Objective To test a scalable health system intervention to improve long term adherence to secondary prevention treatments among patients who have had a recent myocardial infarction. Design Three arm, pragmatic randomised controlled trial with blinded outcome assessment. Setting Nine cardiac centres in Ontario, Canada. Participants 2632 patients with obstructive coronary artery disease after a myocardial infarction, identified from a centralised cardiac registry. Interventions Participants were randomised 111 to receive usual care, five mail-outs developed through a user centred design process, or mail-outs plus phone calls. The phone calls were delivered first by an interactive automated system to screen for non-adherence to treatment. Trained lay health workers followed up as necessary. Interventions were coordinated centrally but delivered from each patient’s hospital site. Main outcome measures Co-primary outcomes were completion of cardiac rehabilitation and adherence to recommended medication. Data were phone can increase completion of cardiac rehabilitation after myocardial infarction but not adherence to medication. More intensive interventions should be tested to improve adherence to medication and to evaluate the association between attendance at cardiac rehabilitation and adherence to medication. Trial registration ClinicalTrials.gov NCT02382731, registered 9 March 2015 before any patient enrolment.Objective To evaluate potential risk factors that may make patients susceptible to nephrotoxicity in those concomitantly receiving vancomycin in the hospital. Methods This was a single-centre retrospective analysis of patients treated with vancomycin for gram-positive or mixed infections in the Renmin Hospital of Wuhan University from January 2017 to May 2018. All of them were treated for ≥48 hours and had no kidney disease. Nephrotoxicity refers to acute kidney diseases and disorders after the use of vancomycin, and includes acute kidney injury. Univariate analysis and binary logistic regression analysis with the forward stepwise method were used to assess the risk factors associated with nephrotoxicity. Results Of the 790 patients treated with vancomycin, only 257 patients met the inclusion criteria, and 40 (15.6%) subjects developed nephrotoxicity. Significant differences (p less then 0.05) were seen in the number of combined antimicrobials (p=0.012), dose adjustment (p less then 0.001), more than three antimicrobials (p=0.015), monitoring trough concentrations (p=0.001), furosemide (p less then 0.001), torasemide (p less then 0.001), cefoperazone sodium tazobactam sodium (p=0.039), voriconazole (p=0.012) and ganciclovir (p=0.008). Regression analysis further indicated that furosemide (OR 7.983, p less then 0.001) and torasemide (OR 3.496, p less then 0.001) were risk factors for vancomycin nephrotoxicity. Diabetes mellitus (OR 3.062, p=0.035), voriconazole (OR 3.515, p=0.020) and fluconazole (OR 3.326, p=0.018) might be also risk factors. Conclusion Fluconazole and voriconazole might be potential risk factors for vancomycin nephrotoxicity, besides furosemide and torasemide. It is not recommended to use imipenem cilastatin sodium and vancomycin at the same time. If necessary, meropenem may be safer. Appropriate combination drugs, cautious initial dose or timely dose adjustment might reduce the occurrence of nephrotoxicity when using vancomycin.Zika virus infection in humans has been associated with serious reproductive and neurological complications. At present, no protective antiviral drug treatment is available. Here, we describe the testing and evaluation of the antiviral drug, galidesivir, against Zika virus infection in rhesus macaques. We conducted four preclinical studies in rhesus macaques to assess the safety, antiviral efficacy, and dosing strategies for galidesivir (BCX4430) against Zika virus infection. We treated 70 rhesus macaques infected by various routes with the Puerto Rico or Thai Zika virus isolates. We evaluated galidesivir administered as early as 90 min and as late as 72 hours after subcutaneous Zika virus infection and as late as 5 days after intravaginal infection. We evaluated the efficacy of a range of galidesivir doses with endpoints including Zika virus RNA in plasma, saliva, urine, and cerebrospinal fluid. Galidesivir dosing in rhesus macaques was safe and offered postexposure protection against Zika virus infection. Galidesivir exhibited favorable pharmacokinetics with no observed teratogenic effects in rats or rabbits at any dose tested. The antiviral efficacy of galidesivir observed in the blood and central nervous system of infected animals warrants continued evaluation of this compound for the treatment of flaviviral infections.The emergence of Zika virus (ZIKV) in the Americas stimulated the development of multiple ZIKV vaccine candidates. We previously developed two related DNA vaccine candidates encoding ZIKV structural proteins that were immunogenic in animal models and humans. We sought to identify neutralizing antibody (NAb) properties induced by each vaccine that correlated with protection in nonhuman primates (NHPs). Despite eliciting equivalent NAb titers in NHPs, these vaccines were not equally protective. The transfer of equivalent titers of vaccine-elicited NAb into AG129 mice also revealed nonequivalent protection, indicating qualitative differences among antibodies (Abs) elicited by these vaccines. Both vaccines elicited Abs with similar binding titers against envelope protein monomers and those incorporated into virus-like particles, as well as a comparable capacity to orchestrate phagocytosis. Functional analysis of vaccine-elicited NAbs from NHPs and humans revealed a capacity to neutralize the structurally mature form of the ZIKV virion that varied in magnitude among vaccine candidates. Conversely, sensitivity to the virion maturation state was not a characteristic of NAbs induced by natural or experimental infection. Passive transfer experiments in mice revealed that neutralization of mature ZIKV virions more accurately predicts protection from ZIKV infection. These findings demonstrate that NAb correlates of protection may differ among vaccine antigens when assayed using standard neutralization platforms and suggest that measurements of Ab quality, including the capacity to neutralize mature virions, will be critical for defining correlates of ZIKV vaccine-induced immunity.Interventional regenerative medicine (IRM) uses image-guided, minimally invasive procedures for the targeted delivery of stem cell-based therapies to regenerate, replace, or repair damaged organs. Although many cellular therapies have shown promise in the preclinical setting, clinical results have been suboptimal. Most intravenously delivered cells become trapped in the lungs and reticuloendothelial system, resulting in little therapy reaching target tissues. IRM aims to increase the efficacy of cell-based therapies by locoregional stem cell delivery via endovascular, endoluminal, or direct injection into tissues. This review highlights routes of delivery, disease states, and mechanisms of action involved in the targeted delivery of stem cells.Heterozygous mutations of the gene encoding the postsynaptic protein SHANK3 are associated with syndromic forms of autism spectrum disorders (ASDs). One of the earliest clinical symptoms in SHANK3-associated ASD is neonatal skeletal muscle hypotonia. This symptom can be critical for the early diagnosis of affected children; however, the mechanism mediating hypotonia in ASD is not completely understood. Here, we used a combination of patient-derived human induced pluripotent stem cells (hiPSCs), Shank3Δ11(-/-) mice, and Phelan-McDermid syndrome (PMDS) muscle biopsies from patients of different ages to analyze the role of SHANK3 on motor unit development. Our results suggest that the hypotonia in SHANK3 deficiency might be caused by dysfunctions in all elements of the voluntary motor system motoneurons, neuromuscular junctions (NMJs), and striated muscles. We found that SHANK3 localizes in Z-discs in the skeletal muscle sarcomere and co-immunoprecipitates with α-ACTININ. SHANK3 deficiency lead to shortened Z-discs and severe impairment of acetylcholine receptor clustering in hiPSC-derived myotubes and in muscle from Shank3Δ11(-/-) mice and patients with PMDS, indicating a crucial role for SHANK3 in the maturation of NMJs and striated muscle. Functional motor defects in Shank3Δ11(-/-) mice could be rescued with the troponin activator Tirasemtiv that sensitizes muscle fibers to calcium. Our observations give insight into the function of SHANK3 besides the central nervous system and imply potential treatment strategies for SHANK3-associated ASD.Longitudinal cancer monitoring is crucial to clinical implementation of precision medicine. There is growing evidence indicating important functions of extracellular vesicles (EVs) in tumor progression and metastasis, including matrix remodeling via transporting matrix metalloproteases (MMPs). However, the clinical relevance of EVs remains largely undetermined, partially owing to challenges in EV analysis. Distinct from existing technologies mostly focused on characterizing molecular constituents of EVs, here we report a nanoengineered lab-on-a-chip system that enables integrative functional and molecular phenotyping of tumor-associated EVs. A generalized, high-resolution colloidal inkjet printing method was developed to allow robust and scalable manufacturing of three-dimensional (3D) nanopatterned devices. With this nanochip platform, we demonstrated integrative analysis of the expression and proteolytic activity of MMP14 on EVs to detect in vitro cell invasiveness and monitor in vivo tumor metastasis, using cancer cell lines and mouse models. Analysis of clinical plasma specimen showed that our technology could be used for cancer detection including accurate classification of age-matched controls and patients with ductal carcinoma in situ, invasive ductal carcinoma, or locally metastatic breast cancer in a training cohort (n = 30, 96.7% accuracy) and an independent validation cohort (n = 70, 92.9% accuracy). With clinical validation, our technology could provide a useful liquid biopsy tool to improve cancer diagnostics and real-time surveillance of tumor evolution in patients to inform personalized therapy.Well-differentiated and dedifferentiated liposarcomas (LPSs) are characterized by a systematic amplification of the MDM2 oncogene, which encodes a key negative regulator of the p53 pathway. The molecular mechanisms underlying MDM2 overexpression while sparing wild-type p53 in LPS remain poorly understood. Here, we show that the p53-independent metabolic functions of chromatin-bound MDM2 are exacerbated in LPS and mediate an addiction to serine metabolism that sustains nucleotide synthesis and tumor growth. Treatment of LPS cells with Nutlin-3A, a pharmacological inhibitor of the MDM2-p53 interaction, stabilized p53 but unexpectedly enhanced MDM2-mediated control of serine metabolism by increasing its recruitment to chromatin, likely explaining the poor clinical efficacy of this class of MDM2 inhibitors. In contrast, genetic or pharmacological inhibition of chromatin-bound MDM2 by SP141, a distinct MDM2 inhibitor triggering its degradation, or interfering with de novo serine synthesis, impaired LPS growth both in vitro and in clinically relevant patient-derived xenograft models. Our data indicate that targeting MDM2 functions in serine metabolism represents a potential therapeutic strategy for LPS.Background Loss to follow-up is an under-recognised problem in primary care. Continuity with a primary care provider improves morbidity and mortality in the Veterans Health Administration. We sought to reduce the percentage of patients lost to follow-up at the Northeast Ohio Veterans Affairs Healthcare System from October 2017 to March 2019. Methods The Panel Retention Tool (PRT) was developed and tested with primary care teams using multiple Plan, Do, Study and Act cycles to identify and schedule lost to follow-up patients. Baseline data on loss to follow-up, defined as the percentage of panelled patients not seen in primary care in the past year, was collected over 6 months during tool development. Outcomes were tracked from implementation through spread and sustainment (12 months) across 14 primary care clinics. Results Of the 96 170 panelled patients at the beginning of the study period, 2715 (2.8%) were found to be inactive and removed from provider panels, improving panel reliability. Among the remaining, 1856 (1.9%) patients without scheduled follow-up were scheduled for future care, and 1239 (1.3%) without recent prior care completed encounters during the study period. The percentage of patients lost to follow-up decreased from 10.1% (lower control limit (LCL) 9.8%-upper control limit (UCL) 10.4%) at baseline to 6.4% (LCL 6.2%-UCL 6.7%) postintervention and patients without planned future care decreased from 21.7% (LCL 21.3%-UCL 22.1%) to 17.1% (LCL 16.7%-UCL 17.5%). Conclusions The PRT allowed primary care teams in an integrated health system to identify and schedule lost to follow-up patients. Ease of use, adaptability and encouraging outcomes facilitated spread. This has the potential to contribute to more appropriate utilisation of healthcare resources and improved access to primary care.Objective To assess the pathophysiologic changes in patients with spontaneous intracranial hypotension (SIH) based on measures of CSF dynamics, and on the duration of symptoms, in a retrospective case-controlled study. Methods We included consecutive patients investigated for SIH at our department from January 2012 to February 2018. CSF leak was considered confirmed if extrathecal contrast spillage was seen on imaging (CT or MRI) after intrathecal contrast application, or dural breach was detected by direct intraoperative visualization. We divided patients with a confirmed CSF leak into 3 groups depending on the symptom duration, as follows ≤10, 11-52, and >52 weeks. Clinical characteristics and measures of CSF fluid dynamics obtained by computerized lumbar infusion testing were analyzed over time and compared with a reference population. Results Among the 137 patients included, 69 had a confirmed CSF leak. Whereas 93.1% with 10 weeks of symptoms did (p = 0.004). Analysis of infusion tests revealed differences between groups with different symptom duration for CSF outflow resistance (p less then 0.001), lumbar baseline pressure (p = 0.013), lumbar plateau pressure (p less then 0.001), baseline pressure amplitude (p = 0.021), plateau pressure amplitude (p = 0.001), pressure-volume index (p = 0.001), elastance (p less then 0.001), and CSF production rate (p = 0.001). Compared to the reference population, only patients with acute symptoms showed a significantly altered CSF dynamics profile. Conclusion A CSF leak dramatically alters CSF dynamics acutely, but the pattern changes over time. There is an association between the clinical presentation and changes in CSF dynamics.Objective To investigate the relationship between the ATN classification system (amyloid, tau, neurodegeneration) and risk of dementia and cognitive decline in individuals with subjective cognitive decline (SCD). Methods We classified 693 participants with SCD (60 ± 9 years, 41% women, Mini-Mental State Examination score 28 ± 2) from the Amsterdam Dementia Cohort and Subjective Cognitive Impairment Cohort (SCIENCe) project according to the ATN model, as determined by amyloid PET or CSF β-amyloid (A), CSF p-tau (T), and MRI-based medial temporal lobe atrophy (N). All underwent extensive neuropsychological assessment. For 342 participants, follow-up was available (3 ± 2 years). As a control population, we included 124 participants without SCD. Results Fifty-six (n = 385) participants had normal Alzheimer disease (AD) biomarkers (A-T-N-), 27% (n = 186) had non-AD pathologic change (A-T-N+, A-T+N-, A-T+N+), 18% (n = 122) fell within the Alzheimer continuum (A+T-N-, A+T-N+, A+T+N-, A+T+N+). ATN profiles were unevenly distributed, with A-T+N+, A+T-N+, and A+T+N+ containing very few participants. Cox regression showed that compared to A-T-N-, participants in A+ profiles had a higher risk of dementia with a dose-response pattern for number of biomarkers affected. Linear mixed models showed participants in A+ profiles showed a steeper decline on tests addressing memory, attention, language, and executive functions. In the control group, there was no association between ATN and cognition. Conclusions Among individuals presenting with SCD at a memory clinic, those with a biomarker profile A-T+N+, A+T-N-, A+T+N-, and A+T+N+ were at increased risk of dementia, and showed steeper cognitive decline compared to A-T-N- individuals. These results suggest a future where biomarker results could be used for individualized risk profiling in cognitively normal individuals presenting at a memory clinic.Objective A prior meta-analysis of reports published between 2000 and 2008 found that women were 30% less likely to receive IV recombinant tissue plasminogen activator (rtPA) treatment for stroke than men; we updated this meta-analysis to determine if this sex difference persisted. Methods We identified studies that reported sex-specific IV rtPA treatment rates for acute ischemic stroke published between 2008 and 2018. Eligible studies included representative populations of patients with ischemic stroke from hospital-based, registry-based, or administrative data. Random effects odds ratios (ORs) were generated to quantify sex differences. Results Twenty-four eligible studies were identified during this 10-year period. The summary unadjusted OR based on 17 studies with data on all ischemic stroke patients was 0.87 (95% confidence interval [CI], 0.82-0.93), indicating that women had 13% lower odds of receiving IV rtPA treatment than men. However, substantial between-study variability existed. Lower treatment odds in women were also observed in 7 studies that provided data on the subgroup of patients eligible for IV rtPA treatment, although the summary OR of 0.95 (95% CI, 0.88-1.02) was not statistically significant. Examination of time trends across 33 studies published between 2000 and 2018 found evidence that the sex difference had narrowed in more recent years. Conclusions Although there is considerable variability in the findings of individual studies, pooled data from recent studies show that women with acute stroke are less likely to be treated with IV thrombolysis compared with men. However, the size of this difference has narrowed compared to studies published before 2008.Purpose To study the longitudinal effect of anterior chamber inflammation on the corneal endothelium in children. Methods In this prospective longitudinal observational study, children (aged less then 18 years) with anterior chamber inflammation and those at risk of developing uveitis due to juvenile idiopathic arthritis (JIA) were included. Changes in central endothelial cell density (ECD) and morphological variables were determined by non-contact specular microscopy, and their correlations with uveitis activity and surgical interventions were analysed. Results Ninety-nine eyes of 99 children (mean age (±SD) 10.0±4.1 years) with a history of anterior chamber inflammation were recruited. Mean follow-up was 12.3±3.5 months. Eleven children, who were under surveillance but had not developed JIA-associated uveitis were included as controls. While there were no significant differences in mean ECD between controls and subjects without prior surgery (group 1) at all time points, those who had prior ophthalmic surgery (group 2) displayed significantly lower ECD than the controls at recruitment (p=0.002) and at follow-up (p=0.004). However, longitudinal ECD assessments did not show significant changes in either group (group 1, p=0.07, group 2, p=0.54). On regression analysis, once the patient’s age was adjusted for, only the occurrence of intraocular procedures during the study (r=0.43, adjusted p=0.03) was associated with a significant annual rate of ECD loss. Conclusion During the study period, longitudinal ECD changes among children with uveitis were associated with intraocular surgery for uveitis-related complications but not uveitis activity. By reducing the need for surgical intervention, the corneal endothelium in these children may be preserved.Background Recent reports have suggested a significant change in the causes of blindness in children in low-income countries cataract becoming the leading cause. We aimed to investigate the presentations and surgical outcomes in children with cataract operated at different ages in Tanzania. Methods We conducted a prospective study of 228 children aged ≤192 months at three tertiary centres, 177 with bilateral cataracts and prospectively followed them for 1-year postsurgery. We collected demographic, surgical, preoperative and postoperative clinical characteristics using the standard childhood cataract surgical assessment questionnaire. Families were encouraged to return for follow-up by phone with travel reimbursement where necessary. Results Preoperatively, 76% bilateral children were blind in the better eye. 86% of children were followed up at 1 year and 54% bilateral children achieved visual acuity of 0.48 logMAR or better in the better eye and 5% were blind. 33% of unilateral children achieved visual acuity of 0.48 logMAR or better and 17% were blind. Preoperative blindness (adjusted OR (AOR) 14.65; 95% CI 2.21 to 97.20), preoperative nystagmus/strabismus (AOR 9.22; 95% CI 2.66 to 31.97) and aphakia (AOR, 5.32; 95% CI 1.05 to 26.97) predicted poor visual outcome in bilateral cases. 9% of 342 refracted eyes had initial postoperative cylinder of 1.5 D or more, as did a similar proportion (11%) of 315 eyes refracted 1 year after surgery. Acute fibrinous uveitis occurred in 41 (12%) eyes. Conclusion Three-quarters of children were blind preoperatively whereas over half had good vision 1-year postoperatively. Preoperative blindness, nystagmus/strabismus and aphakia predicted poor visual outcome, suggesting that cataract density determines density of amblyopia.Aims To identify the association between ranibizumab and risk of stroke and acute myocardial infarction (AMI) in patients with exudative age-related macular degeneration (AMD). Methods We identified patients aged ≥45 years who received ranibizumab for exudative AMD from the Korean National Health Insurance database. Of these, we selected patients suffering stroke or AMI for the self-controlled case series. We estimated incidence rate ratios (IRR) for stroke or AMI by comparing incidence rates of ranibizumab-exposed periods to that of baseline using conditional Poisson regression. The risks of haemorrhagic and ischaemic strokes were also calculated separately. Results Among 33 134 patients receiving ranibizumab, 2397 patients had stroke or AMI. The risk of stroke (IRR=0.83, 95% CI 0.75 to 0.91) was not increased during the overall exposed period; however, there was a marginally elevated risk in ≥57 days exposed period (IRR=1.14, 95% CI 1.001 to 1.31). When analysing by the types of stroke, no increased risks of haemorrhagic (IRR=1.01, 95% CI 0.80 to 1.26) and ischaemic stroke (IRR=0.78, 95% CI 0.71 to 0.86) were observed during the exposed period, although the risks of ischaemic and haemorrhagic stroke were slightly elevated during ≥57 days exposed period. We could not find an association between ranibizumab and AMI. Conclusions Ranibizumab intravitreal injections did not increase the overall risk of stroke or AMI. Although the cardiovascular risk in patient receiving ranibizumab seems to be low, continuous monthly use of ranibizumab for high-risk patients should be judged carefully.Background As a majority of patients with choroidal melanoma do not undergo enucleation, tumour tissue for prognostic testing has to be obtained with alternate methods. Transvitreal incisional biopsies enable histological examination as well as immunohistochemical staining of BRCA1-associated protein-1 (BAP-1). Methods Fifty-nine patients diagnosed with choroidal melanoma in transvitreal biopsies between years 2003 and 2019 were included. Twenty-one of these patients subsequently underwent enucleation. The level of nuclear expression of BAP-1 in transvitreal biopsies and enucleations was evaluated and the concordance calculated. Metastasis-free survival and HR for metastasis were analysed. Results The mean tumour thickness and diameter at biopsy was 3.8 mm (SD 2.1) and 9.3 mm (SD 4.8), respectively. For biopsies, 37 of 59 tumours (63%) were classified as having high nuclear BAP-1 expression, and 22 (37%) as low. For enucleations, 13 of 21 tumours (62%) were classified as having high nuclear BAP-1 expression, and 8 (38%) as low. Eighty-six per cent of biopsies had an identical BAP-1 classification as the subsequent enucleation, yielding a Cohen’s kappa coefficient of 0.70. Patients with low nuclear BAP-1 expression in transvitreal biopsies had a significantly shorter metastasis-free survival (p=0.001), with a size-adjusted Cox regression HR for metastasis of 13.0 (95% CI 3.1 to 54.4, p=0.0004). Conclusion Loss of nuclear BAP-1 expression occurred in a large proportion of the small tumours included in this study. BAP-1 immunoreactivity in transvitreal incisional biopsies of choroidal melanoma is substantially concordant with immunoreactivity in enucleated specimens and identifies patients with poor metastasis-free survival.Background To estimate the 10-year incidence of referable diabetic retinopathy (DR) in a French population with type 1 and 2 diabetes mellitus (DM). A secondary objective was the assessment of safe screening intervals in patients with diabetes without retinopathy. Methods Observational, prospective and multicentric study between June 2004 and September 2017 based on a regional screening programme for DR in the Paris region. The incidence of referable DR in patients without retinopathy at baseline was calculated by the Turnbull survival estimator. A safe screening interval was defined as a 95% probability of remaining without referable DR. Results Among the 25 745 participants with type 1 (n=6086) or type 2 (n=19 659) DM, the 10-year cumulative incidence of referable DR was 19.10% (95% CI 17.21% to 21.14%) and 17.03% (15.78% to 18.35%), median (IQR) follow-up=3.33 (4.24) years. The safe screening interval for patients without DR at the first examination for type 1 and 2 DM was 2.2 (95% CI 2.0 to 2.4) and 3.0 (2.9 to 3.1) years, respectively. In a subgroup of low-risk patients with type 2 DM, the safe screening interval was 4.2 (3.8 to 4.6) years. Conclusions These data suggest that in Paris area, a 2-year, 3-year and 4-year screening interval was considered safe for type 1 DM, type 2 DM and for low-risk patients with type 2 DM, respectively, without DR at the first examination. While these data might be used to support the consideration of extending screening intervals, a randomised clinical trial would be suitable to confirm the safety for patients with DM.Background/aims To compare the accuracy of 13 formulas for intraocular lens (IOL) power calculation in cataract surgery. Methods In this retrospective interventional case series, optical biometry measurements were entered into these formulas Barrett Universal II (BUII) with and without anterior chamber depth (ACD) as a predictor, EVO 2.0 with and without ACD as a predictor, Haigis, Hoffer Q, Holladay 1, Holladay 2AL, Kane, Næser 2, Pearl-DGS, RBF 2.0, SRK/T, T2 and VRF. The mean prediction error (PE), median absolute error (MedAE), mean absolute error and percentage of eyes with a PE within ±0.25, ±0.50, ±0.75 and ±1.00 diopters (D) were calculated. Results Two hundred consecutive eyes were enrolled. With all formulas, the mean PE was zero. The BUII with no ACD had the lowest standard deviation (±0.343 D), followed by the T2 (0.347 D), Kane (0.348 D), EVO 2.0 with no ACD (0.348 D) and BUII with ACD (0.353 D) formulas. The difference among the MedAEs of all formulas was statistically significant (p less then 0.0001); the lowest values were achieved with the Kane (0.214 D), RBF 2.0 (0.215 D), BUII with and without ACD (0.218 D) and SRK/T (0.223 D). A percentage ranging from 80% to 88.5% of eyes showed a PE within ±0.50 D and all formulas achieved more than 50% of eyes with a PE within ±0.25 D. Conclusion All investigated formulas achieved good results; there was a tendency towards better outcomes with newer formulas. Traditional formulas can still be considered an accurate option.Background Microcephalic primordial dwarfism (MPD) is a heterogeneous group of rare disorders. Recent studies have reported a significant percentage of patients with MPD suffering from a spectrum of cerebrovascular abnormalities, including intracranial aneurysms (IAs) and moyamoya syndrome. The neurological literature has not as yet specifically assessed IAs in this population. This systematic review aimed to assess the clinical behavior, characteristics, treatment modalities and outcomes of IAs in patients with MPD. Methods We performed a systematic search in PubMed, Ovid MEDLINE and Ovid EMBASE for cases of MPD with IAs. We included three illustrative cases from our institution. Results Twenty-four patients with 71 aneurysms were included in this study. Twelve patients (50%) presented with subarachnoid hemorrhage. The majority of patients were aged ≤18 years (70.8%), with a mean age of 16.2 years at presentation. Median aneurysm size was 3 (IQR 1.8-6) mm, and the most frequent locations were the internal carotid (37.3%) and middle cerebral arteries (23.8%). Concomitant moyamoya disease was reported in nine (37.5%) patients. Median age of aneurysm detection in screened patients was significantly lower than in non-screened patients (P=0.02). Microsurgical clipping (55.3%) and endovascular coiling (26.3%) were the most used modalities. Twenty-two cases were managed conservatively. Overall, mortality occurred in 45.8% of cases. Conclusions Screening for cerebrovascular disease seems reasonable and effective to detect aneurysms at an earlier age in this population. Efforts in the literature to emphasize early and regular screening for these patients can positively impact outcomes in this population, however more evidence is needed.Background Transverse sinus (TS) stenting is a valid treatment alternative for patients with intracranial hypertension caused by underlying bilateral TS stenoses. Its mid-term patency has, however, not been well documented. Objective To assess the 6-month patency of TS stenting using subtracted CT venography (CTV). Methods A retrospective analysis of a prospectively collected database of patients undergoing TS stenting was performed. The cohort was a single-center, single-operator series of 125 consecutive patients treated between 2008 and 2018. Mid-term follow-up 320-row detector CTV was available for review in 104 patients. Results Follow-up CTV was obtained on average 6 months after stenting. Stents in all patients (100%) were patent. Subtracted reconstructions showed no intraluminal thrombus or neointimal hyperplasia. Native reconstructions confirmed the structural integrity of the stents. De novo stenosis proximal to the stent was noted in 10 cases (10%). A total of 10 patients (10%) received additional treatment due to recurrent symptoms. In univariate analysis, both high body mass index and stent size (>6 mm) were associated with development of de novo stenoses OR 1.12 (95% CI 1.01 to 1.25, p=0.037) and OR 5.63 (95% CI 1.16 to 27.22, p=0.032), respectively. In multivariate analysis, only stent size (>6 mm) remained significant OR 7.19 (95% CI 1.03 to 50.01, p=0.046). Conclusion TS stenting is an effective treatment for intracranial hypertension secondary to dural sinus stenosis in an appropriately selected patient population. A 320-row dynamic CTV is a high-quality non-invasive imaging method that can assess both the physical integrity of the stent and its patency. At mid-term follow-up, all imaged stents were patent. The occurrence of de novo stenoses proximal to the stent (10%) correlated with stent size (>6 mm).Background Accero is an innovative, fully visible, self-expanding braided stent with platinum-nitinol composite wire technology, produced by Acandis. Objective To assess the technical success and safety of this new stent by evaluating the intraprocedural behavior and complication rate, and the short-term follow-up results. Methods Forty-one consecutive patients suitable for stent-assisted coiling were selected for the use of Accero in an 11-month period. Clinical, procedural, and angiographic data, as well as 30-day morbidity, were recorded. The angiographic results, clinical follow-up at 30 days, and early imaging follow-up at 3 or 6 months were analyzed, when available. Results Forty-one aneurysms were treated with stent-assisted coiling. All cases were elective, of which 19 were previously untreated aneurysms and 22 were recurrent aneurysms. Aneurysm location was anterior communicating artery complex (16), basilar (12 cases), middle cerebral artery bifurcation (9 cases), and internal cerebral artery (4 cases). The stent was successfully deployed and aneurysm occlusion with coils achieved in 100% of our patients. One case of on table in-stent thrombosis occurred, which resolved after administration of glycoprotein IIB/IIIA inhibitor, with no clinical consequence, and one case of postoperative hematoma at the arteriotomy site, which was managed conservatively. On early follow-up, available for 37 patients, the complete occlusion rate was 76%, with only two recurrences needing further treatment. Satisfactory aneurysm occlusion was therefore achieved in 95% of cases. Conclusion Stent-assisted coiling with the Accero braided stent proved safe and effective.Context Latinx adolescents are at risk for negative sexual health outcomes, and many interventions have been developed to reduce this risk. Objective In this meta-analysis, we synthesized the literature on sexual health interventions for Latinx adolescents and examined intervention effects on 3 behavioral outcomes (abstinence, condom use, number of sex partners) and 3 psychological outcomes (safer sex knowledge, intentions, self-efficacy). Moderators of intervention success were explored. Data sources A systematic search of studies published through January 2019 was conducted by using PubMed, PsycINFO, and Cumulative Index to Nursing and Allied Health Literature databases. Study selection All studies included a US-based sample of Latinx adolescents, evaluated sexual health intervention by using an experimental or quasiexperimental design, included a behavioral outcome, and were in English. Data extraction Standardized mean difference (d) and 95% confidence intervals (CIs) were meta-analyzed by using random-effects models. Results Effect sizes from 12 studies, sampling 4673 adolescents, were synthesized. Sexual health interventions improved abstinence (d = 0.15, 95% CI 0.02 to 0.28), condom use (d = 0.44, 95% CI 0.18 to 0.70), number of sex partners (d = -0.19, 95% CI -0.37 to -0.001), and sexual health knowledge (d = 0.40, 95% CI 0.10 to 0.70), compared with control conditions. Effects were consistent across a number of demographic and clinical characteristics, although culturally tailored interventions produced greater change in condom use than nontailored interventions. Limitations There was variation across studies in measures of sexual behavior, and some elements of individual study quality were unclear. Conclusions Sexual health interventions have a small but significant impact on improving safer sexual behavior among Latinx adolescents. Health educators should consider the importance of cultural tailoring to program success.Using live microbes as therapeutic candidates is a strategy that has gained traction across multiple therapeutic areas. In the skin, commensal microorganisms play a crucial role in maintaining skin barrier function, homeostasis, and cutaneous immunity. Alterations of the homeostatic skin microbiome are associated with a number of skin diseases. Here, we present the design of an engineered commensal organism, Staphylococcus epidermidis, for use as a live biotherapeutic product (LBP) candidate for skin diseases. The development of novel bacterial strains whose growth can be controlled without the use of antibiotics or genetic elements conferring antibiotic resistance enables modulation of therapeutic exposure and improves safety. We therefore constructed an auxotrophic strain of S. epidermidis that requires exogenously supplied d-alanine. The S. epidermidis NRRL B-4268 Δalr1 Δalr2 Δdat strain (SEΔΔΔ) contains deletions of three biosynthetic genes two alanine racemase genes, alr1 and alr2 (SE1674 and SE1079), and in vitro evidence of a skin commensal whose growth can be controlled through d-alanine. The basis of this strain will support future clinical studies of this strain in humans.Biofilms usually form when the density of bacteria increases during the middle to late periods of growth in culture, commonly induced by quorum-sensing systems. Biofilms attach to the surfaces of either living or nonliving objects and protect bacteria against antibiotics and a host’s immune system. Here, a novel type of biofilm (the „R-biofilm”) is reported. These biofilms were formed by clinically isolated Klebsiella pneumoniae strains following double-stranded-DNA breaks (DSBs), while undamaged bacteria did not form classic biofilms even in the later stages of growth. R-biofilms had a fixed ring-like or discoid shape with good ductility and could protect many living bacterial cells within. We show that extracellular proteins and DNAs released, probably by dead bacteria, were the core structural materials of R-biofilms. We anticipate that novel signaling pathways besides the bacterial SOS response are involved in R-biofilm formation. The observations in this study suggest a limitation to the use of the currently popular Cas9-mediated bactericidal tools to eliminate certain bacteria because the resulting DSBs may lead to the formation of these protective R-biofilms.IMPORTANCE Many pathogenic bacteria can form biofilm matrices that consist of complex molecules such as polysaccharides, proteins, and DNA. These biofilms help the bacteria to infect and colonize a host. Such biofilms may attach and develop on the surfaces of indwelling medical devices or other supportive environments. This study found that following double-strand breaks in their DNA, Klebsiella pneumoniae cells can form a novel type of biofilm with ring-like or discoid morphology. This biofilm structure, named the „R-biofilm,” helps protect the bacteria against adverse conditions such as exposure to ethanol, hydrogen peroxide, and UV radiation.Salmonella comprises more than 2,600 serovars. Very few environmental and uncommon serovars have been characterized for their potential role in virulence and human infections. A complementary in vitro and in vivo systematic high-throughput analysis of virulence was used to elucidate the association between genetic and phenotypic variations across Salmonella isolates. The goal was to develop a strategy for the classification of isolates as a benchmark and predict virulence levels of isolates. Thirty-five phylogenetically distant strains of unknown virulence were selected from the Salmonella Foodborne Syst-OMICS (SalFoS) collection, representing 34 different serovars isolated from various sources. Isolates were evaluated for virulence in 4 complementary models of infection to compare virulence traits with the genomics data, including interactions with human intestinal epithelial cells, human macrophages, and amoeba. In vivo testing was conducted using the mouse model of Salmonella systemic infection. Significane is enormous variation in the virulence of different isolates of Salmonella enterica Identification of foodborne pathogens is a lengthy process based on microbiological, biochemical, and immunological methods. Here, we worked toward new ways of integrating whole-genome sequencing (WGS) approaches into food safety practices. We used WGS to build associations between virulence and genetic diversity within 83 Salmonella isolates representing 77 different Salmonella serovars. Our work demonstrates the potential of combining a genomics approach and virulence tests to improve the diagnostics and assess risk of human illness associated with specific Salmonella isolates.There is a critical need for an improved rapid diagnostic for enteric fever. We have previously demonstrated that serum IgA responses targeting Salmonella enterica serovar Typhi hemolysin E (HlyE) and lipopolysaccharide (LPS) are able to discriminate patients with acute typhoid from healthy controls in areas where enteric fever is endemic (healthy endemic controls) and from patients with other bacterial infections. We now have data demonstrating that IgA antibody responses against these antigens also work well for identifying patients with acute S. Paratyphi A infection. To develop a test for acute enteric fever detection, we have adapted a point-of-care immunochromatographic dual-path platform technology (DPP), which improves on the traditional lateral flow technology by using separate sample and conjugate paths and a compact, portable reader, resulting in diagnostics with higher sensitivity and multiplexing abilities. In this analysis, we have compared our standard enzyme-linked immunosorbent assay (ELISA) endorsing the role of the typhoid conjugate vaccine in communities where enteric fever is endemic. A reliable diagnostic test is needed to assess and evaluate typhoid intervention strategies and determine which high-burden areas may benefit most from a vaccine intervention. Our collaborative team has developed and evaluated a point-of-care serodiagnostic assay based on detection of anti-HlyE and LPS IgA. Our finding of the high diagnostic accuracy of the DPP Typhoid System for the rapid detection of enteric fever has the potential to have significant public health impact by allowing for improved surveillance and for control and prevention programs in areas with limited laboratory capacity.Introduction Short-term survival rates of patients with BRCA-mutated ovarian cancer have been previously shown to be longer than those of non-carriers. We aimed to study the long-term survival rates of these patients and investigate whether the 5-year advantage decreases over time. Methods A systematic review of the literature was conducted according to the Preferred Reporting Items for Systematic reviews and Meta-Analyzes (PRISMA) statement. The study protocol can be assessed at PROSPERO International prospective register of systematic reviews (http//www.crd.york.ac.uk/PROSPERO, registration number CRD42019137455). We considered for inclusion studies providing Kaplan-Meier survival curves up to and including 10 years, comparing patients with ovarian cancer with and without BRCA mutations. Our main outcome was the conditional probability of surviving an additional 5 years. Results A total of 13 references comprising 4565 patients was analyzed, of which 1131 BRCA1/2-mutated carriers and 3434 non-carriers were to prolong the long-term survival of BRCA-mutated patients.Objective The survival and prognostic factors for locally advanced cervical cancer treated with nerve-sparing Okabayashi-Kobayashi radical hysterectomy have not been elucidated. We aimed to evaluate the oncological outcomes of those patients after radical hysterectomy with adjuvant chemotherapy. Methods This retrospective cohort study was conducted from January 2002 to December 2011. Treatment was conducted at a single tertiary center in northern Japan. We used the Okabayashi-Kobayashi radical hysterectomy with lymphadenectomy. We applied unilateral nerve preservation for stage IIA/IIB cancer if there was a one-sided extension of the disease outside the cervix. Indication for adjuvant therapy was based on Sedlis criteria. High-risk was defined as evidence of lymph node metastasis, pathological parametrial invasion, and a positive/close surgical margin. The choice of adjuvant therapy was chemotherapy which consisted of paclitaxel and cisplatin. Results The study included 76 early-stage IB1 (≤4 cm) and IIA1 ceretastasis may be a possible option as a treatment of locally advanced cervical cancer in selected patients.Objective Risk stratification has resulted in patient-initiated follow-up being introduced for low-risk endometrial cancer in place of routine hospital follow-up. The financial benefit to the patient and the healthcare economy of patient-initiated follow-up, as compared with hospital follow-up, has yet to be explored. In this study, we explored the potential impact for both the healthcare economy and patients of patient-initiated follow-up. Methods Women diagnosed with low-risk endometrial cancer enrolled on a patient-initiated follow-up scheme between November 2014 and September 2018 were included. Data on the number of telephone calls to the nurse specialists and clinic appointments attended were collected prospectively. The number of clinic appointments that would have taken place if the patient had continued on hospital follow-up, rather than starting on patient-initiated follow-up, was calculated and costs determined using standard National Health Service (NHS) reference costs. The time/distance traveledmanagement follow-up scheme for low-risk endometrial cancer was associated with financial/time saving to both the patient and the healthcare economy as compared with hospital follow-up.Background Concurrent chemoradiotherapy is the first-line treatment for FIGO stage IIB cervical cancer. Neoadjuvant chemotherapy followed by radical surgery may provide another treatment option. Primary objective To compare the therapeutic outcomes of neoadjuvant chemotherapy followed by surgery with cisplatin-based concurrent chemoradiotherapy for stage IIB cervical cancer. Study hypothesis We hypothesize that the therapeutic effect of neoadjuvant chemotherapy combined with surgery and risk-adapted adjuvant treatment will be superior to that of concurrent chemoradiotherapy in stage IIB cervical cancer. Trial design Patients with stage IIB cervical cancer will be randomized 11 to neoadjuvant chemotherapy followed by surgery (Arm A) or concurrent chemoradiotherapy (Arm B). In arm A, patients will receive three cycles of paclitaxel and cisplatin followed by a type C radical hysterectomy and pelvic ±paraaortic lymphadenectomy. Patients showing progression after neoadjuvant chemotherapy will be referred to concurrent chemoradiotherapy. Adjuvant therapy will be recommended according to the presence of pathological risks. In Arm B, all patients will receive definitive concurrent chemoradiotherapy, including external beam pelvic radiotherapy combined with concurrent weekly cisplatin followed by brachytherapy. Major inclusion/exclusion criteria Patients between 18 and 60 years with histologically confirmed, untreated stage IIB cervical squamous carcinoma, adenocarcinoma, or adeno-squamous carcinoma. Primary endpoint The primary endpoint is 2-year disease-free survival. Sample size An estimated sample size of 240 is required to fulfill the study objectives. Estimated dates for completing accrual and presenting results As of February 2020, 115 eligible patients from four institutions have been enrolled. Enrollment is expected to be completed by December 2022. Trial registration number ClinicalTrials. gov identifier NCT02595554.Introduction Delays from primary surgery to chemotherapy are associated with worse survival in ovarian cancer, however the impact of delays from neoadjuvant chemotherapy to interval debulking surgery is unknown. We sought to evaluate the association of delays from neoadjuvant chemotherapy to interval debulking with survival. Methods Patients with a diagnosis of stage III/IV ovarian cancer receiving neoadjuvant chemotherapy from July 2015 to December 2017 were included in our analysis. Delays from neoadjuvant chemotherapy to interval debulking were defined as time from last preoperative carboplatin to interval debulking >6 weeks. Fisher’s exact/Wilcoxon rank sum tests were used to compare clinical characteristics. The Kaplan-Meier method, log-rank test, and multivariate Cox Proportional-Hazards models were used to estimate progression-free and overall survival and examine differences by delay groups, adjusting for covariates. Results Of the 224 women, 159 (71%) underwent interval debulking and 34 (21%) of these experienced delays from neoadjuvant chemotherapy to interval debulking. These women were older (median 68 vs 65 years, P=0.05) and received more preoperative chemotherapy cycles (median 6 vs 4, P=0.003). Delays from neoadjuvant chemotherapy to interval debulking were associated with worse overall survival (HR 2.4 95% CI 1.2 to 4.8, P=0.01), however survival was not significantly shortened after adjusting for age, stage, and complete gross resection, HR 1.66 95% CI 0.8 to 3.4, P=0.17. Delays from neoadjuvant chemotherapy to interval debulking were not associated with worse progression-free survival (HR 1.55 95% CI 0.97 to 2.5, P=0.062). Increase in number of preoperative cycles (P=0.005) and lack of complete gross resection (P less then 0.001) were the only variables predictive of worse progression-free survival. Discussion Delays from neoadjuvant chemotherapy to interval debulking were not associated with worse overall survival after adjustment for age, stage, and complete gross resection.Strategies to radically suppress incidence of COVID-19, as used in higher-income countries, may be unrealistic and counterproductive in most low- and lower middle-income countries. Instead, strategies should be tailored to the setting, balancing expected benefits, potential harms, and feasibility.Severity of hypoxaemia can be assessed using the partial pressure of arterial oxygen to fraction of inspired oxygen ratio (FiO2). However, in patients breathing through non-rebreather reservoir bag oxygen mask, accuracy of bedside FiO2 estimation methods remains to be tested. In a post-hoc analysis of a multicentre clinical trial, three FiO2 estimation methods were compared with FiO2 measured with a portable oxygen analyser introduced in the oxygen mask. Among 262 patients analysed, mean (SD) measured FiO2 was 65% (13). The 3%-formula (21% + oxygen flow rate in L/min × 3) was the most accurate method to estimate FiO2 Other methods overestimated FiO2 and hypoxaemia severity, so they should be avoided.Crane numbers in the UK are at a 400-year high after conservation efforts. Emma Culjat-Vukman reports.Objectives Exposure to infection is an inherent occupational risk for healthcare workers and may lead them to undergo quarantine during disease outbreaks. Both front-line battle and quarantine are stressful experiences that may make psychological support for healthcare workers necessary. Psychological support measures based on the best available evidence should be included in emergency plans worldwide. We summarise the research evidence on the psychological impact of quarantine on healthcare workers. Methods We retrieved 470 articles on the psychological impact of quarantine on healthcare workers from the Web of Science and included in this review all 12 articles that met our inclusion criteria. Results The reviewed studies reported acute stress during quarantine and long-lasting depressive, post-traumatic stress and alcohol dependency and abuse symptoms. Healthcare workers fear infection for themselves, but more so for their loved ones, and are also concerned about the stigma that may affect their families, most especially their children.