Hierarchical Classification I: Single-Linkage Method

This is the first part of a survey of hierarchical clustering algorithms using joining methods: the Single-Linkage algorithm. Complete-Linkage and general algorithms defined by d(A_i, B) = = α,d(A_i, A_r)±α_sd(A_i, A_s)±βd(A_r, A_s) will be discussed in two subsequent papers.     

Shifts in office and virtual primary care during the early COVID-19 pandemic in Ontario,Canada

BACKGROUND:Globally, primary care changed dramatically as a result of the coronavirus disease 2019 (COVID-19) pandemic. We aimed to understand the degree to which office and virtual primary care changed, and for which patients and physicians, during the initial months of the pandemic in Ontario, Canada.METHODS:This population-based study compared comprehensive, linked primary care physician billing data from Jan. 1 to July 28, 2020, with the same period in 2019. We identified Ontario residents with at least 1 office or virtual (telephone or video) visit during the study period. We compared trends in total physician visits, office visits and virtual visits before COVID-19 with trends after pandemic-related public health measures changed the delivery of care, according to various patient and physician characteristics. We used interrupted time series analysis to compare trends in the early and later halves of the COVID-19 period.RESULTS:Compared with 2019, total primary care visits between March and July 2020 decreased by 28.0%, from 7.66 to 5.51 per 1000 people/day. The smallest declines were among patients with the highest expected health care use (8.3%), those who could not be attributed to a primary care physician (10.2%), and older adults (19.1%). In contrast, total visits in rural areas increased by 6.4%. Office visits declined by 79.1% and virtual care increased 56-fold, comprising 71.1% of primary care physician visits. The lowest uptake of virtual care was among children (57.6%), rural residents (60.6%) and physicians with panels of ≥ 2500 patients (66.0%).INTERPRETATION:Primary care in Ontario saw large shifts from office to virtual care over the first 4 months of the COVID-19 pandemic. Total visits declined least among those with higher health care needs. The determinants and consequences of these major shifts in care require further study.

Primary care is considered the cornerstone of most health systems worldwide, and in higher-income countries, primary care visits are about 30 times more frequent than hospital admissions.¹ Health systems with greater availability of primary care are associated with increased access to care, reduced health inequities, better outcomes and lower costs.² Despite the centrality of primary care to health care systems, little is known about how it has been affected by coronavirus disease 19 (COVID-19).On Mar. 11, 2020, the World Health Organization declared COVID-19 a global pandemic.³ On Mar. 15, Ontario’s Chief Medical Officer of Health issued a directive to ramp down elective surgeries and other nonemergent health services, and on Mar. 19, health care providers and organizations were directed to stop or substantially reduce all nonessential or elective services until further notice.⁴ The Ontario Ministry of Health and the Ontario Medical Association negotiated the addition of temporary billing codes in the province’s schedule of benefits to facilitate virtual care, effective as of Mar. 14 (Appendix 1, available at www.cmaj.ca/lookup/doi/10.1503/cmaj.202303/tab-related-content). In mid to late May 2020, the province undertook a phased resumption of certain in-person health professional services and surgeries.⁴Initial reports from ongoing COVID-19-related surveys of primary care providers in Canada and the United States showed major disruptions to care, decreased payments, challenges keeping offices functioning, lack of personal protective equipment and widespread uptake of virtual care.^5,6 The degree to which virtual care — such as phone calls, video visits and secure text messages — replaced in-person office visits is not known. It is also not known which patients and physicians were most affected by the challenges to office-based practice or the change to virtual visits. We aimed to understand the degree to which office and virtual primary care changed, and for which patients and physicians, during the initial months of the COVID-19 pandemic in Ontario, Canada.     

A closed,autologous bioprocess optimized for TCR-T cell therapies

Autologous cell therapy has proven to be an effective treatment for hematological malignancies. Cell therapies for solid tumors are on the horizon, however the high cost and complexity of manufacturing these therapies remain a challenge. Routinely used open steps to transfer cells and reagents through unit operations further burden the workflow reducing efficiency and increasing the chance for human error. Here we describe a fully closed, autologous bioprocess generating engineered TCR-T cells. This bioprocess yielded 5–12 × 10e9 TCR-expressing T cells, transduced at low multiplicity of infections, within 7–10 days, and cells exhibited an enriched memory T-cell phenotype and enhanced metabolic fitness. It was demonstrated that activating, transducing, and expanding leukapheresed cells in a bioreactor without any T-cell or peripheral blood mononuclear cell enrichment steps had a high level of T-cell purity (~97%). Several critical process parameters of the bioreactor, including culturing at a high cell density (7e6 cells/mL), adjusting rocking agitations during phases of scale-up, lowering glycolysis through the addition of 2-deoxy- d -glucose, and modulating interleukin-2 levels, were investigated on their roles in regulating transduction efficiency, cell growth, and T-cell fitness such as T-cell memory phenotype and resistance to activation-induced cell death. The bioprocess described herein supports scale-out feasibility by enabling the processing of multiple patients' batches in parallel within a Grade C cleanroom.     

Exact compensation of stream drift as an evolutionarily stable strategy

The colonization cycle hypothesis predicts that adults of stream-dwelling insects preferentially disperse in the upstream direction in order to compensate for larval drift. Upstream biased dispersal has indeed been shown in many, albeit not all, natural populations. Based on a recently published analysis, we develop a simple stochastic model for the competition of genotypes with different dispersal strategies in a stream habitat. By means of an invasion analysis, we show that exact compensation of larval drift by upstream biased adult dispersal is an evolutionarily stable strategy. Exact compensation means that, on average, the net movement of individuals from birth to the time of reproduction is zero. At the population level, we show that, in general, upstream biased dispersal is not necessary for persistence, unless the reproductive rate is very low. Under all conditions, however, populations of exact compensators attain highest sizes or persistence times, respectively. Although selection pressure towards exact compensation is arguably very general in populations subject to stream drift, trade-offs or constraints might change the outcome of selection. Therefore, the analysis presented in this paper has to be viewed as a null model for optimal dispersal behavior in stream habitats.     

Impaired in vivo myocardial reactivity to norepinephrine in diabetic rats

The effects of long-term diabetes with and without insulin treatment on in vivo myocardial contractile activity were studied under basal conditions and as a function of intravenously infused norepinephrine. Diabetes was induced by iv injection of streptozotocin (50 mg/kg). Insulin-treated diabetic rats received 5 units per day of isophane insulin suspension. The duration of the study was 8 weeks. In vivo myocardial contractility measurements were performed in ketamine-xylazine-anesthetized rats using a miniature catheter-tip pressure transducer advanced through the right carotid artery into the left ventricle. Peak positive dP/dt and intraventricular developed pressure were comparable among the groups when measured under basal conditions; however, the magnitude of the response to variable doses of norepinephrine (6 X 10(-12) to 6 X 10(-8) mole/kg body wt) were significantly diminished in diabetic rats, but the sensitivity was unchanged. Negative dP/dt was decreased under basal conditions and in response to norepinephrine in diabetic rats. Insulin treatment to diabetic rats prevented these changes, but heart rate was elevated. These results demonstrate that the in vivo cardiovascular reactivity of diabetic rats to norepinephrine is significantly attenuated.