Multicentric evaluation of a specific intrathecal anti-Treponema pallidum IgG index as a diagnostic biomarker of neurosyphilis: results from a retro-prospective case-control study.

BACKGROUND AND OBJECTIVES: The diagnosis of neurosyphilis (NS) lacks a true 'gold standard', making the diagnosis challenging while consequences of a misdiagnosis are potentially severe. The aim of this study was to evaluate the diagnostic performance of measuring an antibody index (AI) for the intrathecal synthesis of specific anti-Treponema pallidum (T. pallidum) IgG for the diagnosis of NS. METHODS: Specific anti-T. pallidum IgG were measured simultaneously in paired cerebrospinal fluid (CSF)-serum samples collected retrospectively and prospectively between 2007 and 2022, from patients suspected of NS, in Switzerland. An AI was calculated to account for blood-brain barrier integrity. Area under the receiver operating characteristic curve, sensitivity/specificity and positive/negative predictive values of AI test were estimated. Two NS definitions were used: NS1 included patients with NS suspicion presenting with neurological symptoms and/or acute neurosensory signs, and positive T. Pallidum Hemagglutinations Assay (TPHA)/T. pallidum particle agglutination assay (TPPA) serology and CSF-TPHA/TPPA ≥320, and either CSF-leucocytes >5 cells/mm3 and/or CSF-protein >0.45 g/L and/or a reactive CSF-venereal disease research laboratory (VDRL)/rapid plasma reagin (RPR) test. NS2 included patients with suspected NS presenting with acute ocular and/or otologic symptoms, and positive TPHA/TPPA serology, and a favourable response to NS treatment. Controls were patients diagnosed with any other central nervous system (CNS) pathologies and with positive TPHA/TPPA serology. RESULTS: The study included 71 NS (43 NS1 and 28 NS2) and 110 controls. With a threshold of ≥1.7, sensitivity and specificity of the specific AI test were 90.7% (CI 77.7 to 97.4) and 100% (CI 96.7 to 100.0), respectively, for NS1 and 14.3% (CI 4 to 32.7) and 100% (CI 96.7 to 100.0) for NS2. In patients suspected of NS with a CNS involvement (NS1 group), NS could be confirmed by the positivity of this specific AI. CONCLUSIONS: Measurement of an intrathecal synthesis index of specific anti-T. pallidum IgG in patients with CSF inflammatory signs appears to be a valuable diagnostic test. However, in otic or ocular syphilis, presenting few CSF abnormalities, AI is not sufficient alone to confirm NS diagnosis. TRIAL REGISTRATION: Swiss Association of Research Ethics Committees number 2019-00232.

[PartnerREC network: Result from a process of coconstruction with patient partners and researchers]. / Réseau PartnerREC.

The PartnerREC network at the Geneva University Hospitals aims to facilitate the collaboration between researchers and patient partners in any type of clinical research, mainly those led at the HUG. It is the result of a coconstruction process initiated in 2019 by physicians, research professionals, cantonal research ethics committee members, a lawyer, and patient partners. The network implemented four initiatives: a) a website providing information to researchers and patients participating to research projects; b) personalized counseling for researchers to explore partnership opportunities in their own research projects; c) a training program related to patient partnership in research developed together with different partners in French-speaking Switzerland and d) its own research program on partnership in clinical research.

Le réseau PartnerREC des Hôpitaux universitaires de Genève a vu le jour afin de faciliter la collaboration entre les chercheur-ses et les patient-es partenaires dans tous les types de projets en recherche clinique, principalement ceux menés aux HUG. Il est le fruit d'une démarche de coconstruction débutée en 2019 par un groupe de médecins, chercheur-ses, membres de la Commission cantonale d'éthique de la recherche, une avocate et des patientes partenaires. Le réseau a mis en place 4 actions : a) la création d'un site internet destiné aux chercheur-ses et aux patient-es participant à des projets de recherche ; b) des conseils personnalisés pour accompagner les chercheur-ses dans leur démarche de partenariat ; c) une formation au partenariat en recherche, en collaboration avec des acteur-rices du partenariat en suisse romande et d) le développement de projets de recherche propres sur le partenariat patient-e en recherche.

[Sex and gender issues in the organisation of tomorrow's medicine]. / Enjeux de sexe et de genre dans l'organisation de la médecine de demain.

Medicine is evolving with increasing feminization and the rise of part-time work. Women now outnumber men among graduates but are underrepresented in leadership roles and in the highest-paid specialties. To meet these economic and organisational challenges, this article proposes a number of courses of action. In addition to an overall increase in the number of medical training places to compensate for retirement and the development of interprofessional integrated care structures, support for academic promotion and management positions for women, as well as an increase in the financial value of professional and non-remunerated activities, are all solutions to be considered. These changes will ensure that medicine is inclusive, efficient and of high quality.

La médecine évolue avec une féminisation croissante et l'émergence de nouveaux modes de travail. Les femmes sont majoritaires parmi les diplômé-es mais sous-représentées aux postes de cadres et dans les spécialités à plus haut revenus. Pour répondre à ces défis économiques et organisationnels, cet article propose des pistes d'actions. En plus d'une augmentation globale des places de formation médicale pour pallier les départs en retraite et du développement de structures interprofessionnelles de soins intégrés, un soutien aux promotions académiques et aux positions de cadres pour les femmes ainsi qu'une revalorisation financière des activités professionnelles et non rémunérées sont autant de solutions à envisager. Ces changements assureront une médecine inclusive, de plus grande efficience et de qualité.

In health research publications, the number of authors is strongly associated with collective self-citations but less so with citations by others.

OBJECTIVE: . This study investigated the associations between the number of authors and collective self-citations versus citations by others. STUDY DESIGN AND SETTING: . We analyzed 88,594 health science articles published in 2015 and citations they received until 2020. The main variables were the number of authors, the number of citations by co-authors (collective self-citations), and the number of citations by others. RESULTS: . The number of authors correlated more strongly with the number of citations by co-authors than with citations by others (Spearman r 0.31 vs. 0.23; mutually adjusted r 0.26 vs. 0.12). The percentage of self-citations among all citations was 10.6% for single-authored articles, and increased gradually with the number of authors to 34.8% for ≥ 50 authors. Collective self-citations increased the proportion of articles reaching or exceeding 30 total citations by 0.7% for single-authored articles, but by 11.6% for articles written by ≥ 50 authors. CONCLUSIONS: . If citations by others reflect scientific utility, then another mechanism must explain the excess of collective self-citations observed for multi-authored articles. The results support the hypothesis that the authors' own motivations explain this excess. The evaluation of scientific utility should also be based on citations by others, excluding collective self-citations.

Evidence of Lack of Treatment Efficacy Derived From Statistically Nonsignificant Results of Randomized Clinical Trials.

Importance: Many randomized clinical trials yield statistically nonsignificant results. Such results are difficult to interpret within the dominant statistical framework. Objective: To estimate the strength of evidence in favor of the null hypothesis of no effect vs the prespecified effectiveness hypothesis among nonsignificant primary outcome results of randomized clinical trials by application of the likelihood ratio. Design, Setting, and Participants: Cross-sectional study of statistically nonsignificant results for primary outcomes of randomized clinical trials published in 6 leading general medical journals in 2021. Outcome measures: The likelihood ratio for the null hypothesis of no effect vs the effectiveness hypothesis stated in the trial protocol (alternate hypothesis). The likelihood ratio quantifies the support that the data provide to one hypothesis vs the other. Results: In 130 articles that reported 169 statistically nonsignificant results for primary outcomes, 15 results (8.9%) favored the alternate hypothesis (likelihood ratio, <1), and 154 (91.1%) favored the null hypothesis of no effect (likelihood ratio, >1). For 117 (69.2%), the likelihood ratio exceeded 10; for 88 (52.1%), it exceeded 100; and for 50 (29.6%), it exceeded 1000. Likelihood ratios were only weakly correlated with P values (Spearman r, 0.16; P = .045). Conclusions: A large proportion of statistically nonsignificant primary outcome results of randomized clinical trials provided strong support for the hypothesis of no effect vs the alternate hypothesis of clinical efficacy stated a priori. Reporting the likelihood ratio may improve the interpretation of clinical trials, particularly when observed differences in the primary outcome are statistically nonsignificant.

The strategic biomarker roadmap for the validation of Alzheimer's diagnostic biomarkers: methodological update.

BACKGROUND: The 2017 Alzheimer's disease (AD) Strategic Biomarker Roadmap (SBR) structured the validation of AD diagnostic biomarkers into 5 phases, systematically assessing analytical validity (Phases 1-2), clinical validity (Phases 3-4), and clinical utility (Phase 5) through primary and secondary Aims. This framework allows to map knowledge gaps and research priorities, accelerating the route towards clinical implementation. Within an initiative aimed to assess the development of biomarkers of tau pathology, we revised this methodology consistently with progress in AD research. METHODS: We critically appraised the adequacy of the 2017 Biomarker Roadmap within current diagnostic frameworks, discussed updates at a workshop convening the Alzheimer's Association and 8 leading AD biomarker research groups, and detailed the methods to allow consistent assessment of aims achievement for tau and other AD diagnostic biomarkers. RESULTS: The 2020 update applies to all AD diagnostic biomarkers. In Phases 2-3, we admitted a greater variety of study designs (e.g., cross-sectional in addition to longitudinal) and reference standards (e.g., biomarker confirmation in addition to clinical progression) based on construct (in addition to criterion) validity. We structured a systematic data extraction to enable transparent and formal evidence assessment procedures. Finally, we have clarified issues that need to be addressed to generate data eligible to evidence-to-decision procedures. DISCUSSION: This revision allows for more versatile and precise assessment of existing evidence, keeps up with theoretical developments, and helps clinical researchers in producing evidence suitable for evidence-to-decision procedures. Compliance with this methodology is essential to implement AD biomarkers efficiently in clinical research and diagnostics.

A cross-sectional study on pelvic floor symptoms in women living with Female Genital Mutilation/Cutting.

BACKGROUND: Female Genital Mutilation/Cutting (FGM/C) concerns over 200 million women and girls worldwide and is associated with obstetric trauma and long-term urogynaecological and psychosexual complications that are often under-investigated and undertreated. The aim of this study was to assess the pelvic floor distress and the impact of pelvic floor and psychosexual symptoms among migrant women with different types of FGM/C. METHODS: This cross-sectional study was conducted between April 2016 and January 2019 at the Division of Gynaecology of the Geneva University Hospitals. The participants were interviewed on socio-demographic and background information, underwent a systematic gynaecological examination to assess the presence and type of FGM/C and eventual Pelvic Organ Prolapse (POP), and completed six validated questionnaires on pelvic floor and psychosexual symptoms (PFDI-20 and PFIQ7 on pelvic floor distress and impact, FISI and WCS on faecal incontinence and constipation, PISQ-IR and FGSIS on sexual function and genital self-image). The participants' scores were compared with scores of uncut women available from the literature. The association between selected variables and higher scores for distress and impact of pelvic floor symptoms was assessed using univariate and multivariable linear regression models. RESULTS: 124 women with a mean age of 31.5 (± 7.5), mostly with a normal BMI, and with no significant POP were included. PFDI-20 and PFIQ-7 mean (± SD) scores were of 49.5 (± 52.0) and 40.7 (± 53.6) respectively. In comparison with the available literature, the participants' scores were lower than those of uncut women with pelvic floor dysfunction but higher than those of uncut women without such disorders. Past violent events other than FGM/C and forced or arranged marriage, age at FGM/C of more than 10, a period of staying in Switzerland of less than 6 months, and nulliparity were significantly associated with higher scores for distress and impact of pelvic floor symptoms, independently of known risk factors such as age, weight, ongoing pregnancy and history of episiotomy. CONCLUSIONS: Women with various types of FGM/C, without POP, can suffer from pelvic floor symptoms responsible for distress and impact on their daily life. TRIAL REGISTRATION: The study protocol was approved by the Swiss Ethics Committee on research involving humans (protocol n°15-224).

Hyperbaric Oxygen Therapy with Iloprost Improves Digit Salvage in Severe Frostbite Compared to Iloprost Alone.

Background and Objectives: Frostbite is a freezing injury that can lead to amputation. Current treatments include tissue rewarming followed by thrombolytic or vasodilators. Hyperbaric oxygen (HBO) therapy might decrease the rate of amputation by increasing cellular oxygen availability to the damaged tissues. The SOS-Frostbite study was implemented in a cross-border program among the hyperbaric centers of Geneva, Lyon, and the Mont-Blanc hospitals. The objective was to assess the efficacy of HBO + iloprost among patients with severe frostbite. Materials and Methods: We conducted a multicenter prospective single-arm study from 2013 to 2019. All patients received early HBO in addition to standard care with iloprost. Outcomes were compared to a historical cohort in which all patients received iloprost alone between 2000 and 2012. Inclusion criteria were stage 3 or 4 frostbite and initiation of medical care <72 h from frostbite injury. Outcomes were the number of preserved segments and the rate of amputated segments. Results: Thirty patients from the historical cohort were eligible and satisfied the inclusion criteria, and 28 patients were prospectively included. The number of preserved segments per patient was significantly higher in the prospective cohort (mean 13 ± SD, 10) compared to the historical group (6 ± 5, p = 0.006); the odds ratio was significantly higher by 45-fold (95%CI: 6-335, p < 0.001) in the prospective cohort compared to the historical cohort after adjustment for age and delay between signs of freezing and treatment start. Conclusions: This study demonstrates that the combination of HBO and iloprost was associated with higher benefit in patients with severe frostbite. The number of preserved segments was two-fold higher in the prospective cohort compared to the historical group (mean of 13 preserved segments vs. 6), and the reduction of amputation was greater in patients treated by HBO + iloprost compared with the iloprost only.

[Covid-19: how the pandemic revealed gender inequalities]. / Covid-19 : dans le genre on peut faire mieux !

The SARS-CoV-2 pandemic has revealed inequalities between men and women and has deepened some existing disparities. While in Switzerland, more women than men have been infected, men have been at greater risk of developing complications and dying. A weaker immune response and more co-morbidities help to explain this poorer prognosis. Socially and economically, women have become more precarious as a result of less stable employment and greater involvement in domestic work. Domestic violence has increased and women's access to sexual and reproductive health services has become more difficult. Finally, women have been under-represented as research authors but also among experts in task forces and media.

La pandémie liée au SARS-CoV-2 a révélé des inégalités entre les hommes et les femmes et a creusé certaines disparités existantes. Si en Suisse les femmes sont plus nombreuses à avoir été infectées que les hommes, ces derniers ont eu un plus grand risque de décéder. Une réponse immunitaire moins performante et davantage de comorbidités contribuent à expliquer ce pronostic défavorable. Sur le plan social et économique, les femmes ont été davantage précarisées du fait d'emplois moins stables et d'une plus grande implication dans les tâches domestiques. La violence domestique a augmenté et l'accès des femmes aux services de santé sexuelle et reproductive a été plus difficile. Finalement, les femmes ont été sous-représentées comme autrices dans la recherche mais également parmi les expert·e·s dans les task forces et les médias.

Study design factors influencing patients' willingness to participate in clinical research: a randomised vignette-based study.

BACKGROUND: High patient participation in clinical research reduces selection bias and ensures the generalizability of study findings. We explored study-related factors that may influence patients' willingness to participate in research. METHODS: We submitted by mail two vignettes that described clinical research studies - a drug trial and a diagnostic study - to patients recently discharged from hospital and assessed their willingness to participate. We used a factorial design to randomly allocate three study attributes per vignette: in the drug trial, presumed superiority of new drug versus equipoise, public versus industry funding, and random versus non-random treatment allocation; in the diagnostic study, common versus rare disease, genetic versus protein analysis, and automatic reporting of results versus reporting on request. RESULTS: Of 2600 patients contacted, 1140 (44%) participated. Globally, willingness to participate in a drug trial was lower than in a diagnostic study (44.8% vs. 76.2%; P < 0.001). In the drug trial, participation was significantly higher when the new drug was presented as presumably better than the old (vs. equipoise) and when the study was funded by public sources (vs. industry), but was not affected by the allocation method. None of the factors tested in the diagnostic study was associated with participation. CONCLUSIONS: Patients were more likely to participate in a hypothetical observational diagnostic study than in a hypothetical drug trial. Participation in the trial was lower when clinical equipoise was expressed and when the trial was funded by industry. These results suggest that some features of study design can influence participation.

Correction to: Alternative graphical displays for the monitoring of epidemic outbreaks, with application to COVID-19 mortality.

An amendment to this paper has been published and can be accessed via the original article.

Alternative graphical displays for the monitoring of epidemic outbreaks, with application to COVID-19 mortality.

BACKGROUND: Classic epidemic curves - counts of daily events or cumulative events over time -emphasise temporal changes in the growth or size of epidemic outbreaks. Like any graph, these curves have limitations: they are impractical for comparisons of large and small outbreaks or of asynchronous outbreaks, and they do not display the relative growth rate of the epidemic. Our aim was to propose two additional graphical displays for the monitoring of epidemic outbreaks that overcome these limitations. METHODS: The first graph shows the growth of the epidemic as a function of its size; specifically, the logarithm of new cases on a given day, N(t), is plotted against the logarithm of cumulative cases C(t). Logarithm transformations facilitate comparisons of outbreaks of different sizes, and the lack of a time scale overcomes the need to establish a starting time for each outbreak. Notably, on this graph, exponential growth corresponds to a straight line with a slope equal to one. The second graph represents the logarithm of the relative rate of growth of the epidemic over time; specifically, log10(N(t)/C(t-1)) is plotted against time (t) since the 25th event. We applied these methods to daily death counts attributed to COVID-19 in selected countries, reported up to June 5, 2020. RESULTS: In most countries, the log(N) over log(C) plots showed initially a near-linear increase in COVID-19 deaths, followed by a sharp downturn. They enabled comparisons of small and large outbreaks (e.g., Switzerland vs UK), and identified outbreaks that were still growing at near-exponential rates (e.g., Brazil or India). The plots of log10(N(t)/C(t-1)) over time showed a near-linear decrease (on a log scale) of the relative growth rate of most COVID-19 epidemics, and identified countries in which this decrease failed to set in in the early weeks (e.g., USA) or abated late in the outbreak (e.g., Portugal or Russia). CONCLUSIONS: The plot of log(N) over log(C) displays simultaneously the growth and size of an epidemic, and allows easy identification of exponential growth. The plot of the logarithm of the relative growth rate over time highlights an essential parameter of epidemic outbreaks.

Effect of tranexamic acid by baseline risk of death in acute bleeding patients: a meta-analysis of individual patient-level data from 28 333 patients.

BACKGROUND: Early administration of the antifibrinolytic drug tranexamic acid reduces death from bleeding in trauma and postpartum haemorrhage. We examined how the effectiveness and safety of antifibrinolytic drugs varies by the baseline risk of death as a result of bleeding. METHODS: We performed an individual patient-level data meta-analysis of randomised trials including more than 1000 patients that assessed antifibrinolytics in acute severe bleeding. We identified trials performed between January 1, 1946 and July 5, 2018 (PROSPERO, number 42016052155). RESULTS: Two randomised trials were selected where 28 333 patients received tranexamic acid treatment within 3 h after the onset of acute bleeding. Baseline characteristics to estimate the risk of death as a result of bleeding were divided into four categories: Low (0-5%), intermediate (6-10%), high (11-20%), and very high (>20%). Most patients had a low baseline risk of death as a result of bleeding (23 008 [81%]). Deaths as a result of bleeding occurred in all baseline risk categories with 240 (1%), 202 (8%), 232 (14%), and 357 (30%) deaths in the low-, intermediate-, high-, and very high-risk categories, respectively. The effectiveness of tranexamic acid did not vary by baseline risk when given within 3 h after bleeding onset (P=0.51 for interaction term). There was no increased risk of vascular occlusive events with tranexamic acid and it did not vary by baseline risk categories (P=0.25). CONCLUSIONS: Tranexamic acid appears to be safe and effective regardless of baseline risk of death. Because many deaths are in patients at low and intermediate risk, tranexamic acid use should not be restricted to the most severely injured or bleeding patients.

Effect of C-Reactive Protein-Guided Antibiotic Treatment Duration, 7-Day Treatment, or 14-Day Treatment on 30-Day Clinical Failure Rate in Patients With Uncomplicated Gram-Negative Bacteremia: A Randomized Clinical Trial.

Importance: Antibiotic overuse drives antibiotic resistance. Gram-negative bacteremia is a common infection that results in substantial antibiotic use. Objective: To compare the clinical effectiveness of C-reactive protein (CRP)-guided, 7-day, and 14-day antibiotic durations 30, 60, and 90 days after treatment initiation. Design, Setting, and Participants: Multicenter, noninferiority, point-of-care randomized clinical trial including adults hospitalized with gram-negative bacteremia conducted in 3 Swiss tertiary care hospitals between April 2017 and May 2019, with follow-up until August 2019. Patients and physicians were blinded between randomization and antibiotic discontinuation. Adults (aged ≥18 years) were eligible for randomization on day 5 (±1 d) of microbiologically efficacious therapy for fermenting, gram-negative bacteria in blood culture(s) if they were afebrile for 24 hours without evidence for complicated infection (eg, abscess) or severe immunosuppression. Intervention: Randomization in a 1:1:1 ratio to an individualized CRP-guided antibiotic treatment duration (discontinuation once CRP declined by 75% from peak; n = 170), fixed 7-day treatment duration (n = 169), or fixed 14-day treatment duration (n = 165). Main Outcomes and Measures: The primary outcome was the clinical failure rate at day 30, defined as the presence of at least 1 of the following, with a non-inferiority margin of 10%: recurrent bacteremia, local suppurative complication, distant complication (growth of the same organism causing the initial bacteremia), restarting gram-negative-directed antibiotic therapy due to clinical worsening suspected to be due to the initial organism, or death due to any cause. Secondary outcomes included the clinical failure rate on day 90 of follow-up. Results: Among 504 patients randomized (median [interquartile range] age, 79 [68-86] years; 306 of 503 [61%] were women), 493 (98%) completed 30-day follow-up and 448 (89%) completed 90-day follow-up. Median antibiotic duration in the CRP group was 7 (interquartile range, 6-10; range, 5-28) days; 34 of the 164 patients (21%) who completed the 30-day follow-up had protocol violations related to treatment assignment. The primary outcome occurred in 4 of 164 (2.4%) patients in the CRP group, 11 of 166 (6.6%) in the 7-day group, and 9 of 163 (5.5%) in the 14-day group (difference in CRP vs 14-day group, -3.1% [1-sided 97.5% CI, -∞ to 1.1]; P < .001; difference in 7-day vs 14-day group, 1.1% [1-sided 97.5% CI, -∞ to 6.3]; P < .001). By day 90, clinical failure occurred in 10 of 143 patients (7.0%) in the CRP group, 16 of 151 (10.6%) in the 7-day group, and 16 of 153 (10.5%) in the 14-day group. Conclusions and Relevance: Among adults with uncomplicated gram-negative bacteremia, 30-day rates of clinical failure for CRP-guided antibiotic treatment duration and fixed 7-day treatment were noninferior to fixed 14-day treatment. However, interpretation is limited by the large noninferiority margin compared with the low observed event rate, as well as low adherence and wide range of treatment durations in the CRP-guided group. Trial Registration: ClinicalTrials.gov Identifier: NCT03101072.

Effect of treatment delay on the effectiveness and safety of antifibrinolytics in acute severe haemorrhage: a meta-analysis of individual patient-level data from 40 138 bleeding patients.

BACKGROUND: Antifibrinolytics reduce death from bleeding in trauma and post-partum haemorrhage. We examined the effect of treatment delay on the effectiveness of antifibrinolytics. METHODS: We did an individual patient-level data meta-analysis of randomised trials done with more than 1000 patients that assessed antifibrinolytics in acute severe bleeding. We identified trials done between Jan 1, 1946, and April 7, 2017, from MEDLINE, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, PubMed, Popline, and the WHO International Clinical Trials Registry Platform. The primary measure of treatment benefit was absence of death from bleeding. We examined the effect of treatment delay on treatment effectiveness using logistic regression models. We investigated the effect of measurement error (misclassification) in sensitivity analyses. This study is registered with PROSPERO, number 42016052155. FINDINGS: We obtained data for 40 138 patients from two randomised trials of tranexamic acid in acute severe bleeding (traumatic and post-partum haemorrhage). Overall, there were 3558 deaths, of which 1408 (40%) were from bleeding. Most (884 [63%] of 1408) bleeding deaths occurred within 12 h of onset. Deaths from post-partum haemorrhage peaked 2-3 h after childbirth. Tranexamic acid significantly increased overall survival from bleeding (odds ratio [OR] 1·20, 95% CI 1·08-1·33; p=0·001), with no heterogeneity by site of bleeding (interaction p=0·7243). Treatment delay reduced the treatment benefit (p<0·0001). Immediate treatment improved survival by more than 70% (OR 1·72, 95% CI 1·42-2·10; p<0·0001). Thereafter, the survival benefit decreased by 10% for every 15 min of treatment delay until 3 h, after which there was no benefit. There was no increase in vascular occlusive events with tranexamic acid, with no heterogeneity by site of bleeding (p=0·5956). Treatment delay did not modify the effect of tranexamic acid on vascular occlusive events. INTERPRETATION: Death from bleeding occurs soon after onset and even a short delay in treatment reduces the benefit of tranexamic acid administration. Patients must be treated immediately. Further research is needed to deepen our understanding of the mechanism of action of tranexamic acid. FUNDING: UK NIHR Health Technology Assessment programme, Pfizer, BUPA Foundation, and J P Moulton Charitable Foundation (CRASH-2 trial). London School of Hygiene & Tropical Medicine, Pfizer, UK Department of Health, Wellcome Trust, and Bill & Melinda Gates Foundation (WOMAN trial).

Risk factors for recurrence of periodontal disease in patients in maintenance care in a private practice.

AIM: To assess periodontal and dental conditions in individuals in maintenance care after periodontal therapy in private practice, and to identify risk factors for recurrence of disease and tooth loss. MATERIALS AND METHODS: One hundred patients attending a routine recall visit were included. All had been treated for periodontal disease and were in maintenance since ≥ 2 years. RESULTS: Examinations took place 18.0 (±8.71) years after the start of periodontal therapy. A total of 40.1 ± 22.5 recall visits were registered during this time. 91% of the participants had an initial diagnosis of chronic, 9% of aggressive periodontitis. The average participant was 46 years old and had 26 teeth. 283 of 2,549 initially present teeth were lost, half of them being molars. Periodontal and endo-periodontal complications accounted for only 16 lost teeth. The prevalence of all probing depth (PD) categories decreased significantly. The longer the time, the more frequent the recall visits, and the more was spent during the maintenance phase, the greater was the reduction. Multivariate analysis rendered BMI and smoking as factors influencing number of sites with PD ≥ 4 mm and bleeding on probing. CONCLUSION: Tooth loss and periodontal tissue damage can be contained over prolonged periods if periodontal disease is treated and patients attend regular maintenance care.

Impact of the new guidelines on the management of premature rupture of membranes for the prevention of late preterm birth: an 11-year retrospective study.

Objectives To evaluate the number of late preterm (LPT) births (between 34 0/7 and 36 6/7 weeks) that could have been prevented if expectant management of preterm premature rupture of membranes (PPROM) had been applied according to new recommendations. Methods A retrospective cohort study included all births at one Swiss center between January 1, 2002 and December 31, 2012. Births were categorized using an adapted evidence-based classification. Two scenarios were considered: best scenario (maximum averted cases) and a conservative scenario (minimum averted cases). Results Among 2017 LPT births (5.0% of all deliveries; n=40,609), 1122 (60.6%) women had PPROM. Spontaneous labor occurred in 473 (42.2%) cases and 649 (57.8%) had induction of labor or an elective cesarean section. In the latter group, 44 (6.8%) had evidence-based indications for LPT delivery and 605 (83.2%) had non-evidence-based indications. Depending on the scenario, the rate of avoided LPT cases would have varied between 4.2% (95% confidence interval [CI]: 3.4-5.2) if the conservative scenario was applied, and 30% (95% CI: 28.0-32.0) for the best scenario. Conclusion Adoption of new guidelines for the management of PPROM will prevent a considerable number of LPT births and help decrease the adverse effects and potential disability associated with late preterm infants.