data, as well as DNA repair capacity (DRC), were compared in 465 BC cases and 661 controls. Crude and multiple logistic regression-derived adjusted odds ratios were used as indicators of the associations between BC and the variables under study., Results: A low DRC level, aging (>61years), family history of BC, and low education level had statistically significant associations with increased BC risk. Endometriosis, full-term pregnancy at an earlier age, higher parity, hysterectomy before age 50, multivitamin and calcium intake, and longer duration of breastfeeding significantly decreased BC risk., Conclusions: This study discusses the major risk factors for BC in Puerto Rico (PR). Because many of these findings represent modifiable risk factors, they can translate into public health initiatives to lower BC risk. In addition, the possibility of using DRC as a simple screening tool for BC risk is explored., (Copyright © 2013 Ministry of Health, Saudi Arabia. Published by Elsevier Ltd. All rights reserved.)

Background: Gonorrhoea infection is one of the most common bacterial sexually transmitted infections and an important cause of morbidity and serious complications. The objectives of this paper are: a) to describe gonorrhoea cases diagnosed in a network of 15 (out of 16) STI clinics in Spain during 2006-2010; b) to analyse differences among men who have sex with men (MSM), men who have sex exclusively with women (MSW) and women; and c) to evaluate factors associated to with HIV co-infection., Methods: All gonorrhoea cases diagnosed in the network were included (25.7% of total cases notified in Spain). Data were collected by clinical staff. Descriptive/bivariate analyses were carried out stratifying by sex and transmission category; association and trends were evaluated using the chi-square test. Factors associated with HIV co-infection were estimated using a logistic regression model., Results: 2385 cases were included: 55.3% among MSM, 31.3% among MSW and 13.3% among females; cases among MSM increased from 55.8% in 2006 to 62.9% in 2010 while no trends were found among the other two groups.Most MSM cases were Spaniards (72%), aged 25-34 years (46%), 49% reported previous STI and 25% concurrent STI (excluding HIV); casual partners were the commonest source of infection, and 21% of cases had rectal gonorrhoea. MSW cases did not differ from MSM by age, origin or source of infection, but frequencies of prior or concurrent STI were lower. Female cases were younger than male, were mostly foreigners (58%), and 41% were sex workers; concurrent STI (other than HIV) were diagnosed in 30%; 20.4% had symptoms (72.5% and 89.2% in MSM and MSW), and pharyngeal location was present in 30%.HIV co-infection was highest in MSM (20.9%). Co-infection was associated with age > 35 years, low educational level, being Western European or Latin-American, being MSM, having previous or concurrent STI and reporting contact with an HIV-infected partner; it was inversely associated with female sex., Conclusion: Differences by sex, transmission route and origin should be considered when implementing care and preventive programmes for gonorrhoea, and MSM are a priority group for intervention, in particular HIV-infected MSM.

Context: Breast cancer (BC) is the most common cancer in women, with over 1 million new cases diagnosed every year worldwide. Over recent decades, considerable interest has emerged regarding whether vitamins and/or other supplements can lower the risk of BC. However, previous epidemiologic studies that investigated the association between intake of multivitamin and supplements of single vitamins and minerals and BC risk have reported conflicting results. Whether vitamins can actually reduce BC risk is still controversial., Objective: This study examined whether multivitamin and calcium use was associated with BC incidence and DNA repair capacity (DRC)., Design: The research team designed an observational, case-control study., Setting: All work was performed at the Ponce School of Medicine and Health Sciences under the direct supervision of principal investigator Dr Jaime Matta., Participants: Participants were 836 women recruited primarily from the private practices of oncologists, gynecologists, and surgeons in Puerto Rico., Interventions: A total of 312 individuals in the breast cancer (BC) group and 524 individuals in the control group were compared for their multivitamin and calcium intake, DRC levels, and other covariates., Outcome Measures: Odds ratios (OR), adjusted using both crude analysis and multiple logistic regression, were used as measures of association between BC and DRC and other selected variables., Results: The BC group had 30% reduced odds of taking multivitamins and calcium as compared to controls: (1) OR = 0.7 (95% CI, 0.4-1.0; P = .073) for multivitamins and (2) OR = 0.7 (95% CI, 0.4-1.2; P = .167) for calcium. Women with low DRC had 50% lower odds of taking calcium and 30% lower odds of currently taking vitamins OR = 0.5 (95% CI, 0.4-0.7; P = .001) for calcium and (2) OR = 0.7 (95% CI, 0.5-0.9.1; P = .047) for vitamins., Conclusions: Although this study is a case-control study in which the risk of BC could not be assessed, results suggest that vitamin supplementation could be an independent protective factor for BC. Calcium intake appears to affect DRC in a positive way, because it was associated with a high DRC level, which in turn is associated with low odds for BC.

Background: Previous studies have found a link between a low DNA repair capacity (DRC) level and increased cancer risk. Our aim was to assess the statistical association of DRC level and breast cancer (BC) using a case-control epidemiological study in a Hispanic community., Methods: We conducted a comparative observational study to assess the validity of DRC in detecting BC in 824 women throughout Puerto Rico. Over a 6-year period, we compared 285 women newly diagnosed with BC to 539 without BC. DRC levels were measured in lymphocytes by means of a host-cell reactivation assay. We assessed the sensitivity, specificity, and association using the receiver operating characteristic curve analysis. Multiple logistic regression-adjusted odds ratios were estimated with 95% confidence level to measure the strength of the association of DRC and BC after adjusting for all confounders simultaneously., Results: Compared to women without cancer, women with BC showed an average decrease of 60% in their DRC levels (p < 0.001). Validity of the association of DRC as a measure of BC risk showed a sensitivity of 83.2% and specificity of 77.6% (p < 0.0001)., Conclusions: Our results support the usefulness of DRC level as a measure of BC risk. Additional studies in other populations are needed to further verify its usefulness.

Epigenetic mechanisms have been ascribed important roles in endometriosis. Covalent histone modifications at lysine residues have been shown to regulate gene expression and thus contribute to pathological states in many diseases. In endometriosis, histone deacetylase inhibition (HDACi) resulted in reactivation of E-cadherin, attenuation of invasion, decreased proliferation of endometriotic cells, and caused lesion regression in an animal model. This study was conducted to assess basal and hormone-regulated gene expression levels of HDAC1 and HDAC2 (HDAC1/2) in cell lines and protein expression levels in tissues. Basal and steroid hormone-regulated HDAC1/2 gene expression levels were determined by quantitative polymerase chain reaction in cell lines and tissues. Protein levels were measured by immunohistochemistry (IHC) in tissues on an endometriosis tissue microarray (TMA). Basal HDAC1/2 gene expression levels were significantly higher in endometriotic versus endometrial stromal cells, which was confirmed by Western blot analysis. Estradiol (E2) and progesterone (P4) significantly downregulated HDAC1 expression in endometrial epithelial cells. Levels of HDAC2 were upregulated by E2 and downregulated by E2 + P4 in endometrial stromal cells. Hormone modulation of HDAC1/2 gene expression was lost in the endometriotic cell line. Immunohistochemistry showed that HDAC1/2 proteins were expressed in a substantial proportion of lesions and endometrium from patients, and their expression levels varied according to lesion localization. The highest proportion of strong HDAC1 immunostaining was seen in ovarian, skin, and gastrointestinal lesions, and of HDAC2 in skin lesions and endometrium from patients with endometriosis. These studies suggest that endometriosis etiology may be partially explained by epigenetic regulation of gene expression due to dysregulations in the expression of HDACs.