"Family doctors are also people": a qualitative analysis of how family physicians managed competing personal and professional responsibilities during the COVID-19 pandemic.

BACKGROUND: Family physicians (FPs) fill an essential role in public health emergencies yet have frequently been neglected in pandemic response plans. This exclusion harms FPs in their clinical roles and has unintended consequences in the management of concurrent personal responsibilities, many of which were amplified by the pandemic. The objective of our study was to explore the experiences of FPs during the first year of the COVID-19 pandemic to better understand how they managed their competing professional and personal priorities. METHODS: We conducted semi-structured interviews with FPs from four Canadian regions between October 2020 and June 2021. Employing a maximum variation sampling approach, we recruited participants until we achieved saturation. Interviews explored FPs' personal and professional roles and responsibilities during the pandemic, the facilitators and barriers that they encountered, and any gender-related experiences. Transcribed interviews were thematically analysed. RESULTS: We interviewed 68 FPs during the pandemic and identified four overarching themes in participants' discussion of their personal experiences: personal caregiving responsibilities, COVID-19 risk navigation to protect family members, personal health concerns, and available and desired personal supports for FPs to manage their competing responsibilities. While FPs expressed a variety of ways in which their personal experiences made their professional responsibilities more complicated, rarely did that affect the extent to which they participated in the pandemic response. CONCLUSIONS: For FPs to contribute fully to a pandemic response, they must be factored into pandemic plans. Failure to appreciate their unique role and circumstances often leaves FPs feeling unsupported in both their professional and personal lives. Comprehensive planning in anticipation of future pandemics must consider FPs' varied responsibilities, health concerns, and necessary precautions. Having adequate personal and practice supports in place will facilitate the essential role of FPs in responding to a pandemic crisis while continuing to support their patients' primary care needs.

Systematic review of photodynamic therapy for the treatment of hidradenitis suppurativa.

OBJECTIVE: To perform a systematic review of available literature regarding the use of 5-aminolevulinic acid (ALA) and ALA derivative photodynamic therapy (PDT) in the treatment of hidradenitis suppurativa (HS) and provide recommendations on its use. METHODS: A systematic review was performed of all published studies up to September 1, 2019 from nine databases, including PubMed, that evaluated PDT in the treatment of HS. For each study, quality of evidence and risk of bias was evaluated. Recommendations from the body of evidence were created based on Strength of Recommendation and Taxonomy (SORT) criteria. RESULTS: Eighteen studies met inclusion criteria. The majority of studies had a high risk of bias. Blue light PDT with 20% ALA and red light PDT with 16% methyl aminolevulinate (MAL) demonstrated some benefit based on a small number of poor-quality studies with a high risk of bias (Grade C, level III evidence). The most promising results were for 1%-5% ALA with intralesional diode, with good to complete response in 78%-94% of anatomic sites treated (Grade B, level II evidence). LIMITATIONS: The majority of studies contained high levels of bias, with significant heterogeneity between studies. Conclusions are limited by small samples sizes, lack of randomized controlled trials, and differing protocols. CONCLUSION: Further studies are needed to determine the clinical efficacy of 20% ALA with blue light and MAL with red light. Intralesional diode PDT shows the most promise and warrants further investigation in larger, randomized controlled trials.

"There's nothing like a good crisis for innovation": a qualitative study of family physicians' experiences with virtual care during the COVID-19 pandemic.

BACKGROUND: Prior to the pandemic, Canada lagged behind other Organisation for Economic Cooperation and Development countries in the uptake of virtual care. The onset of COVID-19, however, resulted in a near-universal shift to virtual primary care to minimise exposure risks. As jurisdictions enter a pandemic recovery phase, the balance between virtual and in-person visits is reverting, though it is unlikely to return to pre-pandemic levels. Our objective was to explore Canadian family physicians' perspectives on the rapid move to virtual care during the COVID-19 pandemic, to inform both future pandemic planning for primary care and the optimal integration of virtual care into the broader primary care context beyond the pandemic. METHODS: We conducted semi-structured interviews with 68 family physicians from four regions in Canada between October 2020 and June 2021. We used a purposeful, maximum variation sampling approach, continuing recruitment in each region until we reached saturation. Interviews with family physicians explored their roles and experiences during the pandemic, and the facilitators and barriers they encountered in continuing to support their patients through the pandemic. Interviews were audio-recorded, transcribed, and thematically analysed for recurrent themes. RESULTS: We identified three prominent themes throughout participants' reflections on implementing virtual care: implementation and evolution of virtual modalities during the pandemic; facilitators and barriers to implementing virtual care; and virtual care in the future. While some family physicians had prior experience conducting remote assessments, most had to implement and adapt to virtual care abruptly as provinces limited in-person visits to essential and urgent care. As the pandemic progressed, initial forays into video-based consultations were frequently replaced by phone-based visits, while physicians also rebalanced the ratio of virtual to in-person visits. Medical record systems with integrated capacity for virtual visits, billing codes, supportive clinic teams, and longitudinal relationships with patients were facilitators in this rapid transition for family physicians, while the absence of these factors often posed barriers. CONCLUSION: Despite varied experiences and preferences related to virtual primary care, physicians felt that virtual visits should continue to be available beyond the pandemic but require clearer regulation and guidelines for its appropriate future use.

Natural history of abdominal pain in family practice: Longitudinal study of electronic medical record data in southwestern Ontario.

OBJECTIVE: To examine the frequency, natural history, and outcomes of 3 subtypes of abdominal pain (general abdominal pain, epigastric pain, localized abdominal pain) among patients visiting Canadian family practices. DESIGN: Retrospective cohort study with a 4-year longitudinal analysis. SETTING: Southwestern Ontario. PARTICIPANTS: A total of 1790 eligible patients with International Classification of Primary Care codes for abdominal pain from 18 family physicians in 8 group practices. MAIN OUTCOME MEASURES: The symptom pathways, the length of an episode, and the number of visits. RESULTS: Abdominal pain accounted for 2.4% of the 15,149 patient visits and involved 14.0% of the 1790 eligible patients. The frequencies of each of the 3 subtypes were as follows: localized abdominal pain, 89 patients, 1.0% of visits, and 5.0% of patients; general abdominal pain, 79 patients, 0.8% of visits, and 4.4% of patients; and epigastric pain, 65 patients, 0.7% of visits, and 3.6% of patients. Those with epigastric pain received more medications, and patients with localized abdominal pain underwent more investigations. Three longitudinal outcome pathways were identified. Pathway 1, in which the symptom remains at the end of the visit with no diagnosis, was the most common among patients with all subtypes of abdominal symptoms at 52.8%, 54.4%, and 50.8% for localized, general, and epigastric pain, respectively, and the symptom episodes were relatively short. Less than 15% of patients followed pathway 2, in which a diagnosis is made and the symptom persists, and yet the episodes were long with 8.75 to 16.80 months' mean duration and 2.70 to 4.00 mean number of visits. Pathway 3, in which a diagnosis is made and there are no further visits for that symptom, occurred approximately one-third of the time, with about 1 visit over about 2 months. Prior chronic conditions were common across all 3 subtypes of abdominal pain ranging from 72.2% to 80.0%. Psychological symptoms consistently occurred at a rate of approximately one-third. CONCLUSION: The 3 subtypes of abdominal pain differed in clinically important ways. The most frequent pathway was that the symptom remained with no diagnosis, suggesting a need for clinical approaches and education programs for care of symptoms themselves, not merely in the service of coming to a diagnosis. The importance of prior chronic conditions and psychological conditions was highlighted by the results.

The roles of family physicians during a pandemic.

Family physicians play important roles throughout all stages of a pandemic response; however, actionable descriptions outlining these roles are absent from current pandemic plans. Using a multiple case study design, we conducted a document analysis and interviewed 68 family physicians in four Canadian regions. We identified roles performed by family physicians in five distinct stages of pandemic response: pre-pandemic, phased closure and re-opening, acute care crisis, vaccination, and pandemic recovery. In addition to adopting public health guidance to ensure continued access to primary care services, family physicians were often expected to operationalize public health roles (eg, staffing assessment centres), modulate access to secondary/tertiary services, help provide surge capacity in acute care facilities, and enhance supports and outreach to vulnerable populations. Future pandemic plans should include family physicians in planning, explicitly incorporate family physician roles, and ensure needed resources are available to allow for an effective primary care response.

Family physician virtual care during COVID-19 in London-Middlesex, Ontario, Canada: a mixed methods exploration.

Context: On March 14, 2020, the Ontario, Canada health insurance plan approved COVID-19 physician virtual billing codes; family physicians (FPs) rapidly adopted a new model of care. Virtual care may remain post-pandemic; however, its future should be informed by evidence that considers access and continuity. Objective: 1) to determine FP virtual visit volumes and patient characteristics and 2) to explore FPs' perspectives on virtual visit adoption and implementation. Study Design: Mixed methods: Secondary analysis of health administrative (HA) data and semi-structured qualitative interviews with FPs. Setting or Dataset: London and Middlesex County, Ontario, Canada. HA data through ICES, Ontario entity holding data. Population studied: FPs and their patients. Outcome Measures: Volumes of FP in-person and virtual visits during early pandemic; characteristics of patients receiving care; FPs' perspectives on adopting and delivering virtual care. Results: Overall visit volume dropped by 36% during first wave, recovered to pre-pandemic levels by October 2020. Sharp in-person visit drop of 73% and virtual visit uptake from 0.08% of total visits to 57% within two weeks of March 2020. FPs described this initial drop in volume as patients not seeking care and practices lacking PPE. The move to virtual care was largely to telephone visits. Patient characteristics compared to pre-pandemic, the proportion seeking care were older (46 vs 50 years), more vulnerable (38% vs 41%), and more multimorbidity (33% vs 41%). This was consistent with FP reports that healthier patients stayed away, routine care deferred, sicker patients needed to be seen. FPs believed most vulnerable patients had access to care but cautioned highly vulnerable such as those homeless did not have cell phone access or a safe place to receive calls. Rural FPs reported access issues because of lack of high-speed internet. FPs attributed success of virtual care to the continuity in relationships they had with patients that were established in person pre-pandemic. Conclusions: FPs moved rapidly to virtual care. FP offices remained open despite PPE concerns but overall volumes dropped initially. Vulnerable and sicker patients received care but FPs expressed concern for highly vulnerable and rural residents. FPs believed they could offer patient-centred care over the phone but indicated the importance of maintaining in-person care to build relationships.

Obesity and sex influence fatty infiltration of the rotator cuff: the Rotator Cuff Outcomes Workgroup (ROW) and Multicenter Orthopaedic Outcomes Network (MOON) cohorts.

BACKGROUND: Fatty infiltration (FI) is one of the most important prognostic factors for outcomes after rotator cuff surgery. Established risk factors include advancing age, larger tear size, and increased tear chronicity. A growing body of evidence suggests that sex and obesity are associated with FI; however, data are limited. METHODS: We recruited 2 well-characterized multicenter cohorts of patients with rotator cuff tears (Multicenter Orthopaedic Outcomes Network [MOON] cohort [n = 80] and Rotator Cuff Outcomes Workgroup [ROW] cohort [n = 158]). We used multivariable logistic regression to evaluate the relationship between body mass index (BMI) and the presence of FI while adjusting for the participant's age at magnetic resonance imaging, sex, and duration of shoulder symptoms, as well as the cross-sectional area of the tear. We analyzed the 2 cohorts separately and performed a meta-analysis to combine estimates. RESULTS: A total of 27 patients (33.8%) in the Multicenter Orthopaedic Outcomes Network (MOON) cohort and 57 patients (36.1%) in the Rotator Cuff Outcomes Workgroup (ROW) cohort had FI. When BMI < 25 kg/m2 was used as the reference category, being overweight was associated with a 2.37-fold (95% confidence interval [CI], 0.77-7.29) increased odds of FI and being obese was associated with a 3.28-fold (95% CI, 1.16-9.25) increased odds of FI. Women were 4.9 times (95% CI, 2.06-11.69) as likely to have FI as men. CONCLUSIONS: Among patients with rotator cuff tears, obese patients had a substantially higher likelihood of FI. Further research is needed to assess whether modifying BMI can alter FI in patients with rotator cuff tears. This may have significant clinical implications for presurgical surgical management of rotator cuff tears. Sex was also significantly associated with FI, with women having higher odds of FI than men. Higher odds of FI in female patients may also explain previously reported early suboptimal outcomes of rotator cuff surgery and higher pain levels in female patients as compared with male patients.

Focused practice in family medicine: Quantitative study.

OBJECTIVE: To determine factors associated with having a focused practice among a sample of family medicine graduates in Canada and to assess the characteristics of FPs with focused practices and the range of services provided by these FPs in relation to the full scope of office-based care. DESIGN: Secondary analyses of cross-sectional data from the 2013-2014 Western Family Medicine Resident Follow-Up Survey. SETTING: Western University in London, Ont. PARTICIPANTS: Western University family medicine residency graduates who completed the program between 1985 and 2012. MAIN OUTCOME MEASURES: Physician and practice characteristics and the clinical services that survey participants provide. RESULTS: Completion of postgraduate third-year (PGY3) training was associated with having a focused practice. Focused practice FPs were more likely to be remunerated by fee-for-service, alternative payment plans, or alternative funding plans compared with non-focused practice FPs, who were more likely to participate in group payment models. Focused practice FPs appeared to be a heterogeneous group who were distinguished by being either an office-based focused practice FP (OBFFP) or a non-office-based focused practice FP (NOBFFP). Office-based focused practice FPs were less likely than NOBFFPs to have completed PGY3 training and more likely to work under a fee-for-service or group payment model. Further, the OBFFP group offered a greater variety of primary care services than the NOBFFP group, but offered less variety than non-focused practice FPs. CONCLUSION: Completion of PGY3 training and payment through certain remuneration models were both associated with focused practice. Important differences exist between OBFFPs and NOBFFPs. The overall service provision of focused practice FPs was centred on specialized areas, especially among those practising in non-office-based settings. Novel findings from this study provide insights for family medicine education, work force planning, and policy making in the Canadian health system.

Abdominal aortic aneurysm screening in an academic family practice: Short-term impact of guideline changes.

OBJECTIVE: To investigate abdominal aortic aneurysm (AAA) screening rates in the 6 months before and after the introduction of updated Canadian Task Force on Preventive Health Care (CTFPHC) guidelines to determine effects on practice patterns, as well as to determine whether certain patient characteristics impact AAA screening rates. DESIGN: Retrospective chart review. SETTING: Academic family health centre in London, Ont. PARTICIPANTS: Male patients between the ages of 65 and 80. MAIN OUTCOME MEASURES: Screening rates for AAA before and after the guideline update were compared using the normal approximation of the binomial distribution. Analysis of demographic characteristic effects on screening rates was completed with the Fisher exact test. Number of visits to the clinic with a primary care provider within the study period and imaging type were collected. RESULTS: Of the 266 patients included in the study, 160 patients were eligible for screening at the start of the study period, 6 months before publication of the CTFPHC AAA guideline. Individuals eligible for screening visited the clinic an average (SD) of 2.44 (1.82) times in the 6 months before and 2.66 (1.99) times in the 6 months after. Overall, 69 individuals had AAA screening completed and 9 had a discussion of AAA screening without any imaging, for a total uptake rate of 88.5% for those who had screening recommended. The overall imaging rate was 48.9%. There was no statistically significant difference in screening rates between the time periods (P=.337) among those eligible for screening. For demographic characteristics for risk stratification, 7 individuals had a documented family history, of whom 5 had imaging of their abdominal aorta performed, plus 1 additional individual who had screening recommended but not completed. This was not statistically significant relative to the total population (P=.0598). Positive smoking status (active or ex-smoker) was more common, with 135 individuals having a relevant smoking history. Approximately half of these current and former smokers (68 individuals [50.4%]) had any sort of abdominal aortic imaging performed or recommended, which was not statistically significantly different compared with non-smokers (62 of 126 imaging performed or recommended, 49.2%; P=.9016). CONCLUSION: Screening practices did not change appreciably with the introduction of the CTFPHC AAA screening guidelines. Further research is needed to improve AAA screening rates. It is worth exploring electronic medical record-based reminders, nursing staff involvement in screening, screening programs via public health, and point-of-care ultrasound screening in a primary care setting.

CUREing biochemistry lab monotony.

Undergraduate research experience is critical to success in post-graduate research settings. The recent movement away from "cookbook" style labs to course-based undergraduate research experiences (CUREs) in undergraduate laboratories has allowed universities to provide inclusive research experience while bypassing the limitations of extracurricular apprenticeships. This paper describes an upper-level biochemistry CURE designed to provide students with an introductory experience to graduate-level research by studying a suspected DNA helicase. This CURE is designed to span multiple semesters, where each student cohort builds upon the work of previous semesters. Pre- and post-course surveys were employed to assess student confidence in bench skills, perceptions of the course, and project ownership. The results show that the incorporation of lab meeting-style recitations and poster presentations led to higher project ownership, while overcoming troubleshooting was a significant challenge. Furthermore, confidence in every experimental technique increased significantly in all but one instance. Based on these results, this CURE is providing students with a realistic experience in graduate-level research.

Systematic scoping review of factors and measures of rurality: toward the development of a rurality index for health care research in Japan.

BACKGROUND: Rural-urban health care disparities are an important topic in health services research. Hence, developing valid and reliable tools to measure rurality is needed to support high quality research. However, Japan, has no index to measure rurality for health care research. In this study, we conducted a systematic scoping review to identify the important factors and methodological approaches to consider in a rurality index to inform the development of a rurality index for Japan. METHODS: For our review, we searched six bibliographic databases (MEDLINE, PubMed, CINAHIL, ERIC, Web of Science and the Grey Literature Report) and official websites of national governments such as Government and Legislative Libraries Online Publications Portal (GALLOP), from 1 January 1989 to 31 December 2018. We extracted relevant variables used in the development of rurality indices, the formulas used to calculate indices, and any measures for reliability and validity of these indices. RESULTS: We identified 17 rurality indices from 7 countries. These indices were primarily developed to assess access to health care or to determine eligibility for incentives for health care providers. Frequently used factors in these indices included population size/density and travel distance/time to emergency care or referral centre. Many indices did not report reliability or validity measures. CONCLUSIONS: While the concept of rurality and concerns about barriers to access to care for rural residents is shared by many countries, the operationalization of rurality is highly context-specific, with few universal measures or approaches to constructing a rurality index. The results will be helpful in the development of a rurality index in Japan and in other countries.

Red Light Irradiation In Vivo Upregulates DJ-1 in the Retinal Ganglion Cell Layer and Protects against Axotomy-Related Dendritic Pruning.

Retinal ganglion cells (RGCs) undergo dendritic pruning in a variety of neurodegenerative diseases, including glaucoma and autosomal dominant optic atrophy (ADOA). Axotomising RGCs by severing the optic nerve generates an acute model of RGC dendropathy, which can be utilized to assess the therapeutic potential of treatments for RGC degeneration. Photobiomodulation (PBM) with red light provided neuroprotection to RGCs when administered ex vivo to wild-type retinal explants. In the current study, we used aged (13-15-month-old) wild-type and heterozygous B6;C3-Opa1Q285STOP (Opa1+/-) mice, a model of ADOA exhibiting RGC dendropathy. These mice were pre-treated with 4 J/cm2 of 670 nm light for five consecutive days before the eyes were enucleated and the retinas flat-mounted into explant cultures for 0-, 8- or 16-h ex vivo. RGCs were imaged by confocal microscopy, and their dendritic architecture was quantified by Sholl analysis. In vivo 670 nm light pretreatment inhibited the RGC dendropathy observed in untreated wild-type retinas over 16 h ex vivo and inhibited dendropathy in ON-center RGCs in wild-type but not Opa1+/- retinas. Immunohistochemistry revealed that aged Opa1+/- RGCs exhibited increased nitrosative damage alongside significantly lower activation of NF-κB and upregulation of DJ-1. PBM restored NF-κB activation in Opa1+/- RGCs and enhanced DJ-1 expression in both genotypes, indicating a potential molecular mechanism priming the retina to resist future oxidative insult. These data support the potential of PBM as a treatment for diseases involving RGC degeneration.

In a Time of Need: A Grassroots Initiative in Response to PPE Shortage in the COVID-19 Pandemic.

SETTING: Primary care is the first line of defence in healthcare, particularly during the coronavirus disease 2019 (COVID-19) pandemic. In the London-Middlesex region of Ontario, a critical shortage of personal protective equipment (PPE) was identified among primary care physicians (PCPs). INTERVENTION: With the help of the London-Middlesex Primary Care Alliance, volunteer administrators, physicians and medical students coordinated the acquisition and redistribution of community-donated PPE to PCPs across London-Middlesex. Our scope evolved to include PPE reusability and stewardship and PCP wellness. OUTCOME: Beginning on March 16, 2020, our initial four-week operation provided PPE to over 200 PCPs. We received 60 donations, including over 118,000 gloves, 13,700 masks, 700 wellness kits and reusable cloth masks and gowns. Each delivery included educational pamphlets, and our online PPE stewardship session was attended by over 30 physicians. IMPLICATIONS: In response to the PPE shortage in COVID-19, our efforts evolved into a complex adaptive system, supported by an organizational body with a pre-existing communication infrastructure, to great success. Our scope extended beyond simple PPE provision to PCPs. Furthermore, our initiative established a framework for a centralized response to PPE shortage in Ontario Health West.

Shared activity patterns arising at genetic susceptibility loci reveal underlying genomic and cellular architecture of human disease.

Genetic variants underlying complex traits, including disease susceptibility, are enriched within the transcriptional regulatory elements, promoters and enhancers. There is emerging evidence that regulatory elements associated with particular traits or diseases share similar patterns of transcriptional activity. Accordingly, shared transcriptional activity (coexpression) may help prioritise loci associated with a given trait, and help to identify underlying biological processes. Using cap analysis of gene expression (CAGE) profiles of promoter- and enhancer-derived RNAs across 1824 human samples, we have analysed coexpression of RNAs originating from trait-associated regulatory regions using a novel quantitative method (network density analysis; NDA). For most traits studied, phenotype-associated variants in regulatory regions were linked to tightly-coexpressed networks that are likely to share important functional characteristics. Coexpression provides a new signal, independent of phenotype association, to enable fine mapping of causative variants. The NDA coexpression approach identifies new genetic variants associated with specific traits, including an association between the regulation of the OCT1 cation transporter and genetic variants underlying circulating cholesterol levels. NDA strongly implicates particular cell types and tissues in disease pathogenesis. For example, distinct groupings of disease-associated regulatory regions implicate two distinct biological processes in the pathogenesis of ulcerative colitis; a further two separate processes are implicated in Crohn's disease. Thus, our functional analysis of genetic predisposition to disease defines new distinct disease endotypes. We predict that patients with a preponderance of susceptibility variants in each group are likely to respond differently to pharmacological therapy. Together, these findings enable a deeper biological understanding of the causal basis of complex traits.

Situational cues surrounding family physicians seeking external resources while self-monitoring in practice.

Many models of safe and effective clinical decision making in medical practice emphasize the importance of recognizing moments of uncertainty and seeking help accordingly. This is not always done effectively, but we know little about what cues prompt health professionals to call on resources beyond their own knowledge or skill set. Such information would offer guidance regarding how systems might be designed to offer better individual support. In this study, the authors explored the situational factors that are present during moments of uncertainty that lead primary care physicians to access external resources. To do so, a generic qualitative exploratory analysis was conducted on 72 narratives collected through audio recorder-based, self-observational, journaling completed by 12 purposively selected family physicians. Participants were asked to provide a detailed descriptive account of the circumstances surrounding their consultation of external resources immediately after 6 sequential patient encounters in which they felt compelled to seek such support. Thematic analysis of the transcripts was performed to better understand participants' experiences of the social, contextual, and personal features surrounding decisions to seek support. When doing so we observed that specific features of patient encounters were routinely present when physicians decided to access external sources for help. These included medical aspects of the case (e.g., complex presentations), social aspects (e.g., the presence of another individual), and personal factors (e.g., feeling a need for reassurance). External resources were seen as an opportunity for verification, a mechanism to increase patient satisfaction, and a means through which to defend decision-making. Accessing such resources appeared to influence the physician-patient relationship for various reasons. Recognition and further study of the cues that prompt use of external information will further our understanding of physicians' behavioural responses to challenging/uncertain situations, highlight mechanisms through which a culture of self-directed assessment seeking might be encouraged, and offer guidance regarding ways in which physicians can be encouraged to practice mindfully. Our results make it clear that reasons for which primary care physicians seek the support of external resources may be multifactorial and, therefore, one should be cautious when inferring reasons for the pursuit of such support.

Robust graft survival and normalized dopaminergic innervation do not obligate recovery in a Parkinson disease patient.

OBJECTIVE: The main goal of dopamine cell replacement therapy in Parkinson disease (PD) is to provide clinical benefit mediated by graft survival with nigrostriatal reinnervation. We report a dichotomy between graft structure and clinical function in a patient dying 16 years following fetal nigral grafting. METHODS: A 55-year-old levodopa-responsive woman with PD received bilateral putaminal fetal mesencephalic grafts as part of an NIH-sponsored double-blind sham-controlled trial. The patient never experienced clinical benefit, and her course was complicated by the development of graft-related dyskinesias. Fluorodopa positron emission tomography demonstrated significant increases postgrafting bilaterally. She experienced worsening of parkinsonism with severe dyskinesias, and underwent subthalamic nucleus deep brain stimulation 8 years after grafting. She died 16 years after transplantation. RESULTS: Postmortem analyses confirmed the diagnosis of PD and demonstrated >300,000 tyrosine hydroxylase (TH)-positive grafted cells per side with normalized striatal TH-immunoreactive fiber innervation and bidirectional synaptic connectivity. Twenty-seven percent and 17% of grafted neurons were serine 129-phosphorylated α-synuclein positive in the left and right putamen, respectively. INTERPRETATION: These findings represent the largest number of surviving dopamine neurons and the densest and most widespread graft-mediated striatal dopamine reinnervation following a transplant procedure reported to date. Despite this, clinical recovery was not observed. Furthermore, the grafts were associated with a form of dyskinesias that resembled diphasic dyskinesia and persisted in the off-medication state. We hypothesize that the grafted cells produced a low level of dopamine sufficient to cause a levodopa-independent continuous form of diphasic dyskinesias, but insufficient to provide an antiparkinsonian benefit. ANN NEUROL 2017;81:46-57.

Presence of tau pathology within foetal neural allografts in patients with Huntington's and Parkinson's disease.

Cell replacement has been explored as a therapeutic strategy to repair the brain in patients with Huntington's and Parkinson's disease. Post-mortem evaluations of healthy grafted tissue in such cases have revealed the development of Huntington- or Parkinson-like pathology including mutant huntingtin aggregates and Lewy bodies. An outstanding question remains if tau pathology can also be seen in patients with Huntington's and Parkinson's disease who had received foetal neural allografts. This was addressed by immunohistochemical/immunofluorescent stainings performed on grafted tissue of two Huntington's disease patients, who came to autopsy 9 and 12 years post-transplantation, and two patients with Parkinson's disease who came to autopsy 18 months and 16 years post-transplantation. We show that grafts also contain tau pathology in both types of transplanted patients. In two patients with Huntington's disease, the grafted tissue showed the presence of hyperphosphorylated tau [both AT8 (phospho-tau Ser202 and Thr205) and CP13 (pSer202) immunohistochemical stainings] pathological inclusions, neurofibrillary tangles and neuropil threads. In patients with Parkinson's disease, the grafted tissue was characterized by hyperphosphorylated tau (AT8; immunofluorescent staining) pathological inclusions, neurofibrillary tangles and neuropil threads but only in the patient who came to autopsy 16 years post-transplantation. Abundant tau-related pathology was observed in the cortex and striatum of all cases studied. While the striatum of the grafted Huntington's disease patient revealed an equal amount of 3-repeat and 4-repeat isoforms of tau, the grafted tissue showed elevated 4-repeat isoforms by western blot. This suggests that transplants may have acquired tau pathology from the host brain, although another possibility is that this was due to acceleration of ageing. This finding not only adds to the recent reports that tau pathology is a feature of these neurodegenerative diseases, but also that tau pathology can manifest in healthy neural tissue transplanted into the brains of patients with two distinct neurodegenerative disorders.

Comprehensive practice: Normative definition across 3 generations of alumni from a single family practice program, 1985 to 2012.

OBJECTIVE: To determine the range of services and procedures offered by family physicians who define themselves as comprehensive practitioners and compare responses across 3 generations of alumni of a single family practice program. DESIGN: Cross-sectional survey. SETTING: Western University in London, Ont. PARTICIPANTS: All graduates of the family medicine program between 1985 and 2012. MAIN OUTCOME MEASURES: Self-reported provision of the following types of care: in-office care, in-hospital care, intrapartum obstetrics, housecalls, palliative care, after-hours care, nursing home care, minor surgery, emergency department care, sport medicine, and walk-in care. Sex, training site (urban or rural), size of community of practice, practice model, and satisfaction with practice were also reported. RESULTS: Participants practised in 7 provinces and 1 territory across Canada, but principally in Ontario. A small number were located in the United States. There was a decline in the number of services provided across 3 generations of graduates, with newer graduates providing fewer services than the older graduates. Significant decreases across the 3 groups were observed in provision of housecalls (P = .004), palliative care (P = .028), and nursing home care (P < .001). Non-significant changes were seen in provision of intrapartum obstetrics across the 3 alumni groups, with an initial decline and then increase in reported activity. Most respondents were in a family health organization or family health network practice model and those in such models reported offering significantly more services than those in family health group or salary models (P < .001). CONCLUSION: The normative definition of comprehensive care varies across 3 generations of graduates of this family medicine program, with newer physicians reporting fewer overall services and procedures than older graduates. Greater understanding of the forces (institutional, regulatory, economic, and personal) that determine the meaning of comprehensive primary care is necessary if this foundational element of family medicine is to be preserved.

CIB1: a small protein with big ambitions.

Calcium- and integrin-binding protein 1 (CIB1) is a small, ubiquitously expressed protein that was first identified as an intracellular binding partner of a platelet-specific α-integrin cytoplasmic tail. Although early studies revealed a role for CIB1 in regulating platelet integrin activity, recent studies have indicated a more diverse role for CIB1 in many different cell types and processes, including calcium signaling, migration, adhesion, proliferation, and survival. Increasing evidence also points to a novel role for CIB1 in cancer and cardiovascular disease. In addition, an array of CIB1 binding partners has been identified that provide important insight into how CIB1 may regulate these processes. Some of these binding partners include the serine/threonine kinases, p21-activated kinase 1 (PAK1), apoptosis signal-regulating kinase 1 (ASK1), and polo-like kinase 3 (PLK3). Structural and mutational studies indicate that CIB1 binds most or all of its partners via a well-defined hydrophobic cleft. Although CIB1 itself lacks known enzymatic activity, it supports the PI3K/AKT and MEK/ERK oncogenic signaling pathways, in part, by directly modulating enzymes in these pathways. In this review, we discuss our current understanding of CIB1 and key questions regarding structure and function and how this seemingly diminutive protein impacts important signaling pathways and cellular processes in human health and disease.-Leisner, T. M., Freeman, T. C., Black, J. L., Parise, L. V. CIB1: a small protein with big ambitions.

Somatic retrotransposition alters the genetic landscape of the human brain.

Retrotransposons are mobile genetic elements that use a germline 'copy-and-paste' mechanism to spread throughout metazoan genomes. At least 50 per cent of the human genome is derived from retrotransposons, with three active families (L1, Alu and SVA) associated with insertional mutagenesis and disease. Epigenetic and post-transcriptional suppression block retrotransposition in somatic cells, excluding early embryo development and some malignancies. Recent reports of L1 expression and copy number variation in the human brain suggest that L1 mobilization may also occur during later development. However, the corresponding integration sites have not been mapped. Here we apply a high-throughput method to identify numerous L1, Alu and SVA germline mutations, as well as 7,743 putative somatic L1 insertions, in the hippocampus and caudate nucleus of three individuals. Surprisingly, we also found 13,692 somatic Alu insertions and 1,350 SVA insertions. Our results demonstrate that retrotransposons mobilize to protein-coding genes differentially expressed and active in the brain. Thus, somatic genome mosaicism driven by retrotransposition may reshape the genetic circuitry that underpins normal and abnormal neurobiological processes.