General practitioners' satisfaction with and attitudes to out-of-hours services

BACKGROUND: In recent years, Dutch general practitioner (GP) out-of-hours service has been reorganised into large-scale GP cooperatives. Until now little is known about GPs' experiences with working at these cooperatives for out-of-hours care. The purpose of this study is to gain insight into GPs' satisfaction with working at GP cooperatives for out-of-hours care in separated and integrated cooperatives. METHODS: A GP cooperative separate from the hospital Accident and Emergency (A&E) department, and a GP cooperative integrated within the A&E department of another hospital. Both cooperatives are situated in adjacent geographic regions in the South of the Netherlands. One hundred GPs were interviewed by telephone; fifty GPs working at the separated GP cooperative and fifty GPs from the integrated GP cooperative. Opinions on different aspects of GP cooperatives for out-of-hours care were measured, and regression analysis was performed to investigate if these could be related to GP satisfaction with out-of-hours care organisation. RESULTS: GPs from the separated model were more satisfied with the organisation of out-of-hours care than GPs from the integrated model (70 vs. 60 on a scale score from 0 to 100; P = 0.020). Satisfaction about out-of-hours care organisation was related to opinions on workload, guarantee of gatekeeper function, and attitude towards out-of-hours care as being an essential part of general practice. Cooperation with medical specialists was much more appreciated at the integrated model (77 vs. 48; P < 0.001) versus the separated model. CONCLUSION: GPs in this study appear to be generally satisfied with the organisation of GP cooperatives for out-of-hours care. Furthermore, GPs working at the separated cooperative seem to be more satisfied compared to GPs working at the integrated cooperative

The coronary microvascular angina cardiovascular magnetic resonance imaging trial: rationale and design

Background: Coronary microvascular dysfunction may cause myocardial ischemia with no obstructive coronary artery disease (INOCA). If functional testing is not performed INOCA may pass undetected. Stress perfusion cardiovascular MRI (CMR) quantifies myocardial blood flow (MBF) but the clinical utility of stress CMR in the management of patients with suspected angina with no obstructive coronary arteries (ANOCA) is uncertain. Objectives: First, to undertake a diagnostic study using stress CMR in patients with ANOCA following invasive coronary angiography and, second, in a nested, double-blind, randomized, controlled trial to assess the effect of disclosure on the final diagnosis and health status in the longer term. Design: All-comers referred for clinically indicated coronary angiography for the investigation of suspected coronary artery disease will be screened in three regional centers in the United Kingdom. Following invasive coronary angiography, patients with ANOCA who provide informed consent will undergo noninvasive endotyping using stress CMR within 3 months of the angiogram. Diagnostic study: Stress perfusion CMR imaging to assess the prevalence of coronary microvascular dysfunction and clinically significant incidental findings in patients with ANOCA. The primary outcome is the between-group difference in the reclassification rate of the initial diagnosis based on invasive angiography versus the final diagnosis after CMR imaging. Randomized, controlled trial: Participants will be randomized to inclusion (intervention group) or exclusion (control group) of myocardial blood flow to inform the final diagnosis. The primary outcome of the clinical trial is the mean within-subject change in the Seattle Angina Questionnaire summary score (SAQSS) at 6 months. Secondary outcome assessments include the EUROQOL EQ-5D-5L questionnaire, the Brief Illness Perception Questionnaire (Brief-IPQ), the Treatment Satisfaction Questionnaire (TSQM-9), the Patient Health Questionnaire-4 (PHQ-4), the Duke Activity Status Index (DASI), the International Physical Activity Questionnaire- Short Form (IPAQ-SF), the Montreal Cognitive Assessment (MOCA) and the 8-item Productivity Cost Questionnaire (iPCQ). Health and economic outcomes will be assessed using electronic healthcare records. Value: To clarify if routine stress perfusion CMR imaging reclassifies the final diagnosis in patients with ANOCA and whether this strategy improves symptoms, health-related quality of life and health economic outcomes. Clinicaltrials.gov: NCT0480581

Dapagliflozin versus metolazone in heart failure resistant to loop diuretics

Background and Aims: To examine the decongestive effect of the sodium-glucose cotransporter 2 inhibitor dapagliflozin compared to the thiazide-like diuretic metolazone in patients hospitalized for heart failure and resistant to treatment with intravenous furosemide. Methods: A multi-centre, open-label, randomized, active-comparator trial. Patients were randomized to dapagliflozin 10 mg once daily or metolazone 5-10 mg once daily for a 3-day treatment period, with follow-up for primary and secondary endpoints until day 5 (96 hours). The primary endpoint was diuretic effect, assessed by change in weight (kg). Secondary endpoints included change in pulmonary congestion (lung ultrasound), loop diuretic efficiency (weight change per 40 mg of furosemide), and a volume assessment score. Results: 61 patients were randomized. The mean (±standard deviation) cumulative dose of furosemide at 96 hours was 976 (±492) mg in the dapagliflozin group and 704 (±428) mg in patients assigned to metolazone. The mean (±standard deviation) decrease in weight at 96 hours was 3.0 (2.5) kg with dapagliflozin compared to 3.6 (2.0) kg with metolazone [mean difference 0.65, 95% confidence interval (CI) -0.12,1.41 kg; p=0.11]. Loop diuretic efficiency was less with dapagliflozin than with metolazone [mean 0.15 (0.12) versus 0.25 (0.19); difference -0.08, 95% CI -0.17,0.01 kg; p=0.10]. Changes in pulmonary congestion and volume assessment score were similar between treatments. Decreases in plasma sodium and potassium and increases in urea and creatinine were smaller with dapagliflozin than with metolazone. Serious adverse events were similar between treatments. Conclusion: In patients with heart failure and loop diuretic resistance, dapagliflozin was not more effective at relieving congestion than metolazone. Patients assigned to dapagliflozin received a larger cumulative dose of furosemide but experienced less biochemical upset than those assigned to metolazone. ClinicalTrials.gov Identifier: NCT04860011

Psychosocial impact of undergoing prostate cancer screening for men with BRCA1 or BRCA2 mutations.

OBJECTIVES: To report the baseline results of a longitudinal psychosocial study that forms part of the IMPACT study, a multi-national investigation of targeted prostate cancer (PCa) screening among men with a known pathogenic germline mutation in the BRCA1 or BRCA2 genes. PARTICPANTS AND METHODS: Men enrolled in the IMPACT study were invited to complete a questionnaire at collaborating sites prior to each annual screening visit. The questionnaire included sociodemographic characteristics and the following measures: the Hospital Anxiety and Depression Scale (HADS), Impact of Event Scale (IES), 36-item short-form health survey (SF-36), Memorial Anxiety Scale for Prostate Cancer, Cancer Worry Scale-Revised, risk perception and knowledge. The results of the baseline questionnaire are presented. RESULTS: A total of 432 men completed questionnaires: 98 and 160 had mutations in BRCA1 and BRCA2 genes, respectively, and 174 were controls (familial mutation negative). Participants' perception of PCa risk was influenced by genetic status. Knowledge levels were high and unrelated to genetic status. Mean scores for the HADS and SF-36 were within reported general population norms and mean IES scores were within normal range. IES mean intrusion and avoidance scores were significantly higher in BRCA1/BRCA2 carriers than in controls and were higher in men with increased PCa risk perception. At the multivariate level, risk perception contributed more significantly to variance in IES scores than genetic status. CONCLUSION: This is the first study to report the psychosocial profile of men with BRCA1/BRCA2 mutations undergoing PCa screening. No clinically concerning levels of general or cancer-specific distress or poor quality of life were detected in the cohort as a whole. A small subset of participants reported higher levels of distress, suggesting the need for healthcare professionals offering PCa screening to identify these risk factors and offer additional information and support to men seeking PCa screening

Bacterial Growth Rate and Host Factors as Determinants of Intracellular Bacterial Distributions in Systemic Salmonella enterica Infections▿

Bacteria of the species Salmonella enterica cause a range of life-threatening diseases in humans and animals worldwide. The within-host quantitative, spatial, and temporal dynamics of S. enterica interactions are key to understanding how immunity acts on these infections and how bacteria evade immune surveillance. In this study, we test hypotheses generated from mathematical models of in vivo dynamics of Salmonella infections with experimental observation of bacteria at the single-cell level in infected mouse organs to improve our understanding of the dynamic interactions between host and bacterial mechanisms that determine net growth rates of S. enterica within the host. We show that both bacterial and host factors determine the numerical distributions of bacteria within host cells and thus the level of dispersiveness of the infection

Attenuated <em>Salmonella</em> Typhimurium Lacking the Pathogenicity Island-2 Type 3 Secretion System Grow to High Bacterial Numbers inside Phagocytes in Mice

<div><p>Intracellular replication within specialized vacuoles and cell-to-cell spread in the tissue are essential for the virulence of <em>Salmonella enterica</em>. By observing infection dynamics at the single-cell level <em>in vivo</em>, we have discovered that the <em>Salmonella</em> pathogenicity island 2 (SPI-2) type 3 secretory system (T3SS) is dispensable for growth to high intracellular densities. This challenges the concept that intracellular replication absolutely requires proteins delivered by SPI-2 T3SS, which has been derived largely by inference from <em>in vitro</em> cell experiments and from unrefined measurement of net growth in mouse organs. Furthermore, we infer from our data that the SPI-2 T3SS mediates exit from infected cells, with consequent formation of new infection foci resulting in bacterial spread in the tissues. This suggests a new role for SPI-2 <em>in vivo</em> as a mediator of bacterial spread in the body. In addition, we demonstrate that very similar net growth rates of attenuated salmonellae in organs can be derived from very different underlying intracellular growth dynamics.</p> </div

SPI-2 T3SS mutants can grow to high intracellular densities in CD18⁺ cells <i>in vivo</i>.

<p>(A) Model of the SPI-2 T3SS. SseB forms part of the translocon; SsaV is located in the inner membrane. (B–E) Representative fluorescence micrographs of <i>Salmonella</i> within phagocytes in infected livers of C57BL/6 mice at 72 h p.i. (B) S12023; (C) S12023 <i>ssaV</i>; (D) S12023 <i>sseB</i>; (E) S12023 <i>sseB</i>(psseB) [CD18⁺ cells (red), <i>Salmonella</i> (green), nucleic acid is stained with DAPI (blue), scale bars, 5 µm]. (F and G) C57BL/6 mice were infected i.v. with ∼Log₁₀ 4.3 CFU ( = 2.15×10⁴ CFU) of S12023, ∼Log₁₀ 6.4 CFU ( = 2.45×10⁶ CFU) of S12023 <i>sseB</i>, or ∼Log₁₀ 4.1 CFU ( = 1.27×10⁴ CFU) of S12023 <i>sseB</i>(psseB). (F) Net bacterial numbers in livers (unbroken lines) and spleens (dotted lines) were determined between 6 to 72 h p.i. from 4 mice per strain per time point (results are expressed as mean Log₁₀ viable count ± standard deviation). (G) The proportion of infected phagocytes relative to the number of bacteria contained within each phagocyte is shown for livers (solid bars) and spleens (diagonal shading) at 72 h p.i. based on the counts obtained from 400 infected phagocytes per strain, from tissue obtained from 4 mice per strain [S12023 - red; S12023 <i>sseB</i> - blue; S12023 <i>sseB</i>(psseB) – green].</p

Phagocyte NADPH oxidase inhibits <i>Salmonella</i> spread in the tissues in the absence of SPI-2 T3SS.

<p>gp91<i>phox</i>^−/− mice were infected i.v. with ∼Log₁₀ 4.2 CFU ( = 1.45×10⁴ CFU) of S12023 or ∼Log₁₀ 4.1 CFU ( = 1.21×10⁴ CFU) of S12023 <i>sseB</i>, C57BL/6 mice were infected i.v. with ∼Log₁₀ 4.3 CFU ( = 2.15×10⁴ CFU) of S12023 or ∼Log₁₀ 6.4 CFU ( = 2.45×10⁶ CFU) of S12023 <i>sseB</i>. (A) Net bacterial numbers in livers (unbroken lines) and spleens (dotted lines) were determined between 6 and 72 h p.i. inclusive (results are expressed as mean Log₁₀ viable count ± standard deviation), the net bacterial growth of S12023 and S12023 <i>sseB</i> in gp91<i>phox</i>^−/− mice was obtained from 3 mice per time point (the data for S12023 and S12023 <i>sseB</i> in C57BL/6 mice is reproduced from <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1003070#ppat-1003070-g001" target="_blank">Figure 1F</a>. S12023 in C57BL/6 mice – red; S12023 in gp91<i>phox</i>^−/− mice – pink; S12023 <i>sseB</i> in C57BL/6 mice – dark blue; S12023 <i>sseB</i> in gp91<i>phox</i>^−/− mice – light blue). (B) The proportion of infected phagocytes relative to the numbers of bacteria contained within each phagocyte for S12023 <i>sseB</i> in gp91<i>phox</i>^−/− mice and S12023 <i>sseB</i> in C57BL/6 mice at 48 h p.i., based on the counts obtained from 100 infected phagocytes per organ, from tissue obtained from 3 mice per time point. (Livers – fully shaded; Spleens – diagonal shading). (C) Box and whisker plot showing the median, interquartile range and maximum and minimum number of infected cells per field-of-view for S12023 <i>sseB</i> in C57BL/6 mice and S12023 <i>sseB</i> in gp91<i>phox</i>^−/− mice at 48 h p.i., from 100 random fields from 3 mice for each strain.</p

Accumulation of SPI-2 T3SS mutants inside cells is due to clonal expansion of a bacterium.

<p>(A) C57BL/6 mice were infected i.v. with ∼Log₁₀ 6.4 CFU ( = 2.44×10⁶ CFU) of <i>Salmonella</i> S12023, ∼Log₁₀ 6.5 CFU ( = 2.86×10⁶ CFU) of S12023 <i>sseB</i>, or ∼Log₁₀ 6.3 CFU ( = 2.17×10⁶ CFU) of S12023 <i>sseB</i>(psseB). The proportion of infected phagocytes relative to the number of bacteria contained within each phagocyte is shown for livers (solid bars) and spleens (diagonal shading) at 0.5 h p.i. based on the counts obtained from 150 infected phagocytes per strain, from tissue obtained from 3 mice per strain [S12023 - red; S12023 <i>sseB</i> - blue; S12023 <i>sseB</i>(psseB) – green]. (B) C57BL/6 mice were infected i.v. with ∼Log₁₀ 6.4 CFU ( = 2.64×10⁶ CFU) of S12023 <i>sseB</i>. The proportion of infected phagocytes relative to the numbers of bacteria contained within each phagocyte is shown for livers (solid bars) and spleens (diagonal shading) at different time points between 0.5 and 72 h p.i. inclusive, based on the counts obtained from 100 infected phagocytes per organ, per time point, from tissue obtained from 4 mice per time point. (C) C57BL/6 mice were infected i.v. with ∼Log₁₀ 6.3 CFU ( = 1.99×10⁶ CFU) of SL5559 <i>sseB</i> and SL5560 <i>sseB</i> bacteria into the same animal <i>via</i> a single injection. Representative fluorescence micrograph of <i>Salmonella</i> SL5559 <i>sseB</i> and SL5560 <i>sseB</i> within phagocytes in an infected spleen at 72 h p.i. [SL5559 <i>sseB</i> (green), SL5560 <i>sseB</i> (red), nucleic acid is stained with DAPI (blue). Scale bar, 75 µm].</p

SPI-2 T3SS mutants are present in far fewer infected foci per organ than the wild-type.

<p>(A to C) Representative fluorescence micrographs of <i>Salmonella</i> within phagocytes in infected livers of C57BL/6 mice at 72 h p.i.. (A) S12023; (B) S12023 <i>sseB</i>; (C) S12023 <i>sseB</i>(psseB) [CD18⁺ cells (red), <i>Salmonella</i> (green), nucleic acid is indicated by DAPI (blue), scale bars, 75 µm]. (D and E) Box and whisker plots showing the median, interquartile range and maximum and minimum number of infected cells per field-of-view in spleens for (D) S12023, S12023 <i>sseB</i> and S12023 <i>sseB</i> p(<i>sseB</i>) at 72 h p.i., obtained from 100 random fields from 4 mice for S12023 and S12023 <i>sseB</i>(psseB) infected tissue and 200 random fields from 7 mice for S12023 <i>sseB</i> infected tissue, and (E) S12023 <i>sseB</i> at 0.5 and 72 h p.i., obtained from 100 random fields from 3 mice for S12023 <i>sseB</i> infected tissue at 0.5 h p.i., and 200 random fields from 7 mice for S12023 <i>sseB</i> infected tissue at 72 h p.i.</p