Family physician practice patterns during COVID-19 and future intentions: Cross-sectional survey in Ontario, Canada.

OBJECTIVE: To determine the extent to which family physicians closed their doors altogether or for in-person visits during the pandemic, their future practice intentions, and related factors. DESIGN: Cross-sectional survey. SETTING: Six geographic areas in Toronto, Ont, aligned with Ontario Health Team regions. PARTICIPANTS: Family doctors practising office-based, comprehensive family medicine. MAIN OUTCOME MEASURES: Practice operations in January 2021, use of virtual care, and future plans. RESULTS: Of the 1016 (85.7%) individuals who responded to the survey, 99.7% (1001 of 1004) indicated their practices were open in January 2021, with 94.8% (928 of 979) seeing patients in person and 30.8% (264 of 856) providing in-person care to patients reporting COVID-19 symptoms. Respondents estimated spending 58.2% of clinical care time on telephone visits, 5.8% on video appointments, and 7.5% on e-mail or secure messaging. Among respondents, 17.5% (77 of 439) were planning to close their existing practices in the next 5 years. There were higher proportions of physicians who worked alone in clinics among those who did not see patients in person (27.6% no vs 12.4% yes, P<.05), among those who did not see symptomatic patients (15.6% no vs 6.5% yes, P<.001), and among those who planned to close their practices in the next 5 years (28.9% yes vs 13.9% no, P<.01). CONCLUSION: Most family physicians in Toronto were open to in-person care in January 2021, but almost one-fifth were considering closing their practices in the next 5 years. Policy makers need to prepare for a growing family physician shortage and better understand factors that support recruitment and retention.

Best Practices for COVID-19 Mass Vaccination Clinics.

PURPOSE: The coronavirus disease 2019 (COVID-19) pandemic is an unprecedented global public health crisis. Mass vaccination is the safest and fastest pandemic exit strategy. Mass vaccination clinics are a particularly important tool in quickly achieving herd immunity. Primary care physicians have played a crucial role in organizing and running vaccination clinics. In this special report, we synthesize existing guidelines and peer-reviewed studies to provide physicians with practical guidance on planning and implementing COVID-19 mass vaccination clinics. METHODS: PubMed, Ovid MEDLINE and Embase were used to search for relevant literature using search terms that included COVID-19, mass vaccination, and best practice. We also identified and analyzed national and international guidelines. RESULTS: Forty-six relevant articles, reports, and guidelines were identified and synthesized. Articles included mass vaccination clinic guidelines and studies before and during the COVID-19 pandemic. Key considerations for COVID-19 mass vaccination clinics include leadership and role designation, site selection, clinic layout and workflow, day-to-day operations, infection prevention, and communication strategies. CONCLUSIONS: Planning and implementing a successful COVID-19 mass vaccination clinic requires several key considerations. Primary care plays an important role in organizing clinics and ensuring populations made vulnerable by social and economic policies are being reached. Ongoing data collection is required to evaluate and continuously improve COVID-19 mass vaccination efforts. As the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine rollout occurs in various countries, research will be required to identify the main factors for success to inform future pandemic responses.VISUAL ABSTRACT.

Implementing High-Quality Primary Care Through a Health Equity Lens.

The COVID-19 pandemic highlighted the importance of centering health equity in future health system and primary care reforms. Strengthening primary care will be needed to correct the longstanding history of mistreatment of First Nations/Indigenous and racialized people, exclusion of health care workers of color, and health care access and outcome inequities further magnified by the COVID-19 pandemic. The National Academies of Sciences, Engineering, and Medicine (NASEM) released a report on Implementing High-Quality Primary Care: Rebuilding the Foundation of Health Care, that provided a framework for defining high-quality primary care and proposed 5 recommendations for implementing that definition. Using the report's framework, we identified health equity challenges and opportunities with examples from primary care systems in the United States and Canada. We are poised to reinvigorate primary care because the recent pandemic and the attention to continued racialized police violence sparked renewed conversations and collaborations around equity, diversity, inclusion, and health equity that have been long overdue. The time to transition those conversations to actionable items to improve the health of patients, families, and communities is now.Appeared as Annals "Online First" article.

Unleashing the therapeutic potential of human kallikrein-related serine proteases.

Tissue kallikreins are a family of fifteen secreted serine proteases encoded by the largest protease gene cluster in the human genome. In the past decade, substantial progress has been made in characterizing the natural substrates, endogenous inhibitors and in vivo functions of kallikreins, and studies have delineated important pathophysiological roles for these proteases in a variety of tissues. Thus, kallikreins are now considered attractive targets for the development of novel therapeutics for airway, cardiovascular, tooth, brain, skin and neoplastic diseases. In this Review, we discuss recent advances in our understanding of the physiological functions and pathological implications of kallikrein proteases, and highlight progress in the identification of kallikrein inhibitors, which together are bringing us closer to therapeutically targeting kallikreins in selected disease settings.

Serum kallikrein-8 correlates with skin activity, but not psoriatic arthritis, in patients with psoriatic disease.

BACKGROUND: About 30% of cutaneous psoriasis (PsC) patients develop psoriatic arthritis (PsA) in the joint, which is under-recognized by dermatologists. Biomarkers for PsA are needed so that early referral to a rheumatologist is made. Kallikreins (KLKs) are secreted serine proteases implicated in skin desquamation and inflammation. This study examined KLK potential as serum biomarkers of PsA in cutaneous psoriasis patients. METHODS: KLKs were measured by ELISAs in synovial fluids of three PsA patients and three control early osteoarthritis (OA) patients, as well as in a cohort of 152 serum samples collected from age- and sex-matched PsC patients, with (n=76) or without PsA (n=76). KLK expression in psoriatic plaques was examined by immunohistochemistry. Univariate and multivariate logistic regression analyses were conducted to analyze the association between serum KLK levels and disease class (PsC, PsA). Serum KLKs that associated with PsA were correlated with clinical parameters of skin and joint activity. RESULTS: Among the seven KLKs tested, KLK6 and KLK8 were elevated in both PsA synovial fluids and psoriatic plaques, but only serum KLK8 levels were associated with psoriatic disease (odds ratio=2.56, p=0.03). Although significantly elevated in PsC and PsA sera compared to healthy controls, KLK8 did not discriminate PsA from PsC patients. KLK8 correlated positively with the psoriasis area and severity index (PASI) (r=0.43, p=0.001) independent of age, sex and psoriasis duration ( ß=1.153, p=0.0003) and exhibited no correlations with tender or swollen joint counts. CONCLUSIONS: Increased KLK8 serum level in PsA patients reflects disease activity in the skin but not in the joints. Serum KLK levels are not useful for screening psoriasis patients for PsA.

Proteinase-activated receptors (PARs): differential signalling by kallikrein-related peptidases KLK8 and KLK14.

We compared signalling pathways such as calcium transients, MAPK activation, ß-arrestin interactions and receptor internalization triggered by kallikrein-related peptidases (KLKs) 8 and 14 in human and rat proteinase-activated receptor (PAR)2-expressing human embryonic kidney (HEK) and Kirsten transformed rat kidney (KNRK) cells. Further, we analysed processing by KLK8 vs. KLK14 of synthetic human and rat PAR2-derived sequences representing the cleavage-activation domain of PAR2. Our data show that like KLK14, KLK8 can unmask a PAR2 receptor-activating sequence from a peptide precursor. However, whilst KLK8, like KLK14, can signal in rat-PAR2-expressing KNRK cells, this enzyme cannot signal via human PAR2 in HEK or KNRK cells, but rather, disarms HEK PAR1. Thus, KLK8 and KLK14 can signal differentially via the PARs to affect tissue function.

Kallikrein-related peptidase-8 (KLK8) is an active serine protease in human epidermis and sweat and is involved in a skin barrier proteolytic cascade.

Kallikrein-related peptidase-8 (KLK8) is a relatively uncharacterized epidermal protease. Although proposed to regulate skin-barrier desquamation and recovery, the catalytic activity of KLK8 was never demonstrated in human epidermis, and its regulators and targets remain unknown. Herein, we elucidated for the first time KLK8 activity in human non-palmoplantar stratum corneum and sweat ex vivo. The majority of stratum corneum and sweat KLK8 was catalytically active, displaying optimal activity at pH 8.5 and considerable activity at pH 5. We also showed that KLK8 is a keratinocyte-specific protease, not secreted by human melanocytes or dermal fibroblasts. KLK8 secretion increased significantly upon calcium induction of terminal keratinocyte differentiation, suggesting an active role for this protease in upper epidermis. Potential activators, regulators, and targets of KLK8 activity were identified by in vitro kinetic assays using pro-KLK8 and mature KLK8 recombinant proteins produced in Pichia pastoris. Mature KLK8 activity was enhanced by calcium and magnesium ions and attenuated by zinc ions and by autocleavage after Arg(164). Upon screening KLK8 cleavage of a library of FRET-quenched peptides, trypsin-like specificity was observed with the highest preference for (R/K)(S/T)(A/V) at P1-P1'-P2'. We also demonstrated that KLK5 and lysyl endopeptidase activate latent pro-KLK8, whereas active KLK8 targets pro-KLK11, pro-KLK1, and LL-37 antimicrobial peptide activation in vitro. Together, our data identify KLK8 as a new active serine protease in human stratum corneum and sweat, and we propose regulators and targets that augment its involvement in a skin barrier proteolytic cascade. The implications of KLK8 elevation and hyperactivity in desquamatory and inflammatory skin disease conditions remain to be studied.

Human tissue kallikreins as promiscuous modulators of homeostatic skin barrier functions.

Human tissue kallikreins (KLKs) are the largest family of secreted serine protease endopeptidases encoded by 15 genes clustered on chromosome 19q13.4. Multiple KLK enzymes are co-localized in the upper stratum granulosum and stratum corneum of human epidermis, and in associated appendages such as hair follicle epithelia and sweat glands. Until recently, kallikrein proteolytic activity in the skin was exclusively attributed to KLK5 and KLK7. However, wider cutaneous roles of kallikreins became evident in recent years as the proposal of KLK proteolytic activation cascades emerged. We postulate that these proteolytic enzymes may serve as promiscuous mediators of different skin barrier functions, since they are capable of proteolysing different substrates that govern skin desquamation, antimicrobial defense, and lipid permeability. Growing evidence now attests to potential kallikrein involvement in skin inflammation, pigmentation, and tumor suppression via their ability to target proteinase-activated receptor signaling pathways. Current knowledge on kallikrein roles in skin physiology and pathobiology is described in this review.