Human Pluripotency Is Initiated and Preserved by a Unique Subset of Founder Cells.

The assembly of organized colonies is the earliest manifestation in the derivation or induction of pluripotency in vitro. However, the necessity and origin of this assemblance is unknown. Here, we identify human pluripotent founder cells (hPFCs) that initiate, as well as preserve and establish, pluripotent stem cell (PSC) cultures. PFCs are marked by N-cadherin expression (NCAD+) and reside exclusively at the colony boundary of primate PSCs. As demonstrated by functional analysis, hPFCs harbor the clonogenic capacity of PSC cultures and emerge prior to commitment events or phenotypes associated with pluripotent reprogramming. Comparative single-cell analysis with pre- and post-implantation primate embryos revealed hPFCs share hallmark properties with primitive endoderm (PrE) and can be regulated by non-canonical Wnt signaling. Uniquely informed by primate embryo organization in vivo, our study defines a subset of founder cells critical to the establishment pluripotent state.

Development of automated metabolite control using mid-infrared probe for bioprocesses and vaccine manufacturing.

Automation of metabolite control in fermenters is fundamental to develop vaccine manufacturing processes more quickly and robustly. We created an end-to-end process analytical technology and quality by design-focused process by replacing manual control of metabolites during the development of fed-batch bioprocesses with a system that is highly adaptable and automation-enabled. Mid-infrared spectroscopy with an attenuated total reflectance probe in-line, and simple linear regression using the Beer-Lambert Law, were developed to quantitate key metabolites (glucose and glutamate) from spectral data that measured complex media during fermentation. This data was digitally connected to a process information management system, to enable continuous control of feed pumps with proportional-integral-derivative controllers that maintained nutrient levels throughout fed-batch stirred-tank fermenter processes. Continuous metabolite data from mid-infrared spectra of cultures in stirred-tank reactors enabled feedback loops and control of the feed pumps in pharmaceutical development laboratories. This improved process control of nutrient levels by 20-fold and the drug substance yield by an order of magnitude. Furthermore, the method is adaptable to other systems and enables soft sensing, such as the consumption rate of metabolites. The ability to develop quantitative metabolite templates quickly and simply for changing bioprocesses was instrumental for project acceleration and heightened process control and automation. ONE-SENTENCE SUMMARY: Intelligent digital control systems using continuous in-line metabolite data enabled end-to-end automation of fed-batch processes in stirred-tank reactors.

Impact of an HIV pre-exposure prophylaxis dashboard on veteran PrEP enrollment.

BACKGROUND: Pre-exposure prophylaxis (PrEP) is highly effective at reducing the risk of human immunodeficiency virus (HIV) acquisition in at-risk individuals; however, it is largely underutilized. The Veterans Health Administration has created an HIV PrEP dashboard to identify at-risk veterans in attempt to increase PrEP enrollment. OBJECTIVE: This study aimed to determine whether the use of an HIV PrEP dashboard would prove effective at increasing PrEP enrollment at a single facility. METHODS: This was a single-center quality improvement project. Three pharmacists used the HIV PrEP dashboard and retrospective chart review to identify eligible patients for PrEP. A multimodal process of contacting patients was conducted. The primary objective was to evaluate the number of patients who enrolled in PrEP during the study period. Secondary objectives included evaluating the ability of the HIV PrEP dashboard to identify eligible patients, identify effective strategies to target PrEP enrollment, and compare those patients who accepted with those who declined PrEP to evaluate barriers to enrollment. RESULTS: Of the 94 patients reviewed, 26 patients (27.7%) were found eligible for PrEP. Of the eligible patients, 3 patients (11.5%) were enrolled, and 7 patients (26.9%) declined PrEP. The others were lost to follow-up (9 of 26, 34.6%), had no action taken on a chart note to provider (6 of 26, 23.1%), or did not have a primary care provider assigned at the local facility (1 of 26, 3.9%). The 3 patients who were successfully enrolled in PrEP were all contacted and prescribed PrEP through the infectious diseases (ID) clinic. There were no statistically significant differences between the cohorts of patients who accepted and declined PrEP. CONCLUSIONS: The use of an HIV PrEP dashboard aided in identifying eligible patients for PrEP. Enrollment through the ID clinic was the most successful modality. Further research is needed to characterize barriers to PrEP uptake and to develop strategies to increase prescribing from non-ID providers.

Disparities in Access to a Regular Primary Care Physician Among First-Generation Migrants with Early Psychosis in Ontario, Canada.

Disparities in primary care utilization among migrants with early psychosis may be related to lack of access to a regular primary care physician. This study aimed to investigate access to a regular primary care physician among first-generation migrants with early psychosis. People aged 14-35 years with first onset non-affective psychotic disorder in Ontario, Canada were identified in health administrative data (N = 39,440). Access to a regular primary care physician through enrollment in the year prior to diagnosis was compared between first-generation migrants (categorized by country of birth) and the general population using modified Poisson regression. Most migrant groups had a lower prevalence of regular primary care physician access relative to the general population, particularly migrants from Africa (African migrants: 81% vs. non-migrants: 89%). Adjustment for sociodemographic and clinical factors attenuated these differences, although the disparities for migrants from Africa remained (PR = 0.96, 95%CI = 0.94-0.99). Interventions aimed at improving primary care physician access in migrant groups may facilitate help-seeking and improve pathways to care in early psychosis.

Risk of Pancreatitis With Incretin Therapies Versus Thiazolidinediones in the Veterans Health Administration.

BACKGROUND: Incretin therapies, comprised of the dipeptidyl peptidase-4 inhibitors (DPP-4i) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs), have been increasingly utilized for the treatment of type 2 diabetes (T2DM). Previous studies have conflicting results regarding risk of pancreatitis associated with these agents-some suggest an increased risk and others find no correlation. Adverse event reporting systems indicate that incretin therapies are some of the most common drugs associated with reports of pancreatitis. OBJECTIVES: This study aimed to compare the odds of developing pancreatitis in veterans with T2DM prescribed an incretin therapy versus thiazolidinediones (TZDs: pioglitazone and rosiglitazone) within the Veterans Health Administration (VHA). METHODS: This was a retrospective cohort study analyzing veterans with T2DM first prescribed an incretin therapy or a TZD between January 1, 2011, and December 31, 2021. A diagnosis of pancreatitis within 365 days of being prescribed either therapy was counted as a positive case. Data was collected and analyzed utilizing VA's Informatics and Computing Infrastructure (VINCI) and an adjusted odds ratio was calculated. RESULTS: The TZD cohort consisted of 42 912 patients compared with the incretin cohort of 304 811 patients. The TZD cohort had a pancreatitis incidence rate of 1.94 cases per 1000 patients. The incretin cohort had a incidence rate of 2.06 cases per 1000 patients. An adjusted odds ratio found no statistical difference of pancreatitis cases between the TZD and incretin cohorts (adjusted odds ratio [AOR] = 0.94, 95% CI [0.75, 1.18]). CONCLUSION AND RELEVANCE: This retrospective cohort study of national VHA data found a relatively low incidence of pancreatitis in both cohorts, and an adjusted odds ratio found no statistical difference of pancreatitis in patients prescribed an incretin therapy compared with a control group. This data adds to growing evidence that incretin therapies do not seem to be associated with an increased risk of developing pancreatitis.

Sex differences in the clinical presentation of early psychosis in a primary care setting.

Primary care is an important part of the help-seeking pathway for young people experiencing early psychosis, but sex differences in clinical presentation in these settings are unexplored. We aimed to identify sex differences in clinical presentation to primary care services in the 1-year period prior to a first diagnosis of psychotic disorder. We identified first-onset cases of non-affective psychotic disorder over a 10-year period (2005-2015) using health administrative data linked with electronic medical records (EMRs) from primary care (n = 465). Detailed information on encounters in the year prior to first diagnosis was abstracted, including psychiatric symptoms, other relevant behaviours, and diagnoses recorded by the family physician (FP). We used modified Poisson regression models to examine sex differences in the signs, symptoms, and diagnoses recorded by the FP, adjusting for various clinical and sociodemographic factors. Positive symptoms (PR = 0.76, 95%CI: 0.58, 0.98) and substance use (PR = 0.54, 95%CI: 0.40, 0.72) were less prevalent in the medical records of women. Visits by women were more likely to be assigned a diagnosis of depression or anxiety (PR = 1.18, 95%CI: 1.00, 1.38), personality disorder (PR = 5.49, 95%CI: 1.22, 24.62), psychological distress (PR = 11.29, 95%CI: 1.23, 103.91), and other mental or behavioral disorders (PR = 3.49, 95%CI: 1.14, 10.66) and less likely to be assigned a diagnosis of addiction (PR = 0.33, 95%CI: 0.13, 0.87). We identified evidence of sex differences in the clinical presentation of early psychosis and recorded diagnoses in the primary care EMR. Further research is needed to better understand sex differences in clinical presentation in the primary care context, which can facilitate better understanding, detection, and intervention for first-episode psychotic disorders.

Quality of antibiotic prescribing for pediatric community-acquired Pneumonia in outpatient care.

BACKGROUND: Antibiotics remain the primary treatment for community acquired pneumonia (CAP), however rising rates of antimicrobial resistance may jeopardize their future efficacy. With higher rates of disease reported in the youngest populations, effective treatment courses for pediatric pneumonia are of paramount importance. This study is the first to examine the quality of pediatric antibiotic use by agent, dose and duration. METHODS: A retrospective cohort study included all outpatient/primary care physician visits for pediatric CAP (aged < 19 years) between January 1 2014 to December 31 2018. Relevant practice guidelines were identified, and treatment recommendations extracted. Amoxicillin was the primary first-line agent for pediatric CAP. Categories of prescribing included: guideline adherent, effective but unnecessary (excess dose and/or duration), under treatment (insufficient dose and/or duration), and not recommended. Proportions of attributable-antibiotic use were examined by prescribing category, and then stratified by age and sex. RESULT(S): A total of 42,452 episodes of pediatric CAP were identified. Of those, 31,347 (76%) resulted in an antibiotic prescription. Amoxicillin accounted for 51% of all prescriptions. Overall, 27% of prescribing was fully guideline adherent, 19% effective but unnecessary, 10% under treatment, and 44% not recommended by agent. Excessive duration was the hallmark of effective but unnecessary prescribing (97%) Macrolides accounted for the majority on non-first line agent use, with only 32% of not recommended prescribing preceded by a previous course of antibiotics. CONCLUSION(S): This study is the first in Canada to examine prescribing quality for pediatric CAP by agent, dose and duration. Utilizing first-line agents, and shorter-course treatments are targets for stewardship.

Total Hip Arthroplasty in Patients Aged 40 to 60 Years Old: A Population-Based Study.

BACKGROUND: Contemporary total hip arthroplasty (THA) has resolved many implant longevity concerns in younger patients. Patients in their fourth and fifth decades of life are projected to be the fastest-growing demographic of THA patients. We aimed to assess this demographic to: 1) evaluate the rate of THA over time; 2) evaluate the cumulative incidence of revision; and 3) identify risk factors for revision. METHODS: A retrospective population-based study of patients between 40 and 60 years old undergoing primary THA was conducted using administrative data from a large clinical data repository. A total of 28,414 patients were included for analysis with a mean age of 53 years (range, 40-60 years) and median follow-up of 9 years (range, 0-17 years). Linear regressions were used to assess annual rates of THA in this cohort over time. Kaplan-Meier analysis was used to determine cumulative incidence of revision. Multivariate Cox proportional hazards models were used to determine association of variables with revision risk. RESULTS: The annual rate of THA in our population increased by 60.7% over the study period (P < .0001). Cumulative incidence of revision was 2.9% at 5 years and 4.8% at 10 years. Younger age, women, non-osteoarthritis diagnosis, medical complications, and annual surgeon volume ≤ 60 THA were associated with increased revision risk. CONCLUSION: Demand for THA continues to dramatically increase in this cohort. Risk of revision was low but multiple risk factors were identified. Future studies will help delineate the effect of these variables on revision risk and assess implant survivorship beyond 10 years.

Models of shared care for the management of psychotic disorder after first diagnosis in Ontario.

OBJECTIVE: To describe the provision of care for young people following first diagnosis of psychotic disorder. DESIGN: Retrospective cohort study using health administrative data. SETTING: Ontario. PARTICIPANTS: People aged 14 to 35 years with a first diagnosis of nonaffective psychotic disorder in Ontario between 2005 and 2015 (N=39,449). MAIN OUTCOME MEASURES: Models of care, defined by psychosis-related service contacts with primary care physicians and psychiatrists during the 2 years after first diagnosis of psychotic disorder. RESULTS: During the 2-year follow-up period, 29% of the cohort received only primary care, 30% received only psychiatric care, and 32% received both primary and psychiatric care (shared care). Among the shared care group, 72% received care predominantly from psychiatrists, 20% received care predominantly from primary care physicians, and 9% received approximately equal care from psychiatry and primary care. Variation in patient and physician characteristics was observed across the different models of care. CONCLUSION: One in 3 young people with psychotic disorder received shared care during the 2-year period after first diagnosis. The findings highlight opportunities for increasing collaboration between primary care physicians and psychiatrists to enhance the quality of care for those with early psychosis.

Patient and Physician Factors Associated with First Diagnosis of Non-affective Psychotic Disorder in Primary Care.

Primary care physicians play a central role in pathways to care for first-episode psychosis, and their increased involvement in early detection could improve service-related outcomes. The aim of this study was to estimate the proportion of psychosis first diagnosed in primary care, and identify associated patient and physician factors. We used linked health administrative data to construct a retrospective cohort of people aged 14-35 years with a first diagnosis of non-affective psychosis in Ontario, Canada between 2005-2015. We restricted the sample to patients with help-seeking contacts for mental health reasons in primary care in the six months prior to first diagnosis of psychotic disorder. We used modified Poisson regression models to examine patient and physician factors associated with a first diagnosis of psychosis in primary care. Among people with early psychosis (n = 39,449), 63% had help-seeking contacts in primary care within six months prior to first diagnosis. Of those patients, 47% were diagnosed in primary care and 53% in secondary/tertiary care. Patients factors associated with lower likelihood of diagnosis in primary care included male sex, younger age, immigrant status, and comorbid psychosocial conditions. Physician factors associated with lower likelihood of diagnosis in primary care included solo practice model, urban practice setting, international medical education, and longer time since graduation. Our findings indicate that primary care is an important contact for help-seeking and diagnosis for a large proportion of people with early psychosis. For physicians less likely to diagnose psychosis in primary care, targeted resources and interventions could be provided to support them in caring for patients with early psychosis.

Cancer Risk and Mortality in Patients With Kidney Disease: A Population-Based Cohort Study.

RATIONALE & OBJECTIVE: Patients with chronic kidney disease (CKD) may be at increased risk for cancer. CKD may also be associated with worse cancer outcomes. This study examined cancer incidence and mortality across the spectrum of CKD. STUDY DESIGN: Population-based cohort study. SETTING & PARTICIPANTS: All adult Ontario residents with data on estimated glomerular filtration rate (eGFR) or who were receiving maintenance dialysis or had received a kidney transplant (2007-2016). EXPOSURE: Patients were categorized as of the first date they had 2 eGFR assessments or were registered as receiving maintenance dialysis or having received a kidney transplant. eGFR levels were further categorized as ≥60, 45-59, 30-44, 15-29, and <15 mL/min/1.73 m2; the latter 4 groups are consistent with KDIGO (Kidney Disease: Improving Global Outcomes) CKD categories G3a, G3b, G4, and G5, respectively. OUTCOMES: Overall and site-specific cancer incidence and mortality. ANALYTICAL APPROACH: Fine and Gray subdistribution hazard models. RESULTS: Among 5,882,388 individuals with eGFR data, 29,809 receiving dialysis, and 4,951 having received a kidney transplant, there were 325,895 cancer diagnoses made during 29,993,847 person-years of follow-up. The cumulative incidence of cancer ranged between 10.8% and 15.3% in patients with kidney disease. Compared with patients with eGFR ≥60 mL/min/1.73 m2, adjusted hazard ratios (AHRs) for a cancer diagnosis among patients with CKD G3a, G3b, G4, and G5 were 1.08 (95% CI, 1.07-1.10), 0.99 (95% CI, 0.97-1.01), 0.85 (95% CI, 0.81-0.88), and 0.81 (95% CI, 0.73-0.90), respectively. The AHRs for patients receiving dialysis and who had received a transplant were 1.01 (95% CI, 0.96-1.07) and 1.25 (95% CI, 1.12-1.39), respectively. Patients with kidney disease had higher proportions of stage 4 cancers at diagnosis. Patients with CKD G3a, G3b, and G4 and transplant recipients had increased risks of cancer-specific mortality (AHRs of 1.27 [95% CI, 1.23-1.32], 1.29 [95% CI, 1.24-1.35], 1.25 [95% CI, 1.18-1.33], and 1.48 [95% CI, 1.18-1.87], respectively). The risks of bladder and kidney cancers and multiple myeloma were particularly increased in CKD, and mortality from these malignancies increased with worsening kidney function. LIMITATIONS: Possible unmeasured confounding and limited ability to infer causal associations. CONCLUSIONS: Cancer incidence in the setting of kidney disease is substantial. Cancer risk was increased in mild to moderate CKD and among transplant recipients, but not in advanced kidney disease. Cancer-related mortality was significantly higher among patients with kidney disease, particularly urologic cancers and myeloma. Strategies to detect and manage these cancers in the CKD population are needed.

Bariatric Center Designation and Outcomes Following Repeat Abdominal Surgery in Bariatric Patients.

INTRODUCTION: Repeat abdominal surgery in the bariatric surgery patient population may be challenging for non-bariatric-accredited institutions. The impact of regionalized bariatric care on clinical outcomes for bariatric surgery patients requiring repeat abdominal surgery is currently unknown. This study aims to investigate the association between bariatric center designation and clinical outcomes following hepatobiliary, hernia, and upper and lower gastrointestinal operations among patients with prior bariatric surgery. METHODS: This is a cohort study of a large sample of Ontario residents who underwent primary bariatric surgery between 2010 and 2017. A comprehensive list of eligible abdominal operations was captured using administrative data. The primary outcome was 30-d complications. Secondary outcomes included 30-d mortality, readmission, and length of stay. RESULTS: Among the 3301 study patients, 1305 (40%) received their first abdominal reoperation following bariatric surgery at a designated bariatric center. Nonbariatric center designation was not associated with significantly higher rates of 30-d complications (5.73% versus 5.72%), mortality (0.80% versus 0.77%), readmissions (1.11% versus 1.85%), or median postoperative length of stay (4 versus 4 d). After grouping the category of reoperations, upper gastrointestinal (odds ratio [OR] 0.66, confidence interval [CI] 0.39-1.11) and abdominal wall hernia surgery (OR 0.52, CI 0.27-0.99) showed a lower adjusted OR for complications among bariatric centers. CONCLUSIONS: Our study demonstrates that after adjustment for case-mix and patient characteristics, bariatric surgery patients undergoing repeat abdominal surgery at nonbariatric centers is not associated with higher proportion of complications or mortality. Complex hernia surgery may be considered the most appropriate for referral.

Underreported Risk of Lisinopril-Induced Angioedema in a Veteran Population.

BACKGROUND: Lisinopril-induced angioedema (LIA) is a rare but serious adverse drug event (ADE) with a published incidence of 0.1% to 0.7%. It is well known that ADEs are widely underreported; however, LIA is one of the most reported ADEs within the Veterans Health Administration (VHA). OBJECTIVE: To estimate the effect of underreporting on the risk of LIA within VHA. METHODS: The reported risk of LIA was calculated from reports submitted to the Veterans Affairs (VA) Adverse Drug Event Reporting System (VA ADERS) and the number of veterans prescribed lisinopril. To estimate underreporting, local chart review identified cases of LIA that were compared to reports submitted. The underreporting rate was then applied to the national reported risk. RESULTS: Locally, 68 reports of LIA were submitted of the 21 262 patients prescribed lisinopril, for a reported risk of 0.32%. Nationwide, 14 289 reports of LIA were submitted of the 3 109 661 patients prescribed lisinopril, for a crude reported risk of 0.46%. Of the 324 patients identified for chart review, 240 patients were diagnosed with LIA, suggesting that at least 71.7% of cases were unreported. When this underreporting rate is extrapolated to the national reported risk, a better estimate of the risk of LIA within VHA could increase to 1.6%. CONCLUSION AND RELEVANCE: When estimating the effect of underreporting, the risk of LIA increases to approximately 1.6% or 1 in 63 patients. Because this ADE may affect more patients than previously understood, providers may wish to take LIA into consideration when prescribing lisinopril.

Physical Activity Coaching via Telehealth for People With Parkinson Disease: A Cohort Study.

BACKGROUND AND PURPOSE: Physical activity (PA) has many known benefits for people with Parkinson disease (PD); however, many people do not meet recommended levels of frequency or intensity. We designed Engage-PD, a PA coaching program delivered via telehealth and grounded in self-determination theory to promote PA uptake and facilitate exercise self-efficacy in people with Parkinson disease. This study aimed to determine the feasibility and preliminary efficacy of Engage-PD, and to explore whether baseline characteristics were associated with outcomes. METHODS: A single cohort of people with PD (n = 62, Hoehn and Yahr I-III) participated in the 3-month Engage-PD program, which consisted of up to 5 telehealth coaching sessions delivered by physical therapists. Feasibility was evaluated based on recruitment and retention rates, along with participants' feedback. Planned and unplanned PA, exercise self-efficacy (ESE), and individualized goals were assessed pre- and post-intervention. Relationships between baseline characteristics and changes in planned PA and ESE were also evaluated. RESULTS: Recruitment (62%) and retention (85%) rates were high, and the intervention was well accepted and perceived by the participants. From pre- to postintervention, participants increased planned PA (d = 0.33), ESE (d = 1.20), and individualized goal performance (d = 1.63) and satisfaction (d = 1.70). Participants with lower baseline planned PA experienced greater improvements in planned PA, and those with lower baseline ESE experienced greater improvements in ESE. DISCUSSION AND CONCLUSIONS: A telehealth PA coaching program for people with PD was feasible and potentially efficacious. Physical therapist-led coaching may be an important component of a consultative model of care starting early in the disease process.Video Abstract available for more insights from the authors (see the Video, Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A393).

A Multicenter Clinical Study To Demonstrate the Diagnostic Accuracy of the GenMark Dx ePlex Blood Culture Identification Gram-Negative Panel.

Bacteremia can progress to septic shock and death without appropriate medical intervention. Increasing evidence supports the role of molecular diagnostic panels in reducing the clinical impact of these infections through rapid identification of the infecting organism and associated antimicrobial resistance genes. We report the results of a multicenter clinical study assessing the performance of the GenMark Dx ePlex investigational-use-only blood culture identification Gram-negative panel (BCID-GN), a rapid diagnostic assay for detection of bloodstream pathogens in positive blood culture (PBC) bottles. Prospective, retrospective, and contrived samples were tested. Results from the BCID-GN were compared to standard-of-care bacterial identification methods. Antimicrobial resistance genes (ARGs) were identified using PCR and sequence analysis. The final BCID-GN analysis included 2,444 PBC samples, of which 926 were clinical samples with negative Gram stain results. Of these, 109 samples had false-negative and/or -positive results, resulting in an overall sample accuracy of 88.2% (817/926). After discordant resolution, overall sample accuracy increased to 92.9% (860/926). Pre- and postdiscordant resolution sample accuracy excludes 37 Gram-negative organisms representing 20 uncommon genera, 10 Gram-positive organisms, and 1 Candida species present in 5% of samples that are not targeted by the BCID-GN. The overall weighted positive percent agreement (PPA), which averages the individual PPAs from the 27 targets (Gram-negative and ARG), was 94.9%. The limit of detection ranged from 104 to 107 CFU/ml, except for one strain of Fusobacterium necrophorum at 108 CFU/ml.

Concussion in adolescence and the risk of multiple sclerosis: A retrospective cohort study.

BACKGROUND: Physical trauma, specifically concussions sustained during adolescence, has been hypothesized to be a risk factor for multiple sclerosis (MS). OBJECTIVE: To examine the association between adolescent concussions and future MS diagnosis. METHODS: This retrospective study using linked administrative databases from Ontario, Canada, identified 97,965 adolescents (age 11-18 years) who sustained ⩾1 concussion and presented to an emergency department between 1992 and 2011. Cases were matched 1:3 with individuals who had not sustained a concussion based on age, sex, address, and index date. The primary outcome was MS diagnosis, using a validated MS diagnosis definition: ⩾1 hospitalization or ⩾5 physician billings within 2 years. RESULTS: A concussion during adolescence was associated with a significantly increased risk of MS (hazard ratio (HR) = 1.29, p = 0.03). Sex-specific analysis revealed that only males who sustained a concussion in adolescence had a raised risk of MS (HR = 1.41, p = 0.04). CONCLUSION: This study supports an association between concussions in adolescence and future MS diagnoses, highlighting the potentially serious long-term effects of concussions.

Patterns of Primary Care Use Prior to a First Diagnosis of Nonaffective Psychotic Disorder in Ontario, Canada: Modèles d'utilisation des soins de première ligne avant un premier diagnostic de trouble psychotique non affectif en Ontario, Canada.

BACKGROUND: Many people experience early signs and symptoms before the onset of psychotic disorder, suggesting that there may be help-seeking prior to first diagnosis. The family physician has been found to play a key role in pathways to care. This study examined patterns of primary care use preceding a first diagnosis of psychotic disorder. METHODS: We used health administrative data from Ontario (Canada) to construct a population-based retrospective cohort. We investigated patterns of primary care use, including frequency and timing of contacts, in the 6 years prior to a first diagnosis of psychosis, relative to a general population comparison group matched on age, sex, geographic area, and index date. We used latent class growth modeling to identify distinct trajectories of primary care service use, and associated factors, preceding the first diagnosis. RESULTS: People with early psychosis contacted primary care over twice as frequently in the 6 years preceding first diagnosis (RR = 2.22; 95% CI, = 2.19 to 2.25), relative to the general population, with a sharp increase in contacts 10 months prior to diagnosis. They had higher contact frequency across nearly all diagnostic codes, including mental health, physical health, and preventative health. We identified 3 distinct service use trajectories: low-, medium-, and high-increasing usage. DISCUSSION: We found elevated patterns of primary care service use prior to first diagnosis of psychotic disorder, suggesting that initiatives to support family physicians in their role on the pathway to care are warranted. Earlier intervention has implications for improved social, educational, and professional development in young people with first-episode psychosis.

Printed educational materials directed at Ontario family physicians do not improve adherence to guideline recommendations for diabetes management: a pragmatic, factorial, cluster randomized controlled trial [ISRCTN72772651].

BACKGROUND: Printed educational materials (PEMs) have long been used to inform clinicians on evidence-based practices. However, the evidence for their effects on patient care and outcomes is unclear. In Ontario, despite widely available clinical practice guidelines recommending antihypertensives and cholesterol-lowering agents for patients with diabetes, prescriptions remain low. We aimed to determine whether PEMs can influence physicians to intensify prescribing of these medications. METHODS: A pragmatic, 2 × 2 factorial, cluster randomized controlled trial was designed to ascertain the effect of two PEM formats on physician prescribing: a postcard-sized message ("outsert") or a longer narrative article ("insert"). Ontario family physician practices (clusters) were randomly allocated to receive the insert, outsert, both or neither. Physicians were eligible if they were in active practice and their patients were included if they were over 65 years with a diabetes diagnosis; both were unaware of the trial. Administrative databases at ICES (formerly the Institute for Clinical Evaluative Sciences) were used to link patients to their physician and to analyse prescribing patterns at baseline and 1 year following PEM mailout. The primary outcome was intensification defined as the addition of a new antihypertensive or cholesterol-lowering agent, or dose increase of a current drug, measured at the patient level. Analyses were by intention-to-treat and accounted for the clustering of patients to physicians. RESULTS: We randomly assigned 4231 practices (39% of Ontario family physicians) with a total population of 185,526 patients (20% of patients with diabetes in Ontario primary care) to receive the insert, outsert, both, and neither; among these, 4118 practices were analysed (n = 1025, n = 1037, n = 1031, n = 1025, respectively). No significant treatment effect was found for the outsert (odds ratio (OR) 1.01, 95% confidence interval (CI) 0.98 to 1.04) or the insert (OR 0.99, 95% CI 0.96 to 1.02). Percent of intensification in the four arms was similar (approximately 46%). Adjustment for physician characteristics (e.g., age, sex, practice location) had no impact on these findings. CONCLUSIONS: PEMs have no effect on physician's adherence to recommendations for the management of diabetes-related complications in Ontario. Further research should investigate the effect of other strategies to narrow this evidence-to-practice gap. TRIAL REGISTRATION: ISRCTN72772651 . Retrospectively registered 21 July 2005.

Multicenter Evaluation of a PCR-Based Digital Microfluidics and Electrochemical Detection System for the Rapid Identification of 15 Fungal Pathogens Directly from Positive Blood Cultures.

Routine identification of fungal pathogens from positive blood cultures by culture-based methods can be time-consuming, delaying treatment with appropriate antifungal agents. The GenMark Dx ePlex investigational use only blood culture identification fungal pathogen panel (BCID-FP) rapidly detects 15 fungal targets simultaneously in blood culture samples positive for fungi by Gram staining. We aimed to determine the performance of the BCID-FP in a multicenter clinical study. Blood culture samples collected at 10 United States sites and tested with BCID-FP at 4 sites were compared to the standard-of-care microbiological and biochemical techniques, fluorescence in situ hybridization using peptide nucleic acid probes (PNA-FISH) and matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS). Discrepant results were analyzed by bi-directional PCR/sequencing of residual blood culture samples. A total of 866 clinical samples, 120 retrospectively and 21 prospectively collected, along with 725 contrived samples were evaluated. Sensitivity and specificity of detection of Candida species (C. albicans, C. auris, C. dubliniensis, C. famata, C. glabrata, C. guilliermondii, C. kefyr, C. krusei, C. lusitaniae, C. parapsilosis, and C. tropicalis) ranged from 97.1 to 100% and 99.8 to 100%, respectively. For the other organism targets, sensitivity and specificity were as follows: 100% each for Cryptococcus neoformans and C. gattii, 98.6% and 100% for Fusarium spp., and 96.2% and 99.9% for Rhodotorula spp., respectively. In 4 of the 141 clinical samples, the BCID-FP panel correctly identified an additional Candida species, undetected by standard-of-care methods. The BCID-FP panel offers a faster turnaround time for identification of fungal pathogens in positive blood cultures that may allow for earlier antifungal interventions and includes C. auris, a highly multidrug-resistant fungus.

Clinical Performance of the Novel GenMark Dx ePlex Blood Culture ID Gram-Positive Panel.

Rapid identification from positive blood cultures is standard of care (SOC) in many clinical microbiology laboratories. The GenMark Dx ePlex Blood Culture Identification Gram-Positive (BCID-GP) Panel is a multiplex nucleic acid amplification assay based on competitive DNA hybridization and electrochemical detection using eSensor technology. This multicenter study compared the investigational-use-only (IUO) BCID-GP Panel to other methods of identification of 20 Gram-positive bacteria, four antimicrobial resistance genes, and both Pan Candida and Pan Gram-Negative targets that are unique to the BCID-GP Panel. Ten microbiology laboratories throughout the United States collected residual, deidentified positive blood culture samples for analysis. Five laboratories tested both clinical and contrived samples with the BCID-GP Panel. Comparator identification methods included each laboratory's SOC, which included matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) and automated identification systems as well as targeted PCR/analytically validated real-time PCR (qPCR) with bidirectional sequencing. A total of 2,342 evaluable samples (1,777 clinical and 565 contrived) were tested with the BCID-GP Panel. The overall sample accuracy for on-panel organisms was 89% before resolution of discordant results. For pathogenic Gram-positive targets (Bacillus cereus group, Enterococcus spp., Enterococcus faecalis, Enterococcus faecium, Staphylococcus spp., Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus lugdunensis, Listeria spp., Listeria monocytogenes, Streptococcus spp., Streptococcus agalactiae, Streptococcus anginosus group, Streptococcus pneumoniae, and Streptococcus pyogenes), positive percent agreement (PPA) and negative percent agreement (NPA) ranged from 93.1% to 100% and 98.8% to 100%, respectively. For contamination rule-out targets (Bacillus subtilis group, Corynebacterium, Cutibacterium acnes, Lactobacillus, and Micrococcus), PPA and NPA ranged from 84.5% to 100% and 99.9% to 100%, respectively. Positive percent agreement and NPA for the Pan Candida and Pan Gram-Negative targets were 92.4% and 95.7% for the former and 99.9% and 99.6% for the latter. The PPAs for resistance markers were as follows: mecA, 97.2%; mecC, 100%; vanA, 96.8%; and vanB, 100%. Negative percent agreement ranged from 96.6% to 100%. In conclusion, the ePlex BCID-GP Panel compares favorably to SOC and targeted molecular methods for the identification of 20 Gram-positive pathogens and four antimicrobial resistance genes in positive blood culture bottles. This panel detects a broad range of pathogens and mixed infections with yeast and Gram-negative organisms from the same positive blood culture bottle.