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Introduction: Epithelioid hemangioendothelioma (EHE) is an ultra-rare sarcoma, marked by distinctive molecular and pathological features and with a variable clinical behavior. Its natural history is still partially understood, reliable prognostic and predictive factors are lacking and many questions are still open on the optimal management. In the context of EURACAN, a prospective registry specifically dedicated to EHE was developed and launched with the aim of providing, through high-quality prospective data collection, a better understanding of this disease. Study design: Registry-based cohort study including only new cases of patients with a pathological and molecularly confirmed diagnosis of EHE Objectives: To improve the understanding of EHE natural history, validate and identify new prognostic and predictive factors, clarify the activity and efficacy of currently available treatment options, describe treatment pattern. Methods: Settings and participants: It is an hospital-based registry established in centers with expertise in EHE including adult patients with a new pathological and molecularly confirmed diagnosis of EHE starting from the 1st December 2023. The characteristics of each patient in the facility who meets the above-mentioned inclusion criteria will be collected prospectively and longitudinally with follow-up at cancer progression and / or cancer relapse or patient death. It is a secondary use of data which will be collected from the clinical records. The data collected for the registry will not entail further examinations or admissions to the facility and/or additional appointments to those normally provided for routine patient follow-up. Variables: Full details on patients and disease features, treatment and outcome will be collected, according to common clinical practice guidelines developed and shared with all the contributing centers. In addition, data on potential confounders (e.g. comorbidity; functional status etc.) will also be collected. Statistical methods: The data analyses will include descriptive statistics and analytical analyses. Multivariable Cox's proportional hazards model and Hazard ratios (HR) for all-cause or cause-specific mortality will be used to determine independent predictors of overall survival, recurrence and progression. Results: The registry has been joined by 21 sarcoma reference centers across EU and UK, covering 10 countries. Patients' recruitment started in December 2023. The estimated completion date is December 2033 upon agreement on the achievement of all the registry objectives. The already established collaboration and participation of EHE patient's associations involved in the project will help in promoting the registry and fostering accrual. [ABSTRACT FROM AUTHOR]

Objectives: Recurrence following recommended treatment for bacterial vaginosis is unacceptably high. While the pathogenesis of recurrence is not well understood, recent evidence indicates re-infection from sexual partners is likely to play a role. The aim of this study was to assess the acceptability and tolerability of topical and oral antimicrobial therapy in male partners of women with bacterial vaginosis (BV), and to investigate the impact of dual-partner treatment on the vaginal and penile microbiota. Methods: Women with symptomatic BV (Nugent Score of 4–10 and ≥3 Amsel criteria) and their regular male sexual partner were recruited from Melbourne Sexual Health Centre, Melbourne, Australia. Women received oral metronidazole 400mg twice daily (or intra-vaginal 2% clindamycin cream, if contraindicated) for 7-days. Male partners received oral metronidazole 400mg twice daily and 2% clindamycin cream topically to the penile skin twice daily for 7-days. Couples provided self-collected genital specimens and completed questionnaires at enrolment and then weekly for 4-weeks. Genital microbiota composition was determined by 16S rRNA gene sequencing. Changes in genital microbiota composition were assessed by Bray-Curtis index. Bacterial diversity was measured by the Shannon Diversity Index. Results: Twenty-two couples were recruited. Sixteen couples (76%) completed all study procedures. Adherence was high; most participants took >90% of prescribed medication. Medication, and particularly topical clindamycin in males, was well tolerated. Dual-partner treatment had an immediate and sustained effect on the composition of vaginal microbiota (median Bray-Curtis score day 0 versus day 8 = 0.03 [IQR 0–0.15], day 0 vs day 28 = 0.03 [0.02–0.11]). We observed a reduction in bacterial diversity of the vaginal microbiota and a decrease in the prevalence and abundance of BV-associated bacteria following treatment. Treatment had an immediate effect on the composition of the cutaneous penile microbiota (median Bray-Curtis score day 0 vs day 8 = 0.09 [0.04–0.17]), however this was not as pronounced at day 28 (median Bray-Curtis score day 0 vs day 28 = 0.38 [0.11–0.59]). A decrease in the prevalence and abundance of BV-associated bacteria in the cutaneous penile microbiota was observed immediately following treatment at day 8. Conclusion: Combined oral and topical treatment of male partners of women with BV is acceptable and well tolerated. The combined acceptability and microbiological data presented in this paper supports the need for larger studies with longer follow up to characterize the sustained effect of dual partner treatment on the genital microbiota of couples and assess the impact on BV recurrence. [ABSTRACT FROM AUTHOR]

Introduction: High grade astrocytic glioma (HGG) is a lethal solid malignancy with high recurrence rates and limited survival. While several cytotoxic agents have demonstrated efficacy against HGG, drug sensitivity testing platforms to aid in therapy selection are lacking. Patient-derived organoids (PDOs) have been shown to faithfully preserve the biological characteristics of several cancer types including HGG, and coupled with the experimental-analytical hybrid platform Quadratic Phenotypic Optimization Platform (QPOP) which evaluates therapeutic sensitivity at a patient-specific level, may aid as a tool for personalized medical decisions to improve treatment outcomes for HGG patients. Methods: This is an interventional, non-randomized, open-label study, which aims to enroll 10 patients who will receive QPOP-guided chemotherapy at the time of first HGG recurrence following progression on standard first-line therapy. At the initial presentation of HGG, tumor will be harvested for primary PDO generation during the first biopsy/surgery. At the point of tumor recurrence, patients will be enrolled onto the main study to receive systemic therapy as second-line treatment. Subjects who undergo surgery at the time of recurrence will have a second harvest of tissue for PDO generation. Established PDOs will be subject to QPOP analyses to determine their therapeutic sensitivities to specific panels of drugs. A QPOP-guided treatment selection algorithm will then be used to select the most appropriate drug combination. The primary endpoint of the study is six-month progression-free survival. The secondary endpoints include twelve-month overall survival, RANO criteria and toxicities. In our radiological biomarker sub-study, we plan to evaluate novel radiopharmaceutical-based neuroimaging in determining blood-brain barrier permeability and to assess in vivo drug effects on tumor vasculature over time. Trial registration: This trial was registered on 8th September 2022 with ClinicalTrials.gov Identifier: NCT05532397. [ABSTRACT FROM AUTHOR]

Background: Visceral Leishmaniasis (VL) is a neglected tropical disease (NTD) with the highest regional burden in East Africa. Relapse and Post Kala-azar Dermal Leishmaniasis (PKDL) contribute to the spread of VL in endemic areas, making their surveillance imperative for control and elimination. Little is known about long-term patient outcomes in Kenya through follow-up after VL treatment, despite its requirement for control and elimination by the World Health Organization (WHO) and the Kenya Ministry of Health (KMOH). Methodology/Principal findings: 36 follow-up patients in Tiaty East and West, sub-counties, Kenya, and records from 248 patients at the regional Chemolingot Sub-county Hospital (CSCH) were analyzed separately using Fisher's Exact Tests, two-sample t-tests, and Welch's t-tests in R (Version 4.3.0). The study found a prevalence rate of 88.89% (n = 32) final cure, 5.56% (n = 2) relapse, and 5.56% (n = 2) PKDL in follow-up patients and 92.74% (n = 230) initial cure, 6.86% (n = 17) relapse, and 0.80% (n = 2) PKDL in overall CSCH patients. The mean lengths of time at which follow-up patients relapsed and developed PKDL were 4.5 and 17 months, respectively. Young age (p = 0.04, 95% CI 0.63–24.31), shorter length of time from initial treatment to follow-up (p = 0.002, 95% CI 1.03-∞), lower Hb level at primary treatment (p = 0.0002, 95% CI 1.23–3.24), and living in Tiaty East sub-county (p = 0.04, 95% CI 0.00–1.43) were significantly associated (p<0.05) with VL relapse in follow-up study patients. Female sex (p = 0.04, 95% CI 0.84-∞) and living in Tiaty East sub-county (p = 0.03, 95% CI 0.00–1.43) were significantly associated with PKDL in follow-up study patients. Conclusions/Significance: More research should be done on PKDL in Kenya with active follow-up to understand its true burden. These results on prevalence and risk factors for PKDL and relapse in Kenya should inform knowledge of patient outcomes and interventions in the region. [ABSTRACT FROM AUTHOR]

Since the emergence of the pandemic H1N1pdm09 virus in Mexico and California, biannual increases in the number of cases have been detected in Mexico. As observed in previous seasons, pandemic A/H1N1 09 virus was detected in severe cases during the 2011–2012 winter season and finally, during the 2013–2014 winter season it became the most prevalent influenza virus. Molecular and phylogenetic analyses of the whole viral genome are necessary to determine the antigenic and pathogenic characteristics of influenza viruses that cause severe outcomes of the disease. In this paper, we analyzed the evolution, antigenic and genetic drift of Mexican isolates from 2009, at the beginning of the pandemic, to 2014. We found a clear variation of the virus in Mexico from the 2011–2014 season due to different markers and in accordance with previous reports. In this study, we identified 13 novel substitutions with important biological effects, including virulence, T cell epitope presented by MHC and host specificity shift and some others substitutions might have more than one biological function. The systematic monitoring of mutations on whole genome of influenza A pH1N1 (2009) virus circulating at INER in Mexico City might provide valuable information to predict the emergence of new pathogenic influenza virus [ABSTRACT FROM AUTHOR]

Objectives: The paper aimed to estimate the incremental cost-effectiveness ratio (ICER) at the public published price for delayed-release dimethyl fumarate versus relevant Multiple Sclerosis disease-modifying therapies available in France in June 2015. Methods: The economic model was adapted to the French setting in accordance with the Haute Autorité de Santé guidelines using a model previously developed for NICE. A cohort of Relapsing Remitting Multiple Sclerosis patients was simulated over a 30-year time horizon. Twenty one health states were taken into account: Kurtzke Expanded Disability Status Scale (EDSS) 0–9 for Relapsing Remitting Multiple Sclerosis patients, EDSS 0–9 for Secondary Progressive Multiple Sclerosis patients, and death. Estimates of relative treatment efficacy were determined using a mixed-treatment comparison. Probabilities of events were derived from the dimethyl fumarate pivotal clinical trials and the London Ontario Dataset. Costs and utilities were extracted from the published literature from both the payer and societal perspectives. Univariate and probabilistic sensitivity analyses were performed to assess the robustness of the model results. Results: From both perspectives, dimethyl fumarate and interferon beta-1a (IFN beta-1a) 44mcg were the two optimal treatments, as the other treatments (IFN beta-1a 30mcg, IFN beta-1b 250mcg, teriflunomide, glatiramer acetate, fingolimod) were dominated on the efficiency frontier. From the societal perspective, dimethyl fumarate versus IFN beta-1a 44mcg incurred an incremental cost of €3,684 and an incremental quality-adjusted life year (QALY) of 0.281, corresponding to an ICER of €13,110/QALY. Conclusions: Despite no reference threshold for France, dimethyl fumarate can be considered as a cost-effective option as it is on the efficiency frontier. [ABSTRACT FROM AUTHOR]

Indigenous Australians experience a high rate of ear disease and hearing loss, yet they have a lower rate of service access and utilisation compared to their non-Indigenous counterparts. Screening, surveillance and timely access to specialist ear, nose and throat (ENT) services are key components in detecting and preventing the recurrence of ear diseases. To address the low access and utilisation rate by Indigenous Australians, a collaborative, community-based mobile telemedicine-enabled screening and surveillance (MTESS) service was trialled in Cherbourg, the third largest Indigenous community in Queensland, Australia. This paper aims to evaluate the cost-effectiveness of the MTESS service using a lifetime Markov model that compares two options: (i) the Deadly Ears Program alone (current practice involving an outreach ENT surgical service and screening program), and (ii) the Deadly Ears Program supplemented with the MTESS service. Data were obtained from the Deadly Ears Program, a feasibility study of the MTESS service and the literature. Incremental cost-utility ratios were calculated from a societal perspective with both costs (in 2013–14 Australian dollars) and quality-adjusted life years (QALYs) discounted at 5% annually. The model showed that compared with the Deadly Ears Program, the probability of an acceptable cost-utility ratio at a willingness-to-pay threshold of $50,000/QALY was 98% for the MTESS service. This cost effectiveness arises from preventing hearing loss in the Indigenous population and the subsequent reduction in associated costs. Deterministic and probability sensitivity analyses indicated that the model was robust to parameter changes. We concluded that the MTESS service is a cost-effective strategy. It presents an opportunity to resolve major issues confronting Australia’s health system such as the inequitable provision and access to quality healthcare for rural and remotes communities, and for Indigenous Australians. Additionally, it may encourage effective health service delivery at a time when the healthcare funding and workforce capacity are limited. [ABSTRACT FROM AUTHOR]

The most common cause of breast cancer-related death is tumor recurrence. To develop more effective treatments, the identification of cancer cell specific malignancy indicators is therefore critical. Lipid droplets are known as an emerging hallmark in aggressive breast tumors. A common technique that can be used for observing molecules in cancer microenvironment is fluorescence microscopy. We describe the design, development and applicability of a smart fluorometer to detect lipid droplet accumulation based on the emitted fluorescence signals from highly malignant (MDA-MB-231) and mildly malignant (MCF7) breast cancer cell lines, that are stained with BODIPY dye. This device uses a visible-range light source as an excitation source and a spectral sensor as the detector. A commercial imaging system was used to examine the fluorescent cancer cell lines before being validated in a preclinical setting with the developed prototype. The outcomes indicate that this low-cost fluorometer can effectively detect the alterations levels of lipid droplets and hence distinguish between "moderately malignant" and "highly malignant" cancer cells. In comparison to prior research that used fluorescence spectroscopy techniques to detect cancer biomarkers, this study revealed enhanced capability in classifying mildly and highly malignant cancer cell lines. [ABSTRACT FROM AUTHOR]

Objective: Mindfulness-based interventions (MBIs) can reduce risk of depressive relapse for people with a history of recurrent depression who are currently well. However, the cognitive, affective and motivational features of depression and anxiety might render MBIs ineffective for people experiencing current symptoms. This paper presents a meta-analysis of randomised controlled trials (RCTs) of MBIs where participants met diagnostic criteria for a current episode of an anxiety or depressive disorder. Method: Post-intervention between-group Hedges g effect sizes were calculated using a random effects model. Moderator analyses of primary diagnosis, intervention type and control condition were conducted and publication bias was assessed. Results: Twelve studies met inclusion criteria (n = 578). There were significant post-intervention between-group benefits of MBIs relative to control conditions on primary symptom severity (Hedges g = −0.59, 95% CI = −0.12 to −1.06). Effects were demonstrated for depressive symptom severity (Hedges g = −0.73, 95% CI = −0.09 to −1.36), but not for anxiety symptom severity (Hedges g = −0.55, 95% CI = 0.09 to −1.18), for RCTs with an inactive control (Hedges g = −1.03, 95% CI = −0.40 to −1.66), but not where there was an active control (Hedges g = 0.03, 95% CI = 0.54 to −0.48) and effects were found for MBCT (Hedges g = −0.39, 95% CI = −0.15 to −0.63) but not for MBSR (Hedges g = −0.75, 95% CI = 0.31 to −1.81). Conclusions: This is the first meta-analysis of RCTs of MBIs where all studies included only participants who were diagnosed with a current episode of a depressive or anxiety disorder. Effects of MBIs on primary symptom severity were found for people with a current depressive disorder and it is recommended that MBIs might be considered as an intervention for this population. [ABSTRACT FROM AUTHOR]

Measurement of malaria burden is fraught with complexity, due to the natural history of the disease, delays in seeking treatment or failure of case management. Attempts to establish an appropriate case definition for a malaria episode has often resulted in ambiguities and challenges because of poor information about treatment seeking, patterns of infection, recurrence of fever and asymptomatic infection. While the primary reason for treating malaria is to reduce disease burden, the effects of treatment are generally ignored in estimates of the burden of malaria morbidity, which are usually presented in terms of numbers of clinical cases or episodes, with the main data sources being reports from health facilities and parasite prevalence surveys. The use of burden estimates that do not consider effects of treatment, leads to under-estimation of the impact of improvements in case management. Official estimates of burden very likely massively underestimate the impact of the roll-out of ACT as first-line therapy across Africa. This paper proposes a novel approach for estimating burden of disease based on the point prevalence of malaria attributable disease, or equivalently, the days with malaria fever in unit time. The technique makes use of data available from standard community surveys, analyses of fever patterns in malaria therapy patients, and data on recall bias. Application of this approach to data from Zambia for 2009–2010 gave an estimate of 2.6 (95% credible interval: 1.5–3.7) malaria attributable fever days per child-year. The estimates of recall bias, and of the numbers of days with illness contributing to single illness recalls, could be applied more generally. To obtain valid estimates of the overall malaria burden using these methods, there remains a need for surveys to include the whole range of ages of hosts in the population and for data on seasonality patterns in confirmed case series. [ABSTRACT FROM AUTHOR]

Background: Tumor necrosis is a significant risk factor affecting patients' prognosis after liver resection (LR) for hepatocellular carcinoma (HCC). We aimed to develop a model with tumor necrosis as a variable to predict early tumor recurrence in HCC patients undergoing LR. Materials and methods: Patients who underwent LR between 2010 and 2018 for newly diagnosed HCC but did not receive neoadjuvant therapy were enrolled in this retrospective study. Six predictive factors based on pathological features—tumor size > 5 cm, multiple tumors, high-grade tumor differentiation, tumor necrosis, microvascular invasion, and cirrhosis—were chosen a priori based on clinical relevance to construct a multivariate logistic regression model. The variables were always retained in the model. The impact of each variable on early tumor recurrence within one year of LR was estimated and visualized using a nomogram. The nomogram's performance was evaluated using calibration plots with bootstrapping. Results: Early tumor recurrence was observed in 161 (21.3%) patients. The concordance index of the proposed nomogram was 0.722. The calibration plots showed good agreement between nomogram predictions and actual observations of early recurrence. Conclusion: We developed a nomogram incorporating tumor necrosis to predict early recurrence of HCC after LR. Its predictive accuracy is satisfactory. [ABSTRACT FROM AUTHOR]

This article considers ethnomedical knowledge and practices among parents related to contraction of acute gastroenteritis among children in Peshawar, Pakistan. Research methods included analysis of the Emergency Pediatric Services’ admission register, a structured interview administered to 47 parents of patients seen in the Khyber Medical College Teaching Hospital, semi-structured interviews of 12 staff, and four home visits among families with children treated at the hospital. The use of native research assistants and participant observation contributed to the reliability of the findings, though the ethnographic, home-visit sample is small. Our research indicated that infection rates are exacerbated in homes through two culturally salient practices and one socioeconomic condition. Various misconceptions propagate the recurrence or perserverance of acute gastroenteritis including assumptions about teething leading to poor knowledge of disease etiology, rehydration solutions leading to increased severity of disease, and diaper usage leading to the spread of disease. In our Discussion, we suggest how hospital structures of authority and gender hierarchy may impact hospital interactions, the flow of information, and its respective importance to the patient’s parents leading to possible propagation of disease. These ethnographic data offer a relatively brief but targeted course of action to improve the effectiveness of prevention and treatment efforts. [ABSTRACT FROM AUTHOR]

Background: Shortening tuberculosis (TB) treatment duration is a research priority. This paper presents data from a prematurely terminated randomized clinical trial, of 4-month moxifloxacin or gatifloxacin regimens, in South India. Methods: Newly diagnosed, sputum-positive HIV-negative pulmonary TB patients were randomly allocated to receive gatifloxacin or moxifloxacin, along with isoniazid and rifampicin for 4 months with pyrazinamide for first 2 months (G or M) or isoniazid and rifampicin for 6 months with ethambutol and pyrazinamide for first 2 months (C). All regimens were administered thrice-weekly. Clinical and bacteriological assessments were done monthly during treatment and for 24 months post-treatment. The Data and Safety Monitoring Board recommended termination of the trial due to high TB recurrence rates in the G and M regimens. Results: Of 416 patients in intent-to-treat analysis, 6 (5%) of 124, 2 (2%) of 110 and 2 (2%) of 137 patients with drug-susceptible TB in the G, M and C arms respectively had unfavorable response at the end of treatment; during the next 24 months, 17 (15%) of 115, 11 (11%) of 104 and 8 (6%) of 132 patients respectively, had TB recurrence. Of 38 drug-resistant patients 1 of 8 and 3 of 26 in the G and C arms respectively had unfavourable response at the end of treatment; and TB recurrence occurred in 2 of 7 and 2 of 23 patients, respectively. The differences in TB recurrence rates between the G and C arms was statistically significant (p = 0.02). Gastro-intestinal symptoms occurred in 23%, 22% and 9% of patients in the G, M and C arms respectively, but most reactions were mild and manageable with symptomatic measures; 1% required regimen modification. Conclusions: 4-month thrice-weekly regimens of gatifloxacin or moxifloxacin with isoniazid, rifampicin and pyrazinamide, were inferior to standard 6-month treatment, in patients with newly diagnosed sputum positive pulmonary TB. Trial Registration: Clinical Trials Registry of India CTRI/2012/10/003060 [ABSTRACT FROM AUTHOR]

Interaction of Clostridioides difficile spores with the intestinal mucosa contributes to the persistence and recurrence of the infection. Advanced age is one of the main risk factors for C. difficile infection and recurrence of the disease. However, interaction of C. difficile spores with the intestinal mucosa during aging has not been evaluated. In the present work, using intestinal ligated loop technique in a mouse model, we analyzed C. difficile spore adherence and internalization to the ileum and colonic mucosa during aging. Additionally, we provide visual documentation of the critical steps of the procedure. Consequently, our data suggest that spore internalization in the ileum and colonic mucosa is higher in elderly mice rather than adults or young mice. Also, our data suggest that spore adherence to the ileum and colonic mucosa decreases with aging. [ABSTRACT FROM AUTHOR]

Objective: To inform quarantine and contact-tracing policies concerning re-positive cases—cases testing positive among those recovered. Materials and methods: We systematically reviewed and appraised relevant literature from PubMed and Embase for the extent of re-positive cases and their epidemiological characteristics. Results: In 90 case reports/series, a total of 276 re-positive cases were found. Among confirmed reinfections, 50% occurred within 90 days from recovery. Four reports related onward transmission. In thirty-five observational studies, rate of re-positives ranged from zero to 50% with no onward transmissions reported. In eight reviews, pooled recurrence rate ranged from 12% to 17.7%. Probability of re-positive increased with several factors. Conclusion: Recurrence of a positive SARS-CoV-2 test is commonly reported within the first weeks following recovery from a first infection. [ABSTRACT FROM AUTHOR]

Alpha-Mannosidosis (AM) is an ultra-rare storage disorder caused by a deficiency of lysosomal alpha-mannosidase encoded by the MAN2B1 gene. Clinical presentation of AM includes mental retardation, recurrent infections, hearing loss, dysmorphic features, and motor dysfunctions. AM has never been reported in Tunisia. We report here the clinical and genetic study of six patients from two Tunisian families with AM. The AM diagnosis was confirmed by an enzymatic activity assay. Genetic investigation was conducted by Sanger sequencing of the mutational hotspots for the first family and by ES analysis for the second one. In the first family, a frameshift duplication p.(Ser802GlnfsTer129) was identified in the MAN2B1 gene. For the second family, ES analysis led to the identification of a missense mutation p.(Arg229Trp) in the MAN2B1 gene in four affected family members. The p.(Ser802GlnfsTer129) mutation induces a premature termination codon which may trigger RNA degradation by the NMD system. The decrease in the levels of MAN2B1 synthesis could explain the severe phenotype observed in the index case. According to the literature, the p.(Arg229Trp) missense variant does not have an impact on MAN2B1 maturation and transportation, which correlates with a moderate clinical sub-type. To explain the intra-familial variability of cognitive impairment, exome analysis allowed the identification of two likely pathogenic variants in GHR and SLC19A3 genes potentially associated to cognitive decline. The present study raises awareness about underdiagnosis of AM in the region that deprives patients from accessing adequate care. Indeed, early diagnosis is critical in order to prevent disease progression and to propose enzyme replacement therapy. [ABSTRACT FROM AUTHOR]

Purpose: Postoperative pancreatic fistula (POPF) with reported incidence rates up to 45% contributes substantially to overall morbidity. In this study, we conducted a retrospective evaluation of POPF along with its potential perioperative clinical risk factors and its effect on tumor recurrence. Methods: Clinical data on patients who had received pancreatoduodenectomy (PD), distal pancreatectomy (DP), or duodenum-preserving pancreatic head resection (DPPHR) were prospectively collected between 2007 and 2016. A Picrosirius red staining score was developed to enable morphological classification of the resection margin of the pancreatic stump. The primary end point was the development of major complications. The secondary end points were overall and recurrence-free survival. Results: 340 patients underwent pancreatic resection including 222 (65.3%) PD, 87 (25.6%) DP, and 31 (9.1%) DPPHR. Postoperative major complications were observed in 74 patients (21.8%). In multivariable logistic regression analysis, POPF correlated with body mass index (BMI) (p = 0.025), prolonged stay in hospital (p<0.001), high Picrosirius red staining score (p = 0.049), and elevated postoperative levels of amylase or lipase in drain fluid (p≤0.001). Multivariable Cox regression analysis identified UICC stage (p<0.001), tumor differentiation (p<0.001), depth of invasion (p = 0.001), nodal invasion (p = 0.001), and the incidence of POPF grades B and C (p = 0.006) as independent prognostic markers of recurrence-free survival. Conclusion: Besides the known clinicopathological risk factors BMI and amylase in the drain fluid, the incidence of POPF correlates with high Picrosirius red staining score in the resection margins of the pancreatic stumps of curatively resected pancreatic ductal adenocarcinoma (PDAC). Furthermore, clinically relevant POPF seems to be a prognostic factor for tumor recurrence in PDAC. [ABSTRACT FROM AUTHOR]

Objective: Teriflunomide is a once-daily, oral disease-modifying therapy (DMT) for relapsing forms of multiple sclerosis (MS). We studied clinical outcomes in a real-world setting involving a population-based large cohort of unselected patients enrolled in The Danish Multiple Sclerosis Registry (DMSR) who started teriflunomide treatment between 2013–2019. Methods: This was a complete nationwide population-based cohort study with prospectively enrolled unselected cases. Demographic and disease-specific patient parameters related to treatment history, efficacy outcomes, and discontinuation and switching rates among other clinical variables were assessed at baseline and during follow-up visits. Results: A total of 3239 patients (65.4% female) started treatment with teriflunomide during the study period, 56% of whom were treatment-naïve. Compared to previously treated patients, treatment-naïve patients were older on average at disease onset, had a shorter disease duration, a lower Expanded Disability Status Scale score at teriflunomide treatment start and more frequently experienced a relapse in the 12 months prior to teriflunomide initiation. In the 3001 patients initiating teriflunomide treatment at least 12 months before the cut-off date, 72.7% were still on treatment one year after treatment start. Discontinuations in the first year were due mainly to adverse events (15.6%). Over the full follow-up period, 47.5% of patients discontinued teriflunomide treatment. Sixty-three percent of the patients treated with teriflunomide for 5 years were relapse-free, while significantly more treatment-naïve versus previously treated patients experienced a relapse during the follow-up (p<0.0001). Furthermore, 85% of the patients with available data were free of disability worsening at the end of follow-up. Conclusions: Solid efficacy and treatment persistence data consistent with other real-world studies were obtained over the treatment period. Treatment outcomes in this real-world scenario of the population-based cohort support previous findings that teriflunomide is an effective and generally well-tolerated DMT for relapsing MS patients with mild to moderate disease activity. [ABSTRACT FROM AUTHOR]

Introduction: Molecular and cellular characteristics of the relapse-prone subset within triple-negative breast cancer (TNBC) remain unclear. Aberrant glycosylation is involved in the malignant behavior of cancer cells. In the present study, we aimed to reveal glycan profiles unique to relapsed TNBC patients. Methods: Thirty TNBC patients who did not undergo neoadjuvant chemotherapy but postoperative standard adjuvant therapy from 2009 through 2016 at Juntendo Hospital were investigated. TNBC cells were resected from primary breast cancer sections of formalin-fixed surgical specimens using laser-assisted microdissection. The binding intensities of the extracted glycoproteins to 45 lectins were quantified using lectin microarray and compared between relapsed and non-relapsed patients. Immunohistochemical staining with TJA-II lectin in specimen sections was performed. Results: Five patients relapsed during the follow-up (range 37–123 months). Lectin microarray analysis revealed that 7 out of 45 lectins showed significant differences in binding intensity between the relapsed and the non-relapsed group. TJA-II, ACA, WFA, and BPL showed stronger binding in the relapsed group. PNGase F treatment of TNBC cell lysates suggested that TJA-II and ACA bind O-glycans. TJA-II staining of tissue sections revealed strong binding to cell surface membranes and to the cytoplasm of TNBC cells, but not to other types of cells. Significantly more TNBC cells were stained in tissue sections from relapsed than non-relapsed patients. Conclusions: TNBC cells from relapsed patients showed a unique lectin reactivity, with higher levels of TJA-II (also WFA and BPL) binding than in non-relapsed patients. The results are potentially useful to develop new prognostic and therapeutic tools. [ABSTRACT FROM AUTHOR]

Breast cancer is the most common invasive cancer and the second leading cause of cancer death in women. and regrettably, this rate is increasing every year. One of the aspects of all cancers, including breast cancer, is the recurrence of the disease, which causes painful consequences to the patients. Moreover, the practical application of data mining in the field of breast cancer can help to provide some necessary information and knowledge required by physicians for accurate prediction of breast cancer recurrence and better decision-making. The main objective of this study is to compare different data mining algorithms to select the most accurate model for predicting breast cancer recurrence. This study is cross-sectional and data gathering of this research performed from June 2018 to June 2019 from the official statistics of Ministry of Health and Medical Education and the Iran Cancer Research Center for patients with breast cancer who had been followed for a minimum of 5 years from February 2014 to April 2019, including 5471 independent records. After initial pre-processing in dataset and variables, seven new and conventional data mining algorithms have been applied that each one represents one kind of data mining approach. Results show that the C5.0 algorithm possibly could be a helpful tool for the prediction of breast cancer recurrence at the stage of distant recurrence and nonrecurrence, especially in the first to third years. also, LN involvement rate, Her2 value, Tumor size, free or closed tumor margin were found to be the most important features in our dataset to predict breast cancer recurrence. [ABSTRACT FROM AUTHOR]

Lyme borreliosis and Relapsing fever are considered emerging and re-emerging diseases that cause major public health problems in endemic countries. Epidemiology and geographical distribution of these diseases are documented in the US and in Europe, yet in Mexico, studies are scarce and scattered. The aims of this study were (1) to present the first confirmatory evidence of an endemic case of Lyme disease in Mexico and (2) to analyze the epidemiological trend of these both diseases by compiling all the information published on Borrelia in Mexico. Two databases were compiled, one of human cases and another of wild and domestic animals in the country. The analysis included the evaluation of risk factors for the human population, the diversity of Borrelia species and their geographic distribution. Six Borrelia species were reported in a total of 1,347 reports, of which 398 were of humans. Women and children from rural communities were shown to be more susceptible for both Lyme borreliosis and Relapsing fever. The remaining reports were made in diverse mammalian species and ticks. A total of 17 mammalian species and 14 tick species were recorded as hosts for this bacterial genus. It is noteworthy that records of Borrelia were only made in 18 of the 32 states, mainly in northern and central Mexico. These results highlight the importance of performing further studies in areas where animal cases have been reported, yet no human studies have been done, in order to complete the epidemiological panorama for Lyme borreliosis and Relapsing fever. Finally, the search for Borrelia infections in other vertebrates, such as reptiles and amphibians is recommended to gain a more accurate view of Borrelia species and their distribution. The geographical approach presented herein justifies an intense sampling effort to improve epidemiological knowledge of these diseases to aid vector control and prevention programs. [ABSTRACT FROM AUTHOR]

Objectives: Human papillomavirus-related oropharyngeal squamous cell carcinoma (HPV+ OPSCC) is increasing in incidence. Although HPV+ OPSCC has favorable prognosis, 10 to 25% of HPV+ OPSCCs eventually recur. We sought to evaluate the feasibility of detection of HPV16 E6/E7 expression in Circulating Tumor Cells (CTCs) and its utility as a prognostic tool in HPV16-associated OPSCC. Materials and methods: We developed a highly sensitive RT-qPCR assay for HPV mRNA expression in EpCAM(+) CTCs. In 22 patients with early stage and locally advanced OPSCC we evaluated HPV16 E6/E7 expression in the EpCAM(+) CTC fraction at baseline and at the end of concurrent chemoradiotherapy. HPV status in pre-therapy formalin-fixed paraffin-embedded (FFPE) tumor biopsies was assessed by p16 immunohistochemistry and polymerase chain reaction (PCR) and double positives were subjected to Real-time qPCR assay for detection of HPV16, 18 and 31 types. Results: Fourteen of 22 OPSCC (63.6%) were HPV DNA+/p16+. Among HPV+/p16+ patients, 10 patients (71.4%) were HPV16 DNA+. HPV16 E6/E7(+) CTCs were detected in 3 of 10 patients (30%) at baseline and 4 of 9 patients (44.4%) at the end-of-treatment, all of which were p16+/HPV16 DNA+. Survival analysis showed a significantly higher risk for disease relapse (p = 0.001) and death (p = 0.005) in patients with HPV16 E6/E7(+) baseline CTCs. Conclusion: Detection of HPV E6/E7(+) CTCs might be a useful noninvasive test in liquid biopsy samples for determination of a clinically relevant HPV infection in HPV+ OPSCC. Combined interpretation of HPV E6/E7(+) CTCs with UICC staging data may lead to alteration of risk definition of patient subsets, with improved risk discrimination in early-stage disease. [ABSTRACT FROM AUTHOR]

Background: The objective of this study was to estimate costs to society and patients’ quality of life (QoL) at all levels of disease severity (measured with the Expanded Disability Status Scale, EDSS) in Brazil. Methods: The study was part of an international, cross-sectional burden-of-illness study carried out in collaboration with national MS patient organizations. All information was collected directly from patients using a validated questionnaire. Direct costs were estimated both from societal and payer perspectives, while total costs are presented as societal costs. Results: The survey included 694 patients (response rate 21%; mean age 40.8 years). 95% of patients were of working age, and around half were working. The mean EDSS score was 3.2 (62.5% of patients with EDSS <3). Relapses were reported by 18.9% of patients. Fatigue affected almost all patients (94%) regardless of EDSS level, and cognitive difficulties were reported by 69.1% of patients. Mean utility ranged from 0.77 at EDSS 0 to negative values at EDSS 9, with a mean score of 0.58; utility was affected by relapses. Total mean annual cost was R$33,872 (€ 8,000) per patient in the societal perspective, with direct costs representing 81% (R$ 27,355, € 6,500). Direct costs for the payer amounted to R$ 16,793 (€ 4,000)/patient. Conclusions: This study included a population with relatively mild and early disease, with a majority of patients with relapsing disease and thus on DMD treatment. It is not possible to conclude directly on the total cost of MS in Brazil. Nevertheless, resource quantities used, QoL and MS symptoms are very similar to what was seen in the European survey. [ABSTRACT FROM AUTHOR]

The surgical treatment of primary solitary fibrous tumors (SFT) involving the pelvic ring has not been reported previously. In this study, we aimed to evaluate the efficacy of surgical treatment for this disease. From 2009 to 2015, 13 patients underwent tumor resection at our hospital, with an average age of 49.5 years (27–68 years). Four patients underwent en bloc resection, and 9 patients underwent piecemeal resections. A Chi-square test was used to compare the postoperative recurrence rates between the en bloc resection and the piecemeal resection groups (p = 0.68), and no significant difference was found between the benign and malignant solitary fibrous tumor groups (p = 0.44). The 5-year survival rate of the patients in this study was 83.3%, and the 5-year progression-free survival rate was 63.5%. The progression-free survival rate was not significantly different between the en bloc resection and piecemeal resection groups (p = 0.97). Piecemeal resection can also achieve acceptable local control, particularly for patients with sacral tumors, as they may achieve even better postoperative function with sacral nerve preservation. Recurrence and metastasis occur relatively late in the course of this disease. Therefore, long-term follow-up is required. [ABSTRACT FROM AUTHOR]

Fatigue is a common and highly disabling symptom of multiple sclerosis. Patients experience an effort-independent general subjective feeling of fatigue as well as excessive fatigability when engaging in physical or mental activity. Previous research using functional magnetic resonance imaging (fMRI) has revealed heterogeneous findings, but some evidence implicates the motor system. To identify brain correlates of fatigue, 44 mildly impaired patients with relapsing-remitting multiple sclerosis and 25 age- and gender-matched healthy controls underwent functional magnetic resonance imaging at 3 Tesla, while they performed alternating blocks of rest and a non-fatiguing precision grip task. We investigated neural correlates of fatigue using the motor subscore of Fatigue Scale for Motor and Cognitive Functions (FSMCMOTOR) using the bilateral motor cerebellum, putamen, and dorsal premotor cortex as regions of interest. Patients and healthy controls performed the grip force task equally well without being fatigued. In patients, task-related activity in lobule VI of right motor cerebellum changed in proportion with individual FSMCMOTOR scores. In right dorsal premotor cortex, linear increases in activity across consecutive task blocks scaled with individual FSMCMOTOR scores in healthy controls, but not in patients. In premotor and dorsomedial prefrontal areas, patients were impaired at upscaling task-related activity the more they were affected by motor fatigue. The results support the notion that increased sensorimotor processing in the cerebellum contributes to the experience of motor fatigue and fatigability in multiple sclerosis. Additionally, downscaling of motivational input or sensorimotor processing in prefrontal and premotor areas may constitute an additional pathophysiological factor. [ABSTRACT FROM AUTHOR]

Context: Despite the high prevalence of work disability due to common mental disorders (CMD), no information exists on the rates and predictors of recurrence in a United States population. Objective: To estimate recurrent work disability statistics and evaluate factors associated with recurrence due to CMDs including adjustment, anxiety, bipolar, and depressive disorders. Methods: Recurrent work disability statistics were calculated using a nationwide database of disability claims. For the CMDs, univariate and multiple variable analyses were used to examine demographic factors and comorbidities associated with the time to recurrence. Results: Of the CMDs, cases with bipolar (n = 3,017) and depressive disorders (n = 20,058) had the highest recurrence densities, 98.7 and 70.9 per 1000 person-years, respectively. These rates were more than three times higher than recurrence rates for other chronic disorders (e.g., diabetes, asthma; n = 105,558) and non-chronic disorders (e.g., injury, acute illnesses; n = 153,786). Individuals with CMD were also more likely to have a subsequent disability distinct from their mental health condition. Risk factors for recurrent CMD disability included being younger, being an hourly employee, living in a geographic area with more college graduates, having more previous psychiatric visits, having a previous work leave, and the type of work industry. Conclusions: Results indicate that CMD patients may benefit from additional care and disability management both during and after their work absence to help prevent subsequent CMD and non-CMD related leaves. [ABSTRACT FROM AUTHOR]

Objectives/Hypothesis: Recurrent respiratory papillomatosis (RRP) is a benign disease caused by human papillomavirus 6 and 11. The characteristic feature of this disease are wart-like lesions covering the respiratory epithelium with a predilection for the larynx. There is no curative treatment for the disease. The goal of the treatment is a total surgical removal of the papillomatous lesions in order to reduce the number of relapses. Therefore, a good visualization method of papillomas is crucial during surgery. The aim of the study was to compare the accuracy of narrow band imaging (NBI) to the use of white light alone in detecting RRP. Methods: The study was carried out between April 2013 and November 2015 at Poznan University of Medical Sciences, Department of Otolaryngology, Poland. Rigid endoscopy with conventional white light (WL) and NBI (CV-260SL processor and CLV- 260SL light source, Olympus Optical Co. Ltd, Tokyo, Japan) was performed in all patients during direct laryngoscopy. All anatomical sites of the larynx and trachea were assessed using the Dikkers scale and Derkay total site scoring system with WL and NBI. The consensus was reached as to the number of lesions seen in WL compared to NBI. Results: During 36 microlaryngoscopies, the number of papillomas detected in the larynx (by Derkay total site score) differed significantly between white light endoscopy and NBI (Wilcoxon test p = 0.000655). In endoscopy with NBI, a mean of 1.3 more papillomas in Derkay total site score was detected in comparison to white light endoscopy NBI showed additional areas of diseased tissue in 15/36 (41.67%) patients. Conclusions: NBI as an additional tool during microlaryngoscopy can improve the detection of papillomatous lesions. [ABSTRACT FROM AUTHOR]

Epilepsy is often associated with modifications in autonomic nervous system, which usually precede the onset of seizures of several minutes. Thus, there is a great interest in identifying these modifications enough time in advance to prevent a dangerous effect and to intervene. In addition, these changes can be a risk factor for epileptic patients and can increase the possibility of death. Notably autonomic changes associated to seizures are highly depended of seizure type, localization and lateralization. The aim of this study was to develop a patient-specific approach to predict seizures using electrocardiogram (ECG) features. Specifically, from the RR series, both time and frequency variables and features obtained by the recurrence quantification analysis were used. The algorithm was applied in a dataset of 15 patients with 38 different types of seizures. A feature selection step, was used to identify those features that were more significant in discriminating preictal and interictal phases. A preictal interval of 15 minutes was selected. A support vector machine (SVM) classifier was then built to classify preictal and interictal phases. First, a classifier was set up to classify preictal and interictal segments of each patient and an average sensibility of 89.06% was obtained, with a number of false positive per hour (FP/h) of 0.41. Then, in those patients who had at least 3 seizures, a double-cross-validation approach was used to predict unseen seizures on the basis of a training on previous ones. The results were quite variable according to seizure type, achieving the best performance in patients with more stereotypical seizure. The results of the proposed approach show that it is feasible to predict seizure in advance, considering patient-specific, and possible seizure specific, characteristics. [ABSTRACT FROM AUTHOR]

Background: Bronchiolitis sometimes triggers the development of subsequent recurrent wheezing. Treatment with either acetaminophen or ibuprofen during the initial episode may affect the occurrence of subsequent wheezing. Materials and methods: We did a retrospective study comparing the effect of prescribing acetaminophen, ibuprofen, or neither for a first episode of bronchiolitis on medical attendances for subsequent wheezing in infants younger than 12 months. We created our cohorts using California Medicaid data from 2003 to 2010. We used propensity score derived inverse probability weights to adjust for non-random drug assignment. We used robust negative binomial regression to model incident rate ratios (IRR) for medical attendances at 365, 30, and 14-day follow-up. We did similar analyses for the effect of antipyretics for a first medically attended upper respiratory tract infection (URI) on subsequent wheezing. Results: Compared with no antipyretic, treatment with acetaminophen or ibuprofen for a first episode of bronchiolitis was associated with decreased wheezing at 365-day follow-up (IRR 0.18, 95% CI 0.15–0.22), and ibuprofen plus acetaminophen over ibuprofen (IRR at 0.12, 95% CI 0.05–0.32). The results were similar at 30 and 14-day follow-up. Ibuprofen alone and ibuprofen plus acetaminophen were associated with decreased visits for subsequent wheezing at 365-day (IRR 0.79, 95% CI 0.68–0.92), but not earlier timepoints, when compared with acetaminophen. A smaller effect was seen for ibuprofen at one year if prescribed for a URI (IRR 0.87, 95% CI 0.76–1.00) but not at earlier follow-up. Conclusion: Children who are prescribed antipyretics for a first episode of bronchiolitis may have less subsequent wheezing than those who are not. We found fewer visits for subsequent wheezing for those prescribed ibuprofen, and ibuprofen combined with acetaminophen, compared with acetaminophen alone. [ABSTRACT FROM AUTHOR]

Background: Internal limiting membrane (ILM) peeling during primary vitrectomy for rhegmatogenous retinal detachment (RRD) prevents the formation of postoperative macular epiretinal membrane (ERM). However, studies that compared vitrectomy with and without ILM peeling for RRD, have reported controversial outcomes. Objective: To assess the efficacy of ILM peeling versus non-ILM peeling during vitrectomy for RRD by a systematic review and meta-analysis of published studies. Methods: PubMed, Medline, Web of Science, Embase databases, and the Cochrane Library were searched up to April 2018 to identify studies that compared primary vitrectomy with and without ILM peeling for RRD with at least six months follow-up. Primary outcomes were the rate of postoperative ERM formation and mean best corrected visual acuity (BCVA) change after vitrectomy. Rate of recurrence of retinal detachment (RD) was assessed as secondary outcome. Risk ratios (RRs) with 95% confidence intervals (CIs) expressed pooled results for rate of ERM formation and rate of RD recurrence in ILM peeling and non-ILM peeling groups. Pooled results for BCVA change in the two groups were expressed as Weighted Mean Difference (WMD) with 95% CIs. Results: Nine studies, one of which was a randomized controlled trial (RCT), with a total number of 404 eyes in the ILM peeling group and 365 eyes in the non-ILM peeling group, were included. The analysis from pooled data indicated a significant lower rate of postoperative ERM formation in the ILM peeling group compared to the non-ILM peeling group (9 studies, 769 eyes, RR = 0.14; CI: 0.07 to 0.28; P < 0.001). There was no statistical difference in mean BCVA change (9 studies, 769 eyes, WMD = 0.02; CI: -0.11 to 0.16; P = 0.75). Rate of recurrence of RD was lower in the ILM peeling group (6 studies, 603 eyes, RR = 0.32; CI = 0.17 to 0.61; P< 0.001). Conclusion: ILM peeling during vitrectomy for RRD prevents the formation of macular epiretinal membrane postoperatively and reduces the incidence of RD recurrence, but better visual outcome was not found compared to non-ILM peeling vitrectomy. [ABSTRACT FROM AUTHOR]

Purpose: To report associations between disease- and treatment-related variables and rates of recurrence-free survival and ocular survival in eyes treated with ophthalmic artery chemosurgery (OAC) for retinoblastoma. Design: Pre-post study. Subjects: All eyes treated with OAC for retinoblastoma at Memorial Sloan Kettering Cancer Center between May 2006 and February 2017. Methods: This retrospective review included 452 retinoblastoma eyes treated with OAC. The Kaplan-Meier method was used to estimate recurrence-free survival (RFS), progression-free survival (PFS) and ocular survival (OcS), and Cox regression was used to estimate hazard ratios. Eyes treated in the pre-intravitreous chemotherapy era were analyzed separately from eyes treated in the intravitreal era. Main outcome measures: Recurrence-free survival, ocular survival, associations with risk of recurrence Results: Disease and treatment characteristics were recorded over a median 23.6 month follow-up. One-year OcS, PFS and RFS were 96% (95% CI 93–99%), 88% (95% CI 88–94%) and 74% (95% CI 67–81%) in the pre-intravitreal era and 96% (95% CI 94–99%), 93% (95% CI 89–96%) and 78% (95% CI 72–83%) in the intravitreal era, respectively. Presence of vitreous seeds was associated with increased risk of recurrence in the pre-intravitreal era but not in the intravitreal era. Longer time interval between OAC sessions was associated with increased risk of recurrence and majority OAC access via the ophthalmic artery was associated with decreased risk of recurrence in both eras. Conclusions: Approximately a quarter of eyes initially treated with ophthalmic artery chemosurgery develop recurrent disease, with the majority of recurrences within the first year following completion of OAC. Despite this, these eyes have a very good chance of salvage. In eyes with vitreous seeds at presentation, intravitreal injections are useful in minimizing future vitreous recurrence. Eyes that receive the majority of drug infusions via non-ophthalmic artery routes or greater interval between OAC are more likely to recur and might warrant closer monitoring. [ABSTRACT FROM AUTHOR]

There is no clear consensus regarding investigating for accompanying genitourinary anomalies (GUAs) in patients with prepubertal acute epididymitis (AE). Moreover, risk factors for the recurrence and the need for a surgical intervention have never been discussed. The purpose of this study was to evaluate the different clinical courses of prepubertal AE based on knowledge of preexisting GUAs. Between January 2005 and December 2014, AE was diagnosed in 189 pediatric patients <10 years old. Clinical characteristics and treatments were retrospectively analyzed. The median age at first AE was 64.3 months. A GUA was detected prior to the development of AE in 49 patients (known GUA group) including 34 with hypospadias. Among the other 140 patients (unknown GUA status group), six patients were diagnosed with a GUA after the first AE episode. In the known GUA group, 35 patients (71.4%) experienced recurrence and the only risk factor associated with recurrence was the presence of cystic dilated prostatic utricle (p = 0.013). In the unknown GUA status group, the risk factors for an existing GUA were being <1-year-old (p<0.001) and positive urine culture (p = 0.015). Only nine patients (6.4%) in this group experienced recurrence. Vasectomy was recommended for patients with recurrent AE with an accompanying GUA and performed in 19 patients (10.1%). Most GUAs are diagnosed prior to AE development. Clinicians should consider different treatment approaches based on whether the AE patient has been diagnosed with a GUA previously, because the clinical characteristics and the recurrence rate are significantly different. [ABSTRACT FROM AUTHOR]

An epidemiological model is presented that provides a comprehensive description of the transmission pathways involved for recurrent tuberculosis (TB), whereby cured individuals can become reinfected. Our main goal is to determine conditions that lead to the appearance of a backward bifurcation. This occurs when an asymptotically stable infection free equilibrium concurrently exists with a stable non-trivial equilibria even though the basic reproduction number R0 is less than unity. Although, some 10-30% cases of TB are recurrent, the role of recurrent TB as far as the formation of backward bifurcation is concerned, is rarely if ever studied. The model used here incorporates progressive primary infection, exogenous reinfection, endogenous reactivation and recurrent TB as transmission mechanisms that contribute to TB progression. Unlike other studies of TB dynamics that make use of frequency dependent transmission rates, our analysis provides exact backward bifurcation threshold conditions without resorting to commonly applied approximations and simplifying assumptions. Exploration of the model through analytical and numerical analysis reveal that recurrent TB is sometimes capable of triggering hysteresis effects which allow TB to persist when R0 < 1 even though there is no backward bifurcation. Furthermore, recurrent TB can independently induce backward bifurcation phenomena if it exceeds a certain threshold. [ABSTRACT FROM AUTHOR]

Post-traumatic stress disorder (PTSD) is a common consequence of exposure to a life-threatening event. Currently, pharmacological treatments are limited by high rates of relapse, and novel treatment approaches are needed. We have recently demonstrated that propranolol, a β-adrenergic antagonist, inhibited aversive memory reconsolidation in animals. Following this, in an open-label study 70% of patients with PTSD treated with propranolol during reactivation of traumatic memory exhibited full remission. However, the reason why 30% of these patients did not respond positively to propranolol treatment is still unclear. One of the major candidates as factor of treatment resistance is the patient's early-life traumatic history. To test the role of this factor, mice with pre- or postnatal stress are being tested in fear conditioning and in a new behavioral task, the "city-like", specifically designed as a mouse model of PTSD. After reactivation of the traumatic event, mice received propranolol injection to block the noradrenergic system during memory reconsolidation. Results show that, in the “city-like” test, control mice strongly avoided the shock compartment but also the compartments containing cues associated with the electric shocks. Injection of propranolol after reactivation greatly reduced the memory of the traumatic event, but this effect was not present when mice had received pre- or postnatal stress. Moreover, propranolol produced only a very weak effect in the fear conditioning test, and never changed the corticosterone level whatever the behavioral experiment. Taken together our results suggest that our new behavioural paradigm is well adapted to PTSD study in mice, and that early stress exposure may have an impact on propranolol PTSD treatment outcome. These data are critical to understanding the effect of propranolol treatment, in order to improve the therapeutic protocol currently used in humans. [ABSTRACT FROM AUTHOR]

Objectives: To develop prognostic models for risk of a breakthrough seizure, risk of seizure recurrence after a breakthrough seizure, and likelihood of achieving 12-month remission following a breakthrough seizure. A breakthrough seizure is one that occurs following at least 12 months remission whilst on treatment. Methods: We analysed data from the SANAD study. This long-term randomised trial compared treatments for participants with newly diagnosed epilepsy. Multivariable Cox models investigated how clinical factors affect the probability of each outcome. Best fitting multivariable models were produced with variable reduction by Akaike’s Information Criterion. Risks associated with combinations of risk factors were calculated from each multivariable model. Results: Significant factors in the multivariable model for risk of a breakthrough seizure following 12-month remission were number of tonic-clonic seizures by achievement of 12-month remission, time taken to achieve 12-month remission, and neurological insult. Significant factors in the model for risk of seizure recurrence following a breakthrough seizure were total number of drugs attempted to achieve 12-month remission, time to achieve 12-month remission prior to breakthrough seizure, and breakthrough seizure treatment decision. Significant factors in the model for likelihood of achieving 12-month remission after a breakthrough seizure were gender, age at breakthrough seizure, time to achieve 12-month remission prior to breakthrough, and breakthrough seizure treatment decision. Conclusions: This is the first analysis to consider risk of a breakthrough seizure and subsequent outcomes. The described models can be used to identify people most likely to have a breakthrough seizure, a seizure recurrence following a breakthrough seizure, and to achieve 12-month remission following a breakthrough seizure. The results suggest that focussing on achieving 12-month remission swiftly represents the best therapeutic aim to reduce the risk of a breakthrough seizure and subsequent negative outcomes. This will aid individual patient risk stratification and the design of future epilepsy trials. [ABSTRACT FROM AUTHOR]

Environmental exposures to essential and toxic elements may alter health trajectories, depending on the timing, intensity, and mixture of exposures. In epidemiologic studies, these factors are typically analyzed as a function of elemental concentrations in biological matrices measured at one or more points in time. Such an approach, however, fails to account for the temporal cyclicity in the metabolism of environmental chemicals, which if perturbed may lead to adverse health outcomes. Here, we conceptualize and apply a non-linear method–recurrence quantification analysis (RQA)–to quantify cyclical components of prenatal and early postnatal exposure profiles for elements essential to normal development, including Zn, Mn, Mg, and Ca, and elements associated with deleterious health effects or narrow tolerance ranges, including Pb, As, and Cr. We found robust evidence of cyclical patterns in the metabolic profiles of nutrient elements, which we validated against randomized twin-surrogate time-series, and further found that nutrient dynamical properties differ from those of Cr, As, and Pb. Furthermore, we extended this approach to provide a novel method of quantifying dynamic interactions between two environmental exposures. To achieve this, we used cross-recurrence quantification analysis (CRQA), and found that elemental nutrient-nutrient interactions differed from those involving toxicants. These rhythmic regulatory interactions, which we characterize in two geographically distinct cohorts, have not previously been uncovered using traditional regression-based approaches, and may provide a critical unit of analysis for environmental and dietary exposures in epidemiological studies. [ABSTRACT FROM AUTHOR]

Background: There is little evidence on the accuracy of psychosis relapse prediction models. Our objective was to undertake a systematic review of relapse prediction models in psychosis. Method: We conducted a literature search including studies that developed and/or validated psychosis relapse prediction models, with or without external model validation. Models had to target people with psychosis and predict relapse. The key databases searched were; Embase, Medline, Medline In-Process Citations & Daily Update, PsychINFO, BIOSIS Citation Index, CINAHL, and Science Citation Index, from inception to September 2016. Prediction modelling studies were assessed for risk of bias and applicability using the PROBAST tool. Results: There were two eligible studies, which included 33,088 participants. One developed a model using prodromal symptoms and illness-related variables, which explained 14% of relapse variance but was at high risk of bias. The second developed a model using administrative data which was moderately discriminative (C = 0.631) and associated with relapse (OR 1.11 95% CI 1.10, 1.12) and achieved moderately discriminative capacity when validated (C = 0.630). The risk of bias was low. Conclusions: Due to a lack of high quality evidence it is not possible to make any specific recommendations about the predictors that should be included in a prognostic model for relapse. For instance, it is unclear whether prodromal symptoms are useful for predicting relapse. The use of routine data to develop prediction models may be a more promising approach, although we could not empirically compare the two included studies. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) are inflammatory diseases of the central nervous system. Although several studies have characterized the metabolome in the cerebrospinal fluid (CSF) from MS and NMOSD patients, comparative analyses between them and between the relapse and the remission of each disease have not been performed. Both univariate and multivariate analyses were used to compare 1H-NMR spectra of CSF from MS, NMOSD, and healthy controls (HCs). The statistical analysis showed alterations of eight metabolites that were dependent on the disease. Levels of 2-hydroxybutyrate, acetone, formate, and pyroglutamate were higher and levels of acetate and glucose were lower in both MS and NMOSD. Citrate was lower in MS patients, whereas lactate was higher in only NMOSD specifically. The shared feature of metabolic changes between MS and NMOSD may be related to altered energy metabolism and fatty acid biosynthesis in the brain. Another analysis to characterize relapse and remission status showed that isoleucine and valine were down-regulated in MS relapse compared to MS remission. The other metabolites identified in the disease comparison showed the same alterations regardless of disease activity. These findings would be helpful in understanding the biological background of these diseases, and distinguishing between MS and NMOSD, as well as determining the disease activity. [ABSTRACT FROM AUTHOR]

The main etiological factor of precancerous lesion and invasive cervical cancer are oncogenic human papillomaviruses types (HPVs). The objective of this study was to establish the distribution of the most common HPVs in different cervical lesions and cancer prior to the implementation of organized population-based cervical screening and HPV vaccination in Croatia. In this study, 4,432 cervical specimens, collected through a 16-year period, were tested for the presence of HPV-DNA by polymerase chain reaction (PCR) with three sets of broad-spectrum primers and type-specific primers for most common low-risk (LR) types (HPV-6, 11) and the most common high-risk (HR) types (HPV-16, 18, 31, 33, 45, 52, 58). Additional 35 archival formalin-fixed, paraffin embedded tissue of cervical cancer specimens were analyzed using LiPA25 assay. The highest age-specific HPV-prevalence was in the group 18–24 years, which decreased continuously with age (P<0.0001) regardless of the cytological diagnosis. The prevalence of HR-HPV types significantly increased (P<0.0001) with the severity of cervical lesions. HPV-16 was the most common type found with a prevalence (with or without another HPV-type) of 6.9% in normal cytology, 15.5% in atypical squamous cells of undetermined significance, 14.4% in low-grade squamous intraepithelial lesions, 33.3% in high-grade squamous intraepithelial lesions, and 60.9% in cervical cancer specimens (P<0.0001). This study provides comprehensive and extensive data on the distribution of the most common HPV types among Croatian women, which will enable to predict and to monitor the impact of HPV-vaccination and to design effective screening strategies in Croatia. [ABSTRACT FROM AUTHOR]

Purpose: One of the major determinants of Dupyutren disease (DD) treatment efficacy is recurrence of the contracture. Unfortunately, lack of agreement in the literature on what constitutes recurrence makes it nearly impossible to compare the multiple treatments alternatives available today. The aim of this study is to bring an unbiased pool of experts to agree upon what would be considered a recurrence of DD after treatment; and from that consensus establish a much-needed definition for DD recurrence. Methods: To reach an expert consensus on the definition of recurrence we used the Delphi method and invited 43 Dupuytren’s research and treatment experts from 10 countries to participate by answering a series of questionnaire rounds. After each round the answers were analyzed and the experts received a feedback report with another questionnaire round to further hone in of the definition. We defined consensus when at least 70% of the experts agreed on a topic. Results: Twenty-one experts agreed to participate in this study. After four consensus rounds, we agreed that DD recurrence should be defined as “more than 20 degrees of contracture recurrence in any treated joint at one year post-treatment compared to six weeks post-treatment”. In addition, “recurrence should be reported individually for every treated joint” and afterwards measurements should be repeated and reported yearly. Conclusion: This study provides the most comprehensive to date definition of what should be considered recurrence of DD. These standardized criteria should allow us to better evaluate the many treatment alternatives. [ABSTRACT FROM AUTHOR]

Background: This study compared outcomes following fingolimod or BRACE treatments (beta-interferons/glatiramer acetate) in patients with active MS (≥ 1 relapse in the previous year) following previous BRACE treatment. Methods and findings: Patients with active MS who previously received BRACE were identified from German prospective, observational studies, PANGAEA and PEARL. A novel methodology was developed to compare outcomes between propensity-score-matched cohorts (3:1 ratio) from the independent single-arm studies. Patients in PANGAEA (n = 1287) experienced 48% fewer relapses per year than those in PEARL (n = 429; annualized relapse rate ratio: 0.52; p < 0.001). The risk of 3-month or 6-month confirmed disability progression (CDP) was reduced in PANGAEA versus PEARL (3-month: 37% reduction; hazard ratio [HR], 0.63; p < 0.001; 6-month: 47% reduction; HR, 0.53; p < 0.001). A higher proportion of patients in PANGAEA (n = 1234) than PEARL (n = 401) were free from relapses and 3-month (65.7% vs 38.7%; p < 0.001) or 6-month (68.2% vs 39.2%; p < 0.001) CDP. The probability of confirmed disability improvement was higher in PANGAEA (n = 1163) than PEARL (n = 372; 3-month: 175% increase; HR, 2.75; p < 0.001; 6-month: 126% increase; HR, 2.26; p < 0.001). Patients in PANGAEA (n = 149) were less likely than those in PEARL (n = 307) to have taken sick leave (proportion with 0 days off work: 62.4% vs 44.6%; p = 0.0005). For change in disease severity from baseline (assessed by clinicians using the Clinical Global Impressions scale; PANGAEA, n = 1207; PEARL, n = 427), a larger proportion of patients had subjective improvement and a smaller proportion had worsening status in PANGAEA than PEARL (improvement: 28.2% vs 15.2%; worsening: 16.4% vs 30.4%; p < 0.0001). Conclusions: Fingolimod appears to be more effective than BRACE in improving clinical and physician-/patient-reported outcomes in individuals with active MS. [ABSTRACT FROM AUTHOR]

Interleukins are a group of immunomodulatory proteins that mediate a variety of immune reactions in the human body. To investigate the association between interleukin gene polymorphisms and recurrent pregnancy loss (RPL), we reviewed 21 studies from MEDLINE, EMBASE, OVID SP and PubMed to evaluate RPL-related interleukin gene polymorphisms. Meta-analysis was performed on 12 of the polymorphisms, and a review included the others. Our integrated results indicated that IL-1β (-511C/T) (P = 0.02, 95% CI 0.77[0.62,0.96]), IL-6 (-634C/G) (P<0.001, 95% CI 2.91[2.01,4.22]), IL-10 (-1082G/A, –819T/C) (P = 0.01, 95% CI 0.80[0.67,0.96]; P<0.01, 95% CI 0.66[0.49,0.89]), and IL-18 (-137G/C, -105G/A) (P<0.01, 95% CI 1.69[1.24,2.31]; P = <0.01, 95% CI 1.41[1.17,1.70]) consistently associated with RPL after meta-analysis. IL-17A rs2275913 and IL-17F rs763780, IL-21 rs2055979 and rs13143866, IL-1β (-31C/T), IL-6 (-2954G/C), and IL-10 (-536A/G) were reported only once as having a significant association with RPL. The potential mechanism underlying miscarriage and these polymorphisms and future research directions are also discussed. [ABSTRACT FROM AUTHOR]

Background: The goal of this study was to perform a systematic review to examine the efficacy and safety of various salvage therapy regimens on patients with relapsed/refractory PTCL. Method: The electronic searches were performed using PubMed, Cochrane Library, EMBASE, and Web of Science from inception through June 2015, with search terms related to relapsed/refractory PTCL, salvage chemotherapy regimens, and clinical trials. An eligible study met the following inclusion criteria: (1) Patients had refractory or relapsed PTCL; (2) drug regimens were used for salvage therapy; (3) the study was a clinical trial; (4) the study reported on a series of at least 10 patients of PTCL. Results: Of 35 records identified, a total of 14 studies were eligible for systematic reviews, and 12 different salvage regimens were investigated. A total of 618 relapsed/refractory PTCL patients were identified. The ORRs ranged from 22% for those treated with lenalidomide to 86% for those with brentuximab vedotin. By the three most frequent subtypes, the ORRs ranged from 14.2% to 71.5% for patients with the PTCL-NOS subtype, 8% to 54% for AITL subtypes, and 24% to 86% for the ALCL subtype. The medians of DOR, PFS, and OS ranged from 2.5 to 16.6 months, 2.6 to 13.3 months, and 3.6 to 14.5 months, respectively. The most frequently reported grade 3 or 4 adverse events (AEs) were hematological AEs, such as neutropenia and thrombocytopenia. Conclusion: The efficacy of salvage therapy regimens is highly diverse for patients with relapsed/refractory PTCL; this heterogeneity in therapeutic effects might be due to the diversity in mechanisms, PTCL subtype distribution, and/or numbers/profiles of prior therapy. Comparative studies with matched pair analysis are warranted for more evidence of the salvage treatment effect on relapsed or heavily pretreated patients with PTCL. [ABSTRACT FROM AUTHOR]

Background: Physical inactivity is highly prevalent after stroke, increasing the risk of poor health outcomes including recurrent stroke. Tailoring of exercise programs to individual preferences can improve adherence, but no tools exist for this purpose in stroke. Methods: We identified potential questionnaire items for establishing exercise preferences via: (i) our preliminary Exercise Preference Questionnaire in stroke, (ii) similar tools used in other conditions, and (iii) expert panel consultations. The resulting 35-item questionnaire (SEPI-35) was administered to stroke survivors, along with measures of disability, depression, anxiety, fatigue and self-reported physical activity. Exploratory factor analysis was used to identify a factor structure in exercise preferences, providing a framework for item reduction. Associations between exercise preferences and personal characteristics were analysed using multivariable regression. Results: A group of 134 community-dwelling stroke survivors (mean age 64.0, SD 13.3) participated. Analysis of the SEPI-35 identified 7 exercise preference factors (Supervision-support, Confidence-challenge, Health-wellbeing, Exercise context, Home-alone, Similar others, Music-TV). Item reduction processes yielded a 13-item version (SEPI-13); in analysis of this version, the original factor structure was maintained. Lower scores on Confidence-challenge were significantly associated with disability (p = 0.002), depression (p = 0.001) and fatigue (p = 0.001). Self-reported barriers to exercise were particularly prevalent in those experiencing fatigue and anxiety. Conclusions: The SEPI-13 is a brief instrument that allows assessment of exercise preferences and barriers in the stroke population. This new tool can be employed by health professionals to inform the development of individually tailored exercise interventions. [ABSTRACT FROM AUTHOR]

Introduction: Adherence to treatment, including early treatment discontinuation, in patients with multiple sclerosis or clinically isolated syndrome can be affected by: treatment tolerability, route of drug administration, patient age, disease duration, comorbidities, medical care, and support from their caregivers. Aim: This study aimed to identify the risk factors for poor adherence to Betaferon® treatment, including early discontinuation and omitting doses. Materials and Methods: 852 adult patients treated with Betaferon participated in this 24-month study. All patients were interviewed using the Risk of Drop-out Questionnaire, the Center for Epidemiologic Studies Depression Scale and the Kurtzke Expanded Disability Status Scale. Results: Patients who stopped therapy were younger (p = 0.003) had a higher mean EDSS score (p = 0.022), higher mean number of relapses (p = 0.017), and reported more often fear of injection (p = 0.027) and adverse events (p = 0.007) than those who did not stop treatment. Comparing patients who stopped therapy in the first and the second year, patients who stopped therapy in the first year of treatment more frequently reported flu-like symptoms and fever, and those who stopped therapy in the second year reported—ineffectiveness of treatment and disease progression. Multivariable logistic regression models confirmed that young age, short disease duration, advanced and progressing disease, and poor Betaferon tolerability were related to premature treatment discontinuation. The risk of omitting a dose during therapy was increased in patients who were working or studying, who had more advanced disease or more adverse events, and in patients who received less support from their caregivers. Conclusions: Several reasons may lead to problems with adherence to Betaferon treatment. Patients at higher risk of discontinuing treatment need to be identified early to make caregivers’ support available to them. [ABSTRACT FROM AUTHOR]

Introduction: Dynamic relationships between the symptoms of psychosis can be shown in individual networks of psychopathology. In a single patient, data collected with the Experience Sampling Method (ESM–a method to construct intensive time series of experience and context) can be used to study lagged associations between symptoms in relation to illness severity and pharmacological treatment. Method: The patient completed, over the course of 1 year, for 4 days per week, 10 daily assessments scheduled randomly between 10 minutes and 3 hours apart. Five a priori selected symptoms were analysed: ‘hearing voices’, ‘down’, ‘relaxed’, ‘paranoia’ and ‘loss of control’. Regression analysis was performed including current level of one symptom as the dependent variable and all symptoms at the previous assessment (lag) as the independent variables. Resulting regression coefficients were printed in graphs representing a network of symptoms. Network graphs were generated for different levels of severity: stable, impending relapse and full relapse. Results: ESM data showed that symptoms varied intensely from moment to moment. Network representations showed meaningful relations between symptoms, e.g. ‘down’ and ‘paranoia’ fuelling each other, and ‘paranoia’ negatively impacting ‘relaxed’. During relapse, symptom levels as well as the level of clustering between symptoms markedly increased, indicating qualitative changes in the network. While ‘hearing voices’ was the most prominent symptom subjectively, the data suggested that a strategic focus on ‘paranoia’, as the most central symptom, had the potential to bring about changes affecting the whole network. Conclusion: Construction of intensive ESM time series in a single patient is feasible and informative, particularly if represented as a network, showing both quantitative and qualitative changes as a function of relapse. [ABSTRACT FROM AUTHOR]

Magnetic resonance spectroscopy (MRS) provides the unique ability to monitor several disease-related pathological processes via their characteristic metabolic markers in vivo. In the present study metabolic compositions were assessed every six months over the period of two years in 36 patients with Multiple Sclerosis (MS) including 21 relapsing-remitting (RR), 15 secondary progressive (SP) patients and 12 normal subjects. The concentrations of the main MRS-detectable metabolites N-acetylaspartate and N-acetylaspartylglutamate (tNAA), creatine and phosphocreatine (tCr), choline containing compounds (Cho), myo-Inositol (Ins), glutamine and glutamate (Glx) and their ratios were calculated in the normal appearing white matter (NAWM) and in selected non-enhancing white matter (WM) lesions. Association between metabolic concentrations in the NAWM and disability were investigated. Concentration of tNAA, a marker for neuroaxonal integrity, did not show any difference between the investigated groups. However, the patients with SPMS showed significant reduction of tNAA in the NAWM over the investigation period of two years indicating diffuse neuroaxonal loss during the disease course. Furthermore, we found a significant increase of Ins, Ins/tCr and Ins/tNAA in WM lesions independently from the course of the disease suggesting ongoing astrogliosis in silent-appearing WM lesions. Analyzing correlations between MRS metabolites in the NAWM and patients clinical status we found the positive correlation of Ins/tNAA with disability in patients with RRMS. In SPMS positive correlation of Cho with disability was found. [ABSTRACT FROM AUTHOR]

Background: Frontalis suspension surgery is considered the procedure of choice in cases of blepharoptosis. Among all the materials used in this type of surgery, ophthalmic and plastic surgeons prefer to use autologous Fascia Lata. However, during years, other autogenous and exogenous materials have been introduced. Objectives: The aim of this study was therefore that of systematically reviewing the functional results and the rate of complications of different synthetic materials, as compared to autogenous Fascia Lata. The primary objective was to determine the rates of Successful Surgeries (SSs) of these materials. The secondary objective was to assess the onset of complications. The following materials were investigated: Fascia Lata, Mersilene, polytetrafluoroethylene (PTFE) and Silicon. Data Source and Methods: Following the Prisma procedure, on January 30th, 2016 we used the following electronic databases to select the studies: MEDLINE and Scopus. Results: The search strategy retrieved 48 publications that met the eligibility criteria of the systematic review. All studies were non-comparative. PTFE (n = 5) showed the best rate of SSs among the materials compared (statistically significant). Surgeries performed with autogenous Fascia Lata (n = 19) had a 87% rate of success those performed with Mersilene (n = 12)had 92% and those performed with Silicon (n = 17)88%. PTFE had the best outcome, with 99% success rate. As for complications, surgeries performed with PTFE had a higher rate of suture infections (1.9%) as compared to Fascia Lata, but lower incidence for all other complications. Conclusions: Although most studies were good quality cohort studies, the overall quality of this evidence should be regarded as low due to their non-comparative design. Our data suggest that PTFE seems to be the most valid alternative material for frontalis suspension surgery, with low recurrence rates and good cosmetic and functional results. [ABSTRACT FROM AUTHOR]

Objective: Antibiotic treatment of acute otitis media (AOM) has been suggested to increase the risk of future AOM episodes by causing unfavorable shifts in microbial flora. Because current evidence on this topic is inconclusive and long-term follow-up data are scarce, we wanted to estimate the effect of antibiotic treatment for a first AOM episode occurring during infancy on AOM recurrences and AOM-related health care utilization later in life. Methods: We obtained demographic information and risk factors from data of the Wheezing Illnesses Study Leidsche Rijn, a prospective birth cohort study in which all healthy newborns born in Leidsche Rijn (between 2001 and 2012), The Netherlands, were enrolled. These data were linked to children’s primary care electronic health records up to the age of four. Children with at least one family physician-diagnosed AOM episode before the age of two were included in analyses. The exposure of interest was the prescription of oral antibiotics (yes vs no) for a child’s first AOM episode before the age of two years. Results: 848 children were included in analyses and 512 (60%) children were prescribed antibiotics for their first AOM episode. Antibiotic treatment was not associated with an increased risk of total AOM recurrences (adjusted rate ratio: 0.94, 95% CI: 0.78–1.13), recurrent AOM (≥3 episodes in 6 months or ≥4 in one year; adjusted risk ratio: 0.79, 95% CI: 0.57–1.11), or with increased AOM-related health care utilization during children’s first four years of life. Conclusions: Oral antibiotic treatment of a first AOM episode occurring during infancy does not affect the number of AOM recurrences and AOM-related health care utilization later in life. This information can be used when weighing the pros and cons of various AOM treatment options. [ABSTRACT FROM AUTHOR]

Background: South African HIV treatment guidelines call for patients who fail first-line antiretroviral therapy (ART) to be switched to second-line ART, yet logistical issues, clinician decisions and patient preferences make delay in switching to second-line likely. We explore the impact of delaying second-line ART after first-line treatment failure on rates of death and virologic failure. Methods: We include patients with documented virologic failure on first-line ART from an observational cohort of 9 South African clinics. We explored predictors of delayed second-line switch and used marginal structural models to analyze rates of death following first-line failure by categorical time to switch to second-line. Cox proportional hazards models were used to examine virologic failure on second-line ART among patients who switched to second-line. Results: 5895 patients failed first-line ART, and 63% switched to second-line. Among patients who switched, median time to switch was 3.4 months (IQR: 1.1–8.7 months). Longer time to switch was associated with higher CD4 counts, lower viral loads and more missed visits prior to first-line failure. Worse outcomes were associated with delay in second-line switch among patients with a peak CD4 count on first-line treatment ≤100 cells/mm3. Among these patients, marginal structural models showed increased risk of death (adjusted HR for switch in 6–12 months vs. 0–1.5 months = 1.47 (95% CI: 0.94–2.29), and Cox models showed increased rates of second-line virologic failure despite the presence of survivor bias (adjusted HR for switch in 3–6 months vs. 0–1.5 months = 2.13 (95% CI: 1.01–4.47)). Conclusions: Even small delays in switch to second-line ART were associated with increased death and second-line failure among patients with low CD4 counts on first-line. There is opportunity for healthcare providers to switch patients to second-line more quickly. [ABSTRACT FROM AUTHOR]