A simplified grading system for in vivo and in vitro derived vitrified equine embryos.

The ability to predict the viability of embryos before vitrification and thawing has important commercial applications in any breeding program. The aim of this study was to develop and evaluate a simplified embryo grading system for both in vivo- and in vitro-derived vitrified day 8 embryos. The in vivo derived (n=109) and in vitro - intracytoplasmic sperm injection derived (n=145) embryos were produced in a commercial embryo program. The embryos were classified as Grade 1, 2 or 3 based on the amount of extruded material between the trophoblast and the zona pellucida observed during the vitrification process. The embryos were vitrified at day 8 of development in a two-step system with increasing concentrations of dimethylsulfoxide and ethylene glycol and 0.5 M sucrose in the final solution. Each embryo was thawed in 0.3 M and then 0.15 M sucrose before transfer into holding medium for non-surgical transfer into a recipient mare. Analysis of the relationship between the embryo grading system and pregnancy rates after vitrification, thawing and transfer of in vivo and in vitro derived embryos confirmed that there was a significant effect of origin (in vivo vs in vitro; P ≤ 0.05), and embryo grade (P ≤ 0.001) on embryo survival after transfer. In conclusion, this simplified grading system is predictive of embryo survival for both in vivo- and in vitro- derived vitrified equine embryos.

Reliability and validity testing of the ASSIST functional performance index.

Reliability and validity testing of the ASSIST Functional Performance Index (AFPI) was conducted, focusing on persons with physical disabilities (PwPD). The AFPI was iteratively developed to assess persons' needs for Mainstream Smart Home Technologies (MSHT) as Assistive Technology (AT) and to measure the impact of a service delivery model for MSHT. The AFPI consists of 46 items organized by functional domains. A total of N = 22 PwPD completed the AFPI twice. The median response time between these two time points was four days. Test-retest reliability of overall scores was assessed using the Intraclass Correlation Coefficient model (ICC, 3.1). The weighted kappa coefficient was applied to conduct an item analysis, demonstrating moderate to substantial agreement in all but one of the items. During the second administration, validity was established by correlating the number of hours of assistance and total AFPI scores with the SCI-FI Self-Care and Basic Mobility Short Form Questionnaires. Results indicate that the AFPI demonstrates good to very good validity as an assessment tool and outcome measure in recommending and evaluating the impact of MSHT for PwPD. Future studies, including more participants and persons with cognitive and sensory disabilities, may further establish the clinical utility of the AFPI.

Leveraging big data of immune checkpoint blockade response identifies novel potential targets.

BACKGROUND: The development of immune checkpoint blockade (ICB) has changed the way we treat various cancers. While ICB produces durable survival benefits in a number of malignancies, a large proportion of treated patients do not derive clinical benefit. Recent clinical profiling studies have shed light on molecular features and mechanisms that modulate response to ICB. Nevertheless, none of these identified molecular features were investigated in large enough cohorts to be of clinical value. MATERIALS AND METHODS: Literature review was carried out to identify relevant studies including clinical dataset of patients treated with ICB [anti-programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1), anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) or the combination] and available sequencing data. Tumor mutational burden (TMB) and 37 previously reported gene expression (GE) signatures were computed with respect to the original publication. Biomarker association with ICB response (IR) and survival (progression-free survival/overall survival) was investigated separately within each study and combined together for meta-analysis. RESULTS: We carried out a comparative meta-analysis of genomic and transcriptomic biomarkers of IRs in over 3600 patients across 12 tumor types and implemented an open-source web application (predictIO.ca) for exploration. TMB and 21/37 gene signatures were predictive of IRs across tumor types. We next developed a de novo GE signature (PredictIO) from our pan-cancer analysis and demonstrated its superior predictive value over other biomarkers. To identify novel targets, we computed the T-cell dysfunction score for each gene within PredictIO and their ability to predict dual PD-1/CTLA-4 blockade in mice. Two genes, F2RL1 (encoding protease-activated receptor-2) and RBFOX2 (encoding RNA-binding motif protein 9), were concurrently associated with worse ICB clinical outcomes, T-cell dysfunction in ICB-naive patients and resistance to dual PD-1/CTLA-4 blockade in preclinical models. CONCLUSION: Our study highlights the potential of large-scale meta-analyses in identifying novel biomarkers and potential therapeutic targets for cancer immunotherapy.

How long does it take patients to find a new primary care physician when theirs retires: a population-based, longitudinal study.

BACKGROUND: The retirement of a family physician can represent a challenge in accessibility and continuity of care for patients. In this population-based, longitudinal cohort study, we assess whether and how long it takes for patients to find a new majority source of primary care (MSOC) when theirs retires, and we investigate the effect of demographic and clinical characteristics on this process. METHODS: We used provincial health insurance records to identify the complete cohort of patients whose majority source of care left clinical practice in either 2007/2008 or 2008/2009 and then calculated the number of days between their last visit with their original MSOC and their first visit with their new one. We compared the clinical and sociodemographic characteristics of patients who did and did not find a new MSOC in the three years following their original physician's retirement using Chi-square and Fisher's exact test. We also used Cox proportional hazards models to determine the adjusted association between patient age, sex, socioeconomic status, location and morbidity level (measured using Johns Hopkins' Aggregated Diagnostic Groupings), and time to finding a new primary care physician. We produce survival curves stratified by patient age, sex, income and morbidity. RESULTS: Fifty-four percent of patients found a new MSOC within the first 12 months following their physician's retirement. Six percent of patients still had not found a new physician after 36 months. Patients who were older and had higher levels of morbidity were more likely to find a new MSOC and found one faster than younger, healthier patients. Patients located in more urban regional health authorities also took longer to find a new MSOC compared to those in rural areas. CONCLUSIONS: Primary care physician retirements represent a potential threat to accessibility; patients followed in this study took more than a year on average to find a new MSOC after their physician retired. Providing programmatic support to retiring physicians and their patients, as well as addressing shortages of longitudinal primary care more broadly could help to ensure smoother retirement transitions.

A novel approach to 3D modelling ground-penetrating radar (GPR) data - A case study of a cemetery and applications for criminal investigation.

Ground-penetrating radar (GPR) is an established geophysical technique used extensively for the accurate reconstruction of the shallow (<10 m) subsurface. Reconstructions have largely been completed and presented as 2D vertical and horizontal planes, leaving limited visualization of subsurface 3D shapes and their spatial relationships. With technological advancements, particularly the availability and integration of various software platforms, 3D modelling of GPR data is now emerging as the new standard. However, despite these developments, there remains an inadequate examination and testing of these techniques, particularly in determining if their application is beneficial and warranted. In this study we conducted a GPR grid survey on a churchyard cemetery to generate and evaluate 2D and 3D-modelled reconstructions of the cemetery burial sites. Data collection and processing was completed using a Sensors and Software Incorporated pulseEKKO™ Pro SmartCart GPR system and EKKO_Project™ software, respectively. The modelling component was achieved using Schlumberger's Petrel™ E & P software platform, which is tailored to the petroleum industry. The subsurface patterns present in the 2D and 3D models closely matched the cemetery plot plan, validating our data collection, processing, and modelling methods. Both models were adequate for 2D horizontal visualization of reflection patterns at any specific depth. The 3D model was used to identify the presence of a companion burial plot (stacked caskets) and possible leachate plumes below and encircling burial sites, both of which were not evident in the 2D model, highlighting the benefits of 3D modelling when discerning subsurface objects. We expect our findings to be of value to similar GPR studies, with particular significance to geoforensic studies and criminal investigations.

The impact of compliance on Stage 2 uni-ventricular heart circulation: An experimental assessment of the Bidirectional Glenn.

The Bidirectional Glenn (BDG) or cavopulmonary connection is typically undertaken to volume unload the single ventricle in an effort to preserve ventricular and atrioventricular valve function. The geometry of this surgical palliation has been shown to influence the fluid energy loss as well as the distribution of flow that enters through the superior vena cava. In-vitro and in-silico studies to date have been performed on rigid wall models, while this investigation looks at the impact of flexible thin walled models versus rigid walls. Rigid and compliant models of two patient-specific Glenn geometries were fabricated and tested under various flow conditions, within a biosimulator capable of replicating patient specific flow conditions. It was found that the compliant models exhibit greater levels of energy loss compared to the rigid models. Along with these findings greater levels of turbulence was found in both compliant models compared to their rigid counterparts under ultrasound examinations. This shows that vessel compliance has a significant impact on the hemodynamics within hypoplastic left heart syndrome.

Palliative Radiation Therapy in Older Adults With Cancer: Age-Related Considerations.

There are many additional considerations when treating older adults with cancer, especially in the context of palliative care. Currently, radiation therapy is underutilised in some countries and disease sites, but there is also evidence of unnecessary treatment in other contexts. Making rational treatment decisions for older adults necessitates an underlying appraisal of the person's physiological reserve capacity. This is termed 'frailty', and there is considerable heterogeneity in its clinical presentation, from patients who are relatively robust and suitable for standard treatment, to those who are frail and perhaps require a different approach. Frailty assessment also presents an important opportunity for intervention, when followed by Comprehensive Geriatric Assessment (CGA) in those who require it. Generally, a two-step approach, with a short initial screening, followed by CGA, is advocated in geriatric oncology guidelines. This has the potential to optimise care of the older person, and may also reverse or slow the development of frailty. It therefore has an important impact on the patient's quality of life, which is especially valued in the context of palliative care. Frailty assessment also allows a more informed discussion of treatment outcomes and a shared decision-making approach. With regards to the radiotherapy regimen itself, there are many adaptations that can better facilitate the older person, from positioning and immobilisation, to treatment prescriptions. Treatment courses should be as short as possible and take into account the older person's unique circumstances. The additional burden of travel to treatment for the patient, caregiver or family/support network should also be considered. Reducing treatments to single fractions may be appropriate, or alternatively, hypofractionated regimens. In order to enhance care and meet the demands of a rapidly ageing population, future radiation oncology professionals require education on the basic principles of geriatric medicine, as many aspects remain poorly understood.

Advances in the Direct Study of Carbon Burning in Massive Stars.

The ^{12}C+^{12}C fusion reaction plays a critical role in the evolution of massive stars and also strongly impacts various explosive astrophysical scenarios. The presence of resonances in this reaction at energies around and below the Coulomb barrier makes it impossible to carry out a simple extrapolation down to the Gamow window-the energy regime relevant to carbon burning in massive stars. The ^{12}C+^{12}C system forms a unique laboratory for challenging the contemporary picture of deep sub-barrier fusion (possible sub-barrier hindrance) and its interplay with nuclear structure (sub-barrier resonances). Here, we show that direct measurements of the ^{12}C+^{12}C fusion cross section may be made into the Gamow window using an advanced particle-gamma coincidence technique. The sensitivity of this technique effectively removes ambiguities in existing measurements made with gamma ray or charged-particle detection alone. The present cross-section data span over 8 orders of magnitude and support the fusion-hindrance model at deep sub-barrier energies.

Is attending birth dying out? Trends in obstetric care provision among primary care physicians in British Columbia.

OBJECTIVE: To examine trends in and sociodemographic predictors of the provision of obstetric care within the primary care context among physicians in British Columbia (BC). DESIGN: Population-based, longitudinal cohort study using administrative data. SETTING: British Columbia. PARTICIPANTS: All primary care physicians practising in BC between 2005-2006 and 2011-2012. MAIN OUTCOME MEASURES: Fee-for-service payment records were used to identify the provision of prenatal and postnatal care and deliveries. The proportions of physicians who attended deliveries and who included any obstetric care provision in their practices were examined over time using longitudinal mixed-effects log-linear models. RESULTS: The proportion of physicians attending deliveries or providing any obstetric care declined significantly over the study period (deliveries: odds ratio [OR] of 0.92, 95% CI 0.89-0.95; obstetric care: OR = 0.92, 95% CI 0.89-0.95), and obstetric care provision accounted for a smaller proportion of overall practice activity (OR = 0.96, 95% CI 0.94-0.99). Female physicians had higher odds of including obstetric care in their practices (OR = 1.46, 95% CI 1.27-1.69), and by 2011-2012 had significantly higher odds of attending deliveries (OR = 1.22, 95% CI 1.05-1.38). Older physicians and those located in metropolitan centres were less likely to provide obstetric care or attend deliveries. CONCLUSION: The provision of obstetric care by primary care physicians in BC declined over this period, suggesting the possibility of a growing access issue, particularly in rural and remote communities where family physicians are often the sole providers of obstetric services.

Author Correction: A human immune dysregulation syndrome characterized by severe hyperinflammation with a homozygous nonsense Roquin-1 mutation.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

A human immune dysregulation syndrome characterized by severe hyperinflammation with a homozygous nonsense Roquin-1 mutation.

Hyperinflammatory syndromes are life-threatening disorders caused by overzealous immune cell activation and cytokine release, often resulting from defects in negative feedback mechanisms. In the quintessential hyperinflammatory syndrome familial hemophagocytic lymphohistiocytosis (HLH), inborn errors of cytotoxicity result in effector cell accumulation, immune dysregulation and, if untreated, tissue damage and death. Here, we describe a human case with a homozygous nonsense R688* RC3H1 mutation suffering from hyperinflammation, presenting as relapsing HLH. RC3H1 encodes Roquin-1, a posttranscriptional repressor of immune-regulatory proteins such as ICOS, OX40 and TNF. Comparing the R688* variant with the murine M199R variant reveals a phenotypic resemblance, both in immune cell activation, hypercytokinemia and disease development. Mechanistically, R688* Roquin-1 fails to localize to P-bodies and interact with the CCR4-NOT deadenylation complex, impeding mRNA decay and dysregulating cytokine production. The results from this unique case suggest that impaired Roquin-1 function provokes hyperinflammation by a failure to quench immune activation.

The emergency response to multidrug-resistant tuberculosis in Daru, Western Province, Papua New Guinea, 2014-2017.

SETTING: A response to an outbreak of multidrug-resistant tuberculosis (MDR-TB) on Daru Island, South Fly District (SFD), Western Province, Papua New Guinea (PNG) was implemented by a national emergency response taskforce. OBJECTIVE: To describe programmatic interventions for TB in SFD and evaluate characteristics of TB case notifications, drug resistance and treatment outcomes. DESIGN: This was a retrospective cohort study based on routine programmatic data for all patients enrolled on TB treatment at Daru General Hospital from 2014 to 2017. RESULTS: The response involved high-level political commitment, joint planning, resource mobilisation, community engagement and strengthening TB case detection and treatment. Of 1548 people enrolled on TB treatment, 1208 (78%) had drug-susceptible TB (DS-TB) and 333 (21.5%) had MDR-TB. There was an increase in MDR-TB as a proportion of all TB. Treatment success rates increased over the study period from 55% to 86% for DS-TB, and from 70% to 81% for MDR-TB from 2014 to 2015. The 2014 case notification rate for TB in SFD was 1031/100 000, decreasing to 736/100 000 in 2017. CONCLUSION: The outbreak was stabilised through the response from the national and provincial governments and international partners. Additional interventions are needed to decrease the TB burden in Daru.

Successful implementation of bedaquiline for multidrug-resistant TB treatment in remote Papua New Guinea.

SETTING: Bedaquiline (BDQ) was introduced in the multi-drug-resistant tuberculosis (MDR-TB) programme in Daru in remote Papua New Guinea in 2015, along with a core package of active drug-safety monitoring (aDSM). OBJECTIVE: To assess interim results and safety of BDQ for the treatment of MDR-TB from 1 July 2015 to 31 December 2017. DESIGN: A retrospective cohort analysis of routine programme data. RESULTS: Of 277 MDR-TB patients, 77 (39%) received BDQ with a total of 8 serious adverse events including 5 (6.5%) deaths, of which 1 (1.3% QTcF prolongation, grade 3) was attributable to BDQ. Of 200 (61%) patients who did not receive BDQ, there were 17 (9%) deaths. Completeness of monitoring for the BDQ group was 90% for >5 electrocardiograms and 79% for ⩾2 cultures. In the interim result indicator analysis at month 6 in the BDQ and non-BDQ groups, there were respectively 0% and 1% lost to follow-up; 6.5% and 8.5% who died; 94% and 91% in care; and 92% and 96% with negative culture among those monitored. CONCLUSION: Early experience in Daru shows BDQ is safe and feasible to implement with aDSM with good interim effectiveness supporting the rapid adoption and scale-up of the 2019 WHO MDR-TB treatment guidelines in the programme and in similar remote settings.

A pilot model of patient education and counselling for drug-resistant tuberculosis in Daru, Papua New Guinea.

Education and counselling for people with drug-resistant tuberculosis (DR-TB) is recommended by the World Health Organization, given the arduous treatment journey. A model of education and counselling involving counsellors and peer counsellors, standard sessions and novel education tools was piloted in the high DR-TB burden context of Daru, Papua New Guinea. The pilot contributed to high retention in care, highlighting the need for investment in scalable models. Future models will need to be adapted as better tolerated regimens are introduced. A focus on patient-centred care requires prioritisation in order to meet the End TB Strategy targets.

L'éducation et le conseil aux personnes atteintes de tuberculose pharmacorésistante (DR-TB) sont recommandés par l'Organisation Mondiale de la Santé, étant donné les difficultés du parcours thérapeutique. Un modèle d'éducation et de conseil impliquant des conseillers et des pairs éducateurs, des sessions standard et de nouveaux outils d'éducation a été expérimenté dans le contexte de taux élevé de DR-TB de Daru en Papouasie Nouvelle Guinée. Ce projet pilote a contribué à un taux élevé de maintien en soins et a mis en lumière le besoin d'investir dans des modèles évolutifs. Les modèles futurs devront s'adapter aux protocoles mieux tolérés qui seront introduits. Une concentration sur les soins centrés sur le patient requiert une priorisation afin d'atteindre les objectifs de la stratégie Mettre fin à la TB.

La Organización Mundial de la Salud recomienda actividades de educación y orientación dirigidas a las personas con diagnóstico de tuberculosis farmacorresistente (DR-TB), habida cuenta de la trayectoria ardua del tratamiento. En el contexto de Daru, donde la carga de morbilidad por DR-TB es alta, se ensayó un modelo de educación y orientación. El proyecto piloto comportó la participación de consejeros, la orientación entre pares, sesiones ordinarias y nuevas herramientas pedagógicas. El proyecto contribuyó a lograr una alta retención en el servicio de atención y destacó la necesidad de inversión en modelos que se puedan ampliar. Será necesario adaptar los modelos futuros a medida que se introduzcan esquemas terapéuticos mejor tolerados. Un enfoque centrado en el paciente exige la definición de prioridades con miras a cumplir las metas de la Estrategia Fin a la Tuberculosis.

Tuberculosis treatment unmasking leprosy: management of drug-resistant tuberculosis and leprosy co-infection.

Co-infection with tuberculosis (TB) and leprosy is thought to occur infrequently, but has been reported in settings highly endemic for both infectious diseases. We report for the first time a case where treatment for multidrug-resistant TB (MDR-TB) led to the 'unmasking' of clinically silent leprosy through the precipitation of a type-1 immunological reaction. Current treatment regimens for MDR-TB may contain a number of drugs, such as levo-floxacin and clofazimine, which also have activity against M. leprae. A treatment regimen containing drugs active against both mycobacterial species may be used to achieve cure. Individual considerations on drug-drug interactions, potential additive toxicities and other comorbidities should be taken into account.

Il est considéré que la co-infection tuberculose (TB) et la lèpre est peu fréquente, mais elle a été signalée dans des milieux très endémiques pour les deux maladies infectieuses. Nous signalons pour la première fois un cas de traitement de la TB multirésistante (MDR-TB) 'démasquant' la lèpre cliniquement silencieuse par précipitation d'une réaction immunologique de type 1. Les schémas thérapeutiques actuels pour la MDR-TB peuvent contenir un certain nombre de médicaments, comme la lévofloxacine et la clofazimine, qui ont également une activité contre M. leprae. Un régime de traitement contenant des médicaments actifs contre les deux espèces mycobactériennes peut être utilisé pour obtenir la guérison. Les considérations individuelles sur les interactions médicamenteuses, les toxicités additives potentielles et les autres comorbidités doivent être prises en compte.

Se considera que la coinfección por tuberculosis (TB) y lepra es infrecuente, pero se han informado casos de concomitancia en entornos con alta endemicidad por ambas enfermedades infecciosas. En el presente artículo se comunica por primera vez un caso de tratamiento de la TB multirresistente (MDR-TB) que desenmascaró una lepra asintomática, tras desencadenar una reacción inmunitaria de tipo 1. Las pautas actuales de tratamiento de la MDR-TB pueden comportar un cierto número de fármacos como la levofloxacina y la clofazimina, que tienen también actividad contra el Mycobacterium leprae. Con el objeto de alcanzar la curación, se puede utilizar un esquema terapéutico que contenga fármacos activos contra ambas especies de micobacterias. En cada caso, es importante tener en cuenta los aspectos de las interacciones medicamentosas, la posible toxicidad acumulada y otras afecciones concomitantes.

Embolus Analog Trajectory Paths Under Physiological Flowrates Through Patient-Specific Aortic Arch Models.

Atrial fibrillation (AF) is the most common irregular heartbeat among the world's population and is a major contributor to cardiogenic embolisms and acute ischemic stroke (AIS). However, the role AF flow plays in the trajectory paths of cardiogenic emboli has not been experimentally investigated. A physiological simulation system was designed to analyze the trajectory patterns of bovine embolus analogs (EAs) (n = 720) through four patient-specific models, under three flow conditions: steady flow, normal pulsatile flow, and AF pulsatile flow. It was seen that EA trajectory paths were proportional to the percentage flowrate split of 25-31% along the branching vessels. Overall, AF flow conditions increased trajectories through the left- (LCCA) and right (RCCA)-common carotid artery by 25% with respect to normal pulsatile flow. There was no statistical difference in the distribution of clot trajectories when the clot was released from the right, left, or anterior positions. Significantly, more EAs traveled through the brachiocephalic trunk (BCT) than through the LCCA or the left subclavian. Yet of the EAs that traveled through the common carotid arteries, there was a greater affiliation toward the LCCA compared to the RCCA (p < 0.05).

Anthelmintic efficacy of single active and combination products against commonly occurring parasites in foals.

Parasite control in foals is complicated by the concurrent presence of biologically diverse parasites with differing levels of anthelmintic resistance. Several combination anthelmintic products are available for use in horses, but information on their efficacies against important equine parasites is scarce. Two trials were performed in New Zealand during 2008 and 2011 on four different farms with substantially different anthelmintic treatment histories. The first trial evaluated the efficacy of an ivermectin/praziquantel/oxibendazole combination, a single active oxibendazole, and a single-active macrocyclic lactone (ML) in 49 foals located on three farms. The second trial evaluated two combination anthelmintic products and three single-active ML products and enrolled a total of 110 foals on three farms. Foals in the second trial were allocated to one of six anthelmintic treatment groups; oxfendazole/pyrantel embonate, pyrantel embonate/ivermectin/praziquantel, ivermectin/praziquantel, abamectin/praziquantel, moxidectin/praziquantel, and a placebo-treated control. In both trials, foals were monitored monthly prior to treatment, and fecal egg counts (FECs) of Parascaris spp., strongylid, and Strongyloides westeri were determined. A "rolling enrolment" process was implemented whereby foals were systematically allocated to a treatment group and treated with the corresponding anthelmintic following the first appearance of Parascaris spp. eggs in the faeces. A generalised linear model was used to evaluate the effect of farm and treatment on Day14 FEC (ln) for each parasite. Three different FECR calculation methods were employed as follows; i) FECR(T) pre and post treatment ii) FECR (C) in the treated group compared with control, and iii) FECR (P) pre- and post- treatment in the treated and control groups. Across both trials, treatment with ML single active products failed to achieve >95% reduction in Parascaris spp. FEC on two of three farms. The pyrantel embonate/oxfendazole and ivermectin/ praziquantel/oxibendazole combinations demonstrated full efficacy against Parascaris spp. This is in contrast to the anti-strongylid efficacies determined, where the pyrantel embonate/oxfendazole combination and single active oxibendazole had reduced efficacy on one farm, while the macrocyclic lactones generally had good efficacy. Strongyloides egg counts were sporadic in both trials, and allowed limited insight into anthelmintic efficacy. The study illustrated the importance of keeping an untreated or placebo-treated control group in studies evaluating anti-Parascaris efficacy and it demonstrated the utility of a rolling enrolment procedure, where foals are enrolled over the course of a defined period of time. Furthermore, the study demonstrated the value of a farm specific FECR monitoring programme and the complexity of parasite control in foals, where combination anthelmintic products can be employed to target multiple species of parasites.

Trends in Providing Out-of-Office, Urgent After-Hours, and On-Call Care in British Columbia.

PURPOSE: Providing care in alternative (non-office) locations and outside office hours are important elements of access and comprehensiveness of primary care. We examined the trends in and determinants of the services provided in a cohort of primary care physicians in British Columbia, Canada. METHODS: We used physician-level payments for all primary care physicians practicing in British Columbia from 2006-2007 through 2011-2012. We examined the association between physician demographics and practice characteristics and payment for care in alternative locations and after hours across rural, urban, and metropolitan areas using longitudinal mixed-effects models. RESULTS: The proportion of physicians who provided care in alternative locations and after hours declined significantly during the period, in rural, urban, and metropolitan practices. Declines ranged from 5% for long-term care facility visits to 22% for after-hours care. Female physicians, and those in the oldest age category, had lower odds of providing care at alternative locations and for urgent after-hours care. Compared with those practicing in metropolitan centers, physicians working in rural areas had significantly higher odds of providing care both in alternative locations and after hours. CONCLUSION: Care provided in non-office locations and after office hours declined significantly during the study period. Jurisdictions where providing these services are not mandated, and where similar workforce demographic shifts are occurring, may experience similar accessibility challenges.