Differences in the clinical management of women and men after detection of a solitary pulmonary nodule in clinical practice.

OBJECTIVES: To explore differences in the clinical management of men and women in the 5 years after detecting a solitary pulmonary nodule (SPN) by chest radiograph or CT in routine clinical practice. METHODS: We followed up 545 men and 347 women with an SPN detected by chest radiograph or CT in a retrospective cohort of 25,422 individuals undergoing routine thoracic imaging in 2010-2011. We compared the frequency of each management strategy (no further test, immediate intervention or follow up) according to sex by means of chi-squared. We estimated the relative risk of women versus men of having been followed up instead of an immediate intervention using multivariate logistic regression. We compared by sex the time between detection of the nodule and lung cancer diagnosis, the time between diagnosis and death by means of Mann-Whitney U test and the cumulative effective dose of radiation in each management strategy by means of t test. RESULTS: Women were more likely than men to have follow-up rather than immediate intervention (aRR = 1.8, CI 1.3-2.7, p = 0.002), particularly in those who underwent CT (aRR = 4.2, CI 1.9-9.3, p < 0.001). The median time between SPN detection and lung cancer diagnosis was higher in women (4.2 months, interquartile range (IQR) 5.1) than in men (1.5 months, IQR 16.2). The mean cumulative effective dose was 21.3 mSv, 19.4 mSv in men and 23.9mv in women (p = 0.023). CONCLUSIONS: Our results could reflect decisions based on a greater suspicion of lung cancer in men. The incidental detection of SPNs is increasing, and it is necessary to establish clear strategies aimed to reduce variability in their management according to patient's sex. KEY POINTS: • After incidental finding of SPN, women were less likely to receive an immediate intervention. • Accumulative radiation was higher in women than in men. • Our results could reflect decisions based on a greater suspicion of lung cancer in men.

Untangling the association between prostate-specific antigen and diabetes: a systematic review and meta-analysis.

Objectives: Several studies have shown an inverse association between diabetes mellitus and prostate cancer (PCa). Some researchers suggest that this relationship is due to reduced PCa detection in diabetics due to lower prostate-specific antigen (PSA) levels compared to non-diabetics. Our objective is to analyze the impact of diabetes on PSA in asymptomatic men without known prostate pathology and without prior prostate intervention. Methods: We searched Medline (via PubMed), Embase and Scopus. We included studies that reported the relationship between serum PSA levels and diabetes or diabetes treatment in asymptomatic adult men without known prostate pathology, and without prior prostate intervention. Pooled mean differences were compared between diabetics and non-diabetics. Results: Of 2,392 screened abstracts, thirteen studies met the inclusion criteria and 8 (62%) reported appropriate measures that could be included in a meta-analysis. Eleven (85%) examined the influence of diabetes on PSA levels and 8 (62%) evaluated the influence of diabetes treatments on PSA levels. Overall diabetics had a significantly lower PSA level compared to non-diabetics (mean difference: -0.07 ng/mL; 95% CI -0.10, -0.04). Conclusions: Diabetes and related factors (such as disease duration, severity and treatment) were significantly associated with lower PSA levels among asymptomatic men, yet differences were small and are unlikely to influence PCa detection in a screening setting.

Promoting population health with public-private partnerships: Where's the evidence?

BACKGROUND: Although public-private partnerships have become common in the health sector, the evidence supporting their effectiveness is limited, and when the products or services provided by the private partner are harmful to health inherent conflicts of interest may be difficult to overcome. The objective of this study is to appraise the evidence describing process or effectiveness of public-private partnerships (PPPs) that aim to promote population health, and analyse how characteristics such as independence or competing interests influence the results of their evaluation. METHODS: We carried out a systematic search of Medline and Web of Science to identify scientific reports evaluating the process or effectiveness of PPPs that aim to promote population health. Two reviewers applied inclusion criteria, extracted and evaluated study quality. We classified PPPs according to the health problem tackled, the independence of the evaluation, and the potential for competition between business interests of the private partner and health promotion activity undertaken. We classified the conclusions of the evaluation as positive (supportive/tentatively supportive) or negative (semi-critical/critical). RESULTS: We identified 36 studies evaluating 25 PPPs. Evaluations that were favourable to the use of PPPs in health promotion were more frequently classed as "not independent" and of poor quality. On the other hand, negative evaluations were more common when the PPP involved a private partner with a high potential for competition between the health promotion activity undertaken and their financial interests. PPPs that sought to prevent non-communicable diseases were more frequently negatively evaluated compared to PPPs tackling infectious disease or other types of health problem. Almost all of the evaluations evaluated process, with only 2 papers reporting quantitative health related outcomes. CONCLUSIONS: There is still a lack of sound evidence supporting the effectiveness of public-private partnerships in health promotion, and the evidence base is skewed by non-independent evaluations. Public health actors should abstain from engaging in agreements with industries whose business interests have a high potential for competition with the health promotion activity undertaken.

Diagnostic Biomarkers: Are We Moving from Discovery to Clinical Application?

BACKGROUND: Despite considerable research investment, moving from biomarker discovery to clinical application has presented unique challenges. We aimed to evaluate progress toward clinical application of a sample of molecular- and "omics"-based diagnostic tests over a 10-year period. METHODS: We used Scopus to locate studies, published before the December 31, 2016, citing 107 original-research articles published in 2006 that assessed the diagnostic value of a molecular- or "omics"-based test. We identified diagnostic studies of the same test and disease and determined whether the article represented progress in the validation of the molecular test. We classified the types of progress: (a) clinical validation (measuring diagnostic accuracy in a series of patients similar to the population in which the test will be used in practice), (b) technical improvement, (c) extended diagnostic application (modification of the diagnostic question attended initially by the test), (d) economic evaluation, or (e) clinical use or implementation. RESULTS: In the 10-year period analyzed, 4257 articles cited the 107 diagnostic studies; 118 (2.8%) were diagnostic studies of the same test, and of these papers, 25 (21.2%) did not constitute progress toward validation of the test for use in clinical practice (potential research waste). Of the 107 molecular- or "omics"-based tests described in 2006, only 28 (26.2%) appeared to have made progress toward clinical application. Only 4 (9.1%) of 44 proteomics-based tests had made progress toward clinical application. CONCLUSIONS: Articles evaluating molecular- or "omics"-based diagnostic tests are numerous in biomedical journals. Few tests have made progress toward clinical application in the 10 years following their discovery.

Urologists' and general practitioners' knowledge, beliefs and practice relevant for opportunistic prostate cancer screening: a PRISMA-compliant systematic review.

Background: Recent guidelines on opportunistic prostate cancer screening conclude that the decision to screen with prostate-specific antigen should be made by each patient individually together with the clinician. However, there is evidence of a lack of clinicians' awareness of prostate cancer screening. This study sought to assess the recent evidence of clinicians' knowledge, beliefs, and practice regarding opportunistic prostate cancer screening comparing urologists and generals practitioners. Methods: A systematic search was conducted in 3 online databases: MEDLINE, Web of Science and EMBASE (from January 1, 2015, to January 9th, 2023). Studies that explored clinicians' knowledge, beliefs, and practices regarding opportunistic prostate cancer screening were included. Studies were assessed for quality reporting according to the Strengthening the Reporting of Observational studies in Epidemiology guidelines. Results: A total of 14 studies met the inclusion criteria: ten studies included primary care health professionals, three studies included urologists, and one study included both. Studies involving general practitioners showed a generally low level of awareness of the recommended uses of the test, and urologists showed a greater knowledge of clinical practice guidelines. General practitioners' opinion of prostate-specific antigen was generally unfavourable in contrast to urologists' who were more likely to be proactive in ordering the test. Less than half of the included studies evaluated shared-decision making in practice and 50% of clinicians surveyed implemented it. Conclusion: General practitioners had less knowledge of prostate cancer risk factors and clinical practice guidelines in the use of PSA than urologists, which makes them less likely to follow available recommendations. A need to carry out education interventions with trusted resources based on the available evidence and the current guidelines was identified.

Knowledge and practices regarding prostate cancer screening in Spanish men: The importance of personal and clinical characteristics (PROSHADE study).

INTRODUCTION: Patients' decisions on prostate cancer (PCa) opportunistic screening may vary. This study aimed to assess how demographic and health-related characteristics may influence knowledge and decisions regarding PCa screening. METHODS: A cross-sectional survey was conducted among men aged over 40, randomly sampled from the Spanish population, 2022. The survey underwent development and content validation using a modified Delphi method and was administered via telephone. Binomial logistic regression was used to explore the relationship between respondents' characteristics and participants' knowledge and practices concerning PCa and the PSA test. RESULTS: Out of 1,334 men, 1,067 (80%) respondents were interviewed with a mean age of 58.6 years (sd 11.9). Most had secondary or university studies (787, 73.8%) and 61 (5.7%) self-reported their health status as bad or very bad. Most of the respondents (1,018, 95.4%) had knowledge regarding PCa with nearly 70% expressed significant concern about its potential development (720, 70.8%), particularly among those under 64 years (p = 0.001). Out of 847 respondents, 573 (67.7%) reported that they have knowledge regarding the PSA test: 374 (65.4%) reported receiving information from a clinicians, 324 (86.6%) information about the benefits of the test and 189 (49,5%) about its risks, with differences based on educational background. In a multivariable analysis (adjusted for age, educational level and previous prostate problems), respondents with higher levels of education were more likely to have higher knowledge regarding the PSA test (OR 1.75, 95%CI 1.24-2.50, p<0.001). CONCLUSIONS: Although most of the patients reported to have knowledge regarding PCa, half of the interviewed men reported knowledge about PSA test. Differences in knowledge prostate cancer screening and undesirable consequences highlight the need to develop and provide tailored information for patients.

The impact of including different study designs in meta-analyses of diagnostic accuracy studies.

Diagnostic accuracy may be overestimated when using certain study designs; thus, the inclusion of studies using different designs in meta-analyses may have important effects on their results, and influence clinical decision making. The main aim of this study was to explore the influence of heterogeneity (based on the inclusion of different study designs) on diagnostic accuracy in a sample of published meta-analyses of diagnostic accuracy studies. We identified 30 systematic reviews which included 95 separate meta-analyses combining the results from a total of 976 individual studies. We classified each individual study according to the study design (case-control studies, clinically relevant patient series or other), and each meta-analysis according to the heterogeneity of the included studies. Furthermore, we registered how the methodological quality of the individual studies was assessed. Finally, for each meta-analysis, the summary measure of diagnostic accuracy was categorised as Good, Fair or Poor. We used logistic regression to assess the relationship between reporting good diagnostic accuracy and heterogeneity. Meta-analyses with heterogeneous populations were over three times more likely to report good diagnostic accuracy compared to meta-analyses that included only clinically relevant patient series (adjusted odds ratio 3.07 95% CI 1.16-8.11). The combination of studies that use different designs, within the same meta-analysis, may lead to higher estimates of diagnostic accuracy.

Gender Differences in the Impact of Recommendations on Diagnostic Imaging Tests: A Retrospective Study 2007-2021.

(1) Background: The frequency of imaging tests grew exponentially in recent years. This increase may differ according to a patient's sex, age, or socioeconomic status. We aim to analyze the impact of the Council Directive 2013/59/Euratom to control exposure to radiation for men and women and explore the impact of patients' age and socioeconomic status; (2) Methods: The retrospective observational study that includes a catchment population of 234,424. We included data of CT, mammography, radiography (conventional radiography and fluoroscopy) and nuclear medicine between 2007-2021. We estimated the associated radiation effective dose per test according using previously published evidence. We calculated a deprivation index according to the postcode of their residence. We divided the study in 2007-2013, 2014-2019 and 2020-2021 (the pandemic period). (3) Results: There was an increase in the number of imaging tests received by men and women after 2013 (p < 0.001), and this increase was higher in women than in men. The frequency of imaging tests decreased during the pandemic period (2020-2021), but the frequency of CT and nuclear medicine tests increased even during these years (p < 0.001) and thus, the overall effective mean dose. Women and men living in the least deprived areas had a higher frequency of imaging test than those living in the most deprived areas. (4) Conclusions: The largest increase in the number of imaging tests is due to CTs, which account for the higher amount of effective dose. The difference in the increase of imaging tests carried out in men and women and according to the socioeconomic status could reflect different management strategies and barriers to access in clinical practice. Given the low impact of the available recommendations on the population exposure to radiation and the performance of high-dose procedures such as CT, deserve special attention when it comes to justification and optimization, especially in women.

Evaluation of Diagnostic Strategies for Identifying SARS-CoV-2 Infection in Clinical Practice: a Systematic Review and Compliance with the Standards for Reporting Diagnostic Accuracy Studies Guideline (STARD).

We aimed to review strategies for identifying SARS-CoV-2 infection before the availability of molecular test results, and to assess the reporting quality of the studies identified through the application of the STARD guideline. We screened 3,821 articles published until 30 April 2021, of which 23 met the inclusion criteria: including at least two diagnostic variables, being designed for use in clinical practice or in a public health context and providing diagnostic accuracy rates. Data extraction and application of STARD criteria were performed independently by two researchers and discrepancies were discussed with a third author. Most of the studies (16, 69.6%) included symptomatic patients with suspected infection, six studies (26.1%) included patients already diagnosed and one study (4.3%) included individuals with close contact to a COVID-positive patient. The main variables considered in the studies, which included symptomatic patients, were imaging and demographic characteristics, symptoms, and lymphocyte count. The values for area under the receiver operating characteristic curve (AUC)ranged from 53-97.4. Seven studies (30.4%) validated the diagnostic model in an independent sample. The average number of STARD criteria fulfilled was 17.6 (maximum, 27 and minimum, 5). High diagnostic accuracy values are shown when more than one diagnostic variable is considered, mainly imaging and demographic characteristics, symptoms, and lymphocyte count. This could offer the potential to identify individuals with SARS-CoV-2 infection with high accuracy when molecular testing is not available. However, external validation for developed models and evaluations in populations as similar as possible to those in which they will be applied is urgently needed. IMPORTANCE According to this review, the inclusion of more than one diagnostic test in the diagnostic process for COVID-19 infection shows high diagnostic accuracy values. Imaging characteristics, patients' symptoms, demographic characteristics, and lymphocyte count were the variables most frequently included in the diagnostic models. However, developed models should be externally validated before reaching conclusions on their utility in practice. In addition, it is important to bear in mind that the test should be evaluated in populations as similar as possible to those in which it will be applied in practice.

Continuous control of autoimmune disease by antigen-dependent polyclonal CD4+CD25+ regulatory T cells in the regional lymph node.

This study investigated the unresolved issue of antigen-dependency and antigen-specificity of autoimmune disease suppression by CD4+CD25+ T cells (T regs). Based on autoimmune ovarian disease (AOD) in day 3 thymectomized (d3tx) mice and polyclonal T regs expressing the Thy1.1 marker, we determined: (a) the location of recipient T cell suppression, (b) the distribution of AOD-suppressing T regs, and (c) the relative efficacy of male versus female T regs. Expansion of recipient CD4+ T cells, activation/memory marker expression, and IFN-gamma production were inhibited persistently in the ovary-draining LNs but not elsewhere. The cellular changes were reversed upon Thy1.1+ T reg depletion, with emergence of potent pathogenic T cells and severe AOD. Similar changes were detected in the regional LNs during autoimmune dacryoadenitis and autoimmune prostatitis suppression. Although the infused Thy1.1+ T regs proliferated and were disseminated in peripheral lymphoid organs, only those retrieved from ovary-draining LNs adoptively suppressed AOD at a suboptimal cell dose. By depriving d3tx recipients of ovarian antigens, we unmasked the supremacy of ovarian antigen-exposed female over male T regs in AOD suppression. Thus, disease suppression by polyclonal T regs depends on endogenous antigen stimulation; this occurs in a location where potent antigen-specific T regs accumulate and continuously negate pathogenic T cell response.

How useful is it clinically to analyse the K-ras mutational status for the diagnosis of exocrine pancreatic cancer? A systematic review and meta-analysis.

BACKGROUND: More clinically meaningful diagnostic tests are needed in exocrine pancreatic cancer (EPC). K-ras mutations are the most frequently acquired genetic alteration in EPC. We analysed the diagnostic utility of detecting K-ras mutations through a systematic analysis of the literature. METHODS: We searched PubMed using suitable medical subject headings and text words. Original research articles that evaluated the diagnostic accuracy of detecting K-ras mutations for diagnosis of EPC were selected. Two investigators independently extracted data from each study regarding the methodology used, the methodological quality of the study, the diagnostic accuracy reported and the authors' conclusions about clinical applicability of the test. Combined estimates for the sensitivity and specificity of K-ras were determined using bivariate meta-analysis; heterogeneity was explored using meta-regression. RESULTS: We assessed 34 studies from 30 published articles. The research reports were prone to numerous methodological biases and often lacked vital information for assessing external validity. The sensitivity of detecting K-ras status ranged from 0% through 100%, and the specificity from 58% through 100%. Diagnostic accuracy was highest when cytohistological samples were used: sensitivity and specificity were 76·5% (66·7-84·2) and 91·8% (87·6-94·1), respectively. Studies conducted in a clinically relevant population observed lower accuracy than case-control designs (68·4% vs. 82·7%). CONCLUSIONS: Because of the numerous methodological limitations of studies, the utility of analysing K-ras mutations for the diagnosis of EPC remains unknown. Flaws in diagnostic biomarkers with well-established biological properties, as K-ras, become even more relevant when the promises of 'personalized medicine' are pondered.

Clinical validity of detecting K-ras mutations for the diagnosis of exocrine pancreatic cancer: a prospective study in a clinically-relevant spectrum of patients.

The diagnostic utility of detecting K-ras mutations for the diagnosis of exocrine pancreatic cancer (EPC) has not been properly studied, and few reports have analysed a clinically relevant spectrum of patients. The objective was to evaluate the clinical validity of detecting K-ras mutations in the diagnosis of EPC in a large sample of clinically relevant patients. We prospectively identified 374 patients in whom one of the following diagnoses was suspected at hospital admission: EPC, chronic pancreatitis, pancreatic cysts, and cancer of the extrahepatic biliary system. Mutations in the K-ras oncogene were analysed by PCR and artificial RFLP in 212 patients. The sensitivity and specificity of the K-ras mutational status for the diagnosis of EPC were 77.7% (95% CI: 69.2-84.8) and 78.0% (68.1-86.0), respectively. The diagnostic accuracy was hardly modified by sex and age. In patients with either mutated K-ras or CEA > 5 ng/ml, the sensitivity and specificity were 81.0% (72.9-87.6) and 62.6% (72.9-87.6), respectively. In patients with mutated K-ras and CEA > 5 ng/ml the sensitivity was markedly reduced. In comparisons with a variety of non-EPC patient groups sensitivity and specificity were both always greater than 75%. In this clinically relevant sample of patients the sensitivity and specificity of K-ras mutations were not sufficiently high for independent diagnostic use. However, it seems premature to rule out the utility of K-ras analysis in conjunction with other genetic and 'omics' technologies.

A Novel Sampling Model to Study the Epidemiology of Canine Leishmaniasis in an Urban Environment.

Background: Visceral leishmaniasis (VL) is one of the most important parasitic diseases in the world. The domestic dog is the main reservoir of zoonotic VL and a high prevalence of canine leishmaniasis (CanL) is associated with transmission of infection to humans. Here we describe the methodology used to obtain a rapid and representative sample of domestic dogs in the city of Posadas, Misiones, and compare the prevalence of Leishmania infection with a sample of shelter dogs. Methodology: We used the city land registry to make a random selection of homes and systematically recruited 349 domestic dogs from the selected properties. We also included all dogs from the main canine shelter within the city. Dogs were examined by two experienced veterinarians who recorded the presence of clinical signs common in CanL using a standardized protocol. We extracted a blood sample from each dog and performed four different serological tests to reveal the presence of anti-Leishmania antibodies. Results: After clinical examination, 145 domestic dogs (41.5%) and 63 (90%) shelter dogs had clinical signs compatible with CanL (p < 0.001). The seroprevalence among domestic dogs was 20.1% (95% CI 16.1-24.6) which was significantly lower than among the abandoned dogs (38.6%, 95% CI 27.7-50.6, p < 0.001). The spatial distribution of infected dogs was fairly homogenous throughout the city. Among domestic dogs, we observed a positive association between where the dog slept and presence of anti-Leishmania antibodies (p = 0.034). Of the seropositive domestic dogs 38 (54.4%) were asymptomatic. Conclusions: Our findings demonstrate how seroprevalence results can be highly influenced by sampling methodology. We demonstrate how the land registry can be used to estimate the prevalence of CanL in representative sample of domestic dogs in an urban setting, allowing decision makers to deepen their understanding the epidemiology of CanL in a timely and efficient manner for the development of plans to address both human and canine disease.

Overinterpretation of clinical applicability in molecular diagnostic research.

BACKGROUND: We evaluated whether articles on molecular diagnostic tests interpret appropriately the clinical applicability of their results. METHODS: We selected original-research articles published in 2006 that addressed the diagnostic value of a molecular test. We defined overinterpretation of clinical applicability by means of prespecified rules that evaluated study design, conclusions regarding applicability, presence of statements suggesting the need for further clinical evaluation of the test, and diagnostic accuracy. Two reviewers independently evaluated the articles; consensus was reached after discussion and arbitration by a third reviewer. RESULTS: Of 108 articles included in the study, 82 (76%) used a design that used healthy controls or alternative-diagnosis controls, only 15 (11%) addressed a clinically relevant population similar to that in which the test might be applied in practice, 104 articles (96%) made definitely favorable or promising statements regarding clinical applicability, and 61 (56%) of the articles apparently overinterpreted the clinical applicability of their findings. Articles published in journals with higher impact factors were more likely to overinterpret their results than those with lower impact factors (adjusted odds ratio, 1.71 per impact factor quartile; 95% CI, 1.09-2.69; P = 0.020). Overinterpretation was more common when authors were based in laboratories than in clinical settings (adjusted odds ratio, 18.7; 95% CI, 1.41-249; P = 0.036). CONCLUSIONS: Although expectations are high for new diagnostic tests based on molecular techniques, the majority of published research has involved preclinical phases of research. Overinterpretation of the clinical applicability of findings for new molecular diagnostic tests is common.

The determinants of lung cancer after detecting a solitary pulmonary nodule are different in men and women, for both chest radiograph and CT.

OBJECTIVES: To determine the factors associated with lung cancer diagnosis and mortality after detecting a solitary pulmonary nodule (SPN) in routine clinical practice, in men and in women for both chest radiograph and CT. MATERIALS AND METHODS: A 5-year follow-up of a retrospective cohort of of 25,422 (12,594 men, 12,827 women) patients aged ≥35 years referred for chest radiograph or CT in two hospitals in Spain (2010-2011). SPN were detected in 893 (546 men, 347 women) patients. We estimated the cumulative incidence of lung cancer at 5-years, the association of patient and nodule characteristics with SPN malignancy using Poisson logistic regression, stratifying by sex and type of imaging test. We calculated lung cancer specific mortality rate by sex and SPN detection and hazard rates by cox regression. RESULTS: 133 (14.9%) out of 893 patients with an SPN and 505 (2.06%) of the 24,529 patients without SPN were diagnosed with lung cancer. Median diameter of SPN in women who developed cancer was larger than in men. Men who had a chest radiograph were more likely to develop a lung cancer if the nodule was in the upper-lobes, which was not the case for women. In patients with an SPN, smoking increased the risk of lung cancer among men (chest radiograph: RR = 11.3, 95%CI 1.5-83.3; CT: RR = 7.5, 95%CI 2.2, 26.0) but smoking was not significantly associated with lung cancer diagnosis or mortality among women with an SPN. The relative risk of lung cancer diagnosis in women with SPN versus those without was much higher compared to men (13.7; 95%CI 9.2, 20.4 versus 6.2; 95%CI 4.9,7.9). CONCLUSION: The factors associated with SPN malignancy and 5-year lung cancer mortality were different among men and women, especially regarding smoking history and SPN characteristics, where we observed a relatively high rate of lung cancer diagnosis among female non-smokers.

Factors associated with false negative and false positive results of prostate-specific antigen (PSA) and the impact on patient health: Cohort study protocol.

INTRODUCTION: Prostate-specific antigen (PSA) is the main tool for early detection, risk stratification and monitoring of prostate cancer (PCa). However, there are controversies about the use of PSA as a population screening test because of the high potential for overdiagnosis and overtreatment associated. The net benefit of screening is unclear and according to the available recommendations, it should be offered to well-informed men with an adequate health status and a life-expectancy of at least 10 years or to men at elevated risk of having PCa. In addition, the factors that influence test results are unclear, as is impact of false positive or negative results on patient health.Our objective is to assess the clinical and analytical factors associated with the presence of false positive and false negative results and the diagnostic/therapeutic process followed by these patients. METHODS AND ANALYSIS: A prospective observational cohort study will be carried out. We will include a cohort of patients with a positive PSA result (1.081 patients) and a sample of patients with negative results (572 patients); both will be followed for 2 years by reviewing medical records to assess the variables associated with these results, as well as characteristics of patient management after a positive PSA value. We will include those patients with a PSA determination from 2 hospitals in the Valencian Community. Patients who have been previously diagnosed with prostate cancer or who are being followed for previous high PSA values will be excluded. DISCUSSION: The study will estimate the frequency of false positive and false negative PSA results in routine clinical practice, and allow us to quantify the potential harm caused. STUDY REGISTRATION: Clinicaltrials.gov (https://clinicaltrials.gov/): NCT03978299, June 7, 2019.

Neighborhood-targeted and case-triggered use of a single dose of oral cholera vaccine in an urban setting: Feasibility and vaccine coverage.

INTRODUCTION: In June 2015, a cholera outbreak was declared in Juba, South Sudan. In addition to standard outbreak control measures, oral cholera vaccine (OCV) was proposed. As sufficient doses to cover the at-risk population were unavailable, a campaign using half the standard dosing regimen (one-dose) targeted high-risk neighborhoods and groups including neighbors of suspected cases. Here we report the operational details of this first public health use of a single-dose regimen of OCV and illustrate the feasibility of conducting highly targeted vaccination campaigns in an urban area. METHODOLOGY/PRINCIPAL FINDINGS: Neighborhoods of the city were prioritized for vaccination based on cumulative attack rates, active transmission and local knowledge of known cholera risk factors. OCV was offered to all persons older than 12 months at 20 fixed sites and to select groups, including neighbors of cholera cases after the main campaign ('case-triggered' interventions), through mobile teams. Vaccination coverage was estimated by multi-stage surveys using spatial sampling techniques. 162,377 individuals received a single-dose of OCV in the targeted neighborhoods. In these neighborhoods vaccine coverage was 68.8% (95% Confidence Interval (CI), 64.0-73.7) and was highest among children ages 5-14 years (90.0%, 95% CI 85.7-94.3), with adult men being less likely to be vaccinated than adult women (Relative Risk 0.81, 95% CI: 0.68-0.96). In the case-triggered interventions, each lasting 1-2 days, coverage varied (range: 30-87%) with an average of 51.0% (95% CI 41.7-60.3). CONCLUSIONS/SIGNIFICANCE: Vaccine supply constraints and the complex realities where cholera outbreaks occur may warrant the use of flexible alternative vaccination strategies, including highly-targeted vaccination campaigns and single-dose regimens. We showed that such campaigns are feasible. Additional work is needed to understand how and when to use different strategies to best protect populations against epidemic cholera.

Adapting to the global shortage of cholera vaccines: targeted single dose cholera vaccine in response to an outbreak in South Sudan.

Shortages of vaccines for epidemic diseases, such as cholera, meningitis, and yellow fever, have become common over the past decade, hampering efforts to control outbreaks through mass reactive vaccination campaigns. Additionally, various epidemiological, political, and logistical challenges, which are poorly documented in the literature, often lead to delays in reactive campaigns, ultimately reducing the effect of vaccination. In June 2015, a cholera outbreak occurred in Juba, South Sudan, and because of the global shortage of oral cholera vaccine, authorities were unable to secure sufficient doses to vaccinate the entire at-risk population-approximately 1 million people. In this Personal View, we document the first public health use of a reduced, single-dose regimen of oral cholera vaccine, and show the details of the decision-making process and timeline. We also make recommendations to help improve reactive vaccination campaigns against cholera, and discuss the importance of new and flexible context-specific dose regimens and vaccination strategies.

Effectiveness of one dose of oral cholera vaccine in response to an outbreak: a case-cohort study.

BACKGROUND: Oral cholera vaccines represent a new effective tool to fight cholera and are licensed as two-dose regimens with 2-4 weeks between doses. Evidence from previous studies suggests that a single dose of oral cholera vaccine might provide substantial direct protection against cholera. During a cholera outbreak in May, 2015, in Juba, South Sudan, the Ministry of Health, Médecins Sans Frontières, and partners engaged in the first field deployment of a single dose of oral cholera vaccine to enhance the outbreak response. We did a vaccine effectiveness study in conjunction with this large public health intervention. METHODS: We did a case-cohort study, combining information on the vaccination status and disease outcomes from a random cohort recruited from throughout the city of Juba with that from all the cases detected. Eligible cases were those aged 1 year or older on the first day of the vaccination campaign who sought care for diarrhoea at all three cholera treatment centres and seven rehydration posts throughout Juba. Confirmed cases were suspected cases who tested positive to PCR for Vibrio cholerae O1. We estimated the short-term protection (direct and indirect) conferred by one dose of cholera vaccine (Shanchol, Shantha Biotechnics, Hyderabad, India). FINDINGS: Between Aug 9, 2015, and Sept 29, 2015, we enrolled 87 individuals with suspected cholera, and an 898-person cohort from throughout Juba. Of the 87 individuals with suspected cholera, 34 were classified as cholera positive, 52 as cholera negative, and one had indeterminate results. Of the 858 cohort members who completed a follow-up visit, none developed clinical cholera during follow-up. The unadjusted single-dose vaccine effectiveness was 80·2% (95% CI 61·5-100·0) and after adjusting for potential confounders was 87·3% (70·2-100·0). INTERPRETATION: One dose of Shanchol was effective in preventing medically attended cholera in this study. These results support the use of a single-dose strategy in outbreaks in similar epidemiological settings. FUNDING: Médecins Sans Frontières.

Cholera Rapid Test with Enrichment Step Has Diagnostic Performance Equivalent to Culture.

Cholera rapid diagnostic tests (RDT) could play a central role in outbreak detection and surveillance in low-resource settings, but their modest performance has hindered their broad adoption. The addition of an enrichment step may improve test specificity. We describe the results of a prospective diagnostic evaluation of the Crystal VC RDT (Span Diagnostics, India) with enrichment step and of culture, each compared to polymerase chain reaction (PCR), during a cholera outbreak in South Sudan. RDTs were performed on alkaline peptone water inoculated with stool and incubated for 4-6 hours at ambient temperature. Cholera culture was performed from wet filter paper inoculated with stool. Molecular detection of Vibrio cholerae O1 by PCR was done from dry Whatman 903 filter papers inoculated with stool, and from wet filter paper supernatant. In August and September 2015, 101 consecutive suspected cholera cases were enrolled, of which 36 were confirmed by PCR. The enriched RDT had 86.1% (95% CI: 70.5-95.3) sensitivity and 100% (95% CI: 94.4-100) specificity compared to PCR as the reference standard. The sensitivity of culture versus PCR was 83.3% (95% CI: 67.2-93.6) for culture performed on site and 72.2% (95% CI: 54.8-85.8) at the international reference laboratory, where samples were tested after an average delay of two months after sample collection, and specificity was 98.5% (95% CI: 91.7-100) and 100% (95% CI: 94.5-100), respectively. The RDT with enrichment showed performance comparable to that of culture and could be a sustainable alternative to culture confirmation where laboratory capacity is limited.