Exploration of how primary care models influence job satisfaction among primary care providers during the COVID-19 pandemic in New Brunswick: a descriptive and comparative study.

BACKGROUND: The COVID-19 pandemic has highlighted human resource gaps and physician shortages in healthcare systems in New Brunswick (NB), as evidenced by multiple healthcare service interruptions. In addition, the New Brunswick Health Council gathered data from citizens on the type of primary care models (i.e. physicians in solo practice, physicians in collaborative practice, and collaborative practice with physicians and nurse practitioners) they use as their usual place of care. To add to their survey's findings, our study aims to see how these different primary care models were associated with job satisfaction as reported by primary care providers. METHODS: In total, 120 primary care providers responded to an online survey about their primary care models and job satisfaction levels. We used IBM's "SPSS Statistics" software to run Chi-square and Fisher's exact tests to compare job satisfaction levels between variable groups to determine if there were statistically significant variations. RESULTS: Overall, 77% of participants declared being satisfied at work. The reported job satisfaction levels did not appear to be influenced by the primary care model. Participants reported similar job satisfaction levels regardless of if they practiced alone or in collaboration. Although 50% of primary care providers reported having symptoms of burnout and experienced a decline in job satisfaction during the COVID-19 pandemic, the primary care model was not associated with these experiences. Therefore, participants who reported burnout or a decline in job satisfaction were similar in all primary care models. Our study's results suggest that the autonomy to choose a preferred model was important, since 45.8% of participants reported choosing their primary care models, based on preference. Proximity to family and friends and balancing work and family emerged as critical factors that influence choosing a job and staying in that job. CONCLUSION: Primary care providers' staffing recruitment and retention strategies should include the factors reported as determinants in our study. Primary care models do not appear to influence job satisfaction levels, although having the autonomy to choose a preferred model was reported as highly important. Consequently, it may be counterproductive to impose specific primary care models if one aims to prioritize primary care providers' job satisfaction and wellness.

A randomised controlled trial of the effects of Brain Wave Vibration training on mood and well-being.

BACKGROUND: The goal was to investigate the effects of Brain Wave Vibration (BWV), a meditation practised in a class involving rhythmic movements of the head, neck and body practised with related yoga-style exercises, and to isolate the rhythmic effects. METHODS: A randomised controlled trial was conducted with assessments pre- and post-trial and immediately before and after each session. Thirty-one healthy adults were assessed for mood, sleep, mindfulness, health and well-being, and pre- and post-class activation-deactivation. Participants were randomly assigned to either BWV in toto or a control group having similar yoga exercises without the rhythmic components. Participants completed eight to twelve 75-min classes of BWV or control training over 8-12 weeks. To control for expectation participants were told only that the aim was to compare two subtly different styles of Korean yoga. RESULTS: The BWV group had comparatively greater improvements in sleep duration and efficiency, although they had higher baseline inefficiency, and post-trial they had better global sleep and well-being and fewer illness symptoms, and better tiredness and energy post-class. Both groups benefitted in mood, mindfulness and vitality post-trial with improved tension and calmness post-class. CONCLUSIONS: The participants of both interventions had better mood and well-being on the whole following the trial and were more relaxed immediately after a class. However, BWV training was unique in its benefits to sleep, health, well-being, energy and tiredness, warranting further research.

Malarial dihydrofolate reductase as a paradigm for drug development against a resistance-compromised target.

Malarial dihydrofolate reductase (DHFR) is the target of antifolate antimalarial drugs such as pyrimethamine and cycloguanil, the clinical efficacy of which have been compromised by resistance arising through mutations at various sites on the enzyme. Here, we describe the use of cocrystal structures with inhibitors and substrates, along with efficacy and pharmacokinetic profiling for the design, characterization, and preclinical development of a selective, highly efficacious, and orally available antimalarial drug candidate that potently inhibits both wild-type and clinically relevant mutated forms of Plasmodium falciparum (Pf) DHFR. Important structural characteristics of P218 include pyrimidine side-chain flexibility and a carboxylate group that makes charge-mediated hydrogen bonds with conserved Arg122 (PfDHFR-TS amino acid numbering). An analogous interaction of P218 with human DHFR is disfavored because of three species-dependent amino acid substitutions in the vicinity of the conserved Arg. Thus, P218 binds to the active site of PfDHFR in a substantially different fashion from the human enzyme, which is the basis for its high selectivity. Unlike pyrimethamine, P218 binds both wild-type and mutant PfDHFR in a slow-on/slow-off tight-binding mode, which prolongs the target residence time. P218, when bound to PfDHFR-TS, resides almost entirely within the envelope mapped out by the dihydrofolate substrate, which may make it less susceptible to resistance mutations. The high in vivo efficacy in a SCID mouse model of P. falciparum malaria, good oral bioavailability, favorable enzyme selectivity, and good safety characteristics of P218 make it a potential candidate for further development.

Lymphatic absorption of subcutaneously administered proteins: influence of different injection sites on the absorption of darbepoetin alfa using a sheep model.

The relative contribution of the lymph and blood in the absorption of darbepoetin alfa (DA) from different s.c. injection sites was determined using a central lymph-cannulated sheep model. DA was administered to parallel groups either as a bolus i.v. injection (0.5 mug/kg) into the jugular vein or as a bolus s.c. injection (2 mug/kg) into the interdigital space, the abdomen, or the shoulder. In the lymph-cannulated groups, the thoracic lymph duct was cannulated for continuous collection of central lymph, and blood samples were periodically collected via the jugular vein in all the groups. The concentration of DA in serum and lymph was determined by enzyme-linked immunosorbent assay. The total fraction of the dose reaching the systemic circulation and the fractions absorbed via the lymph and the blood were determined. A pharmacokinetic model was constructed to simultaneously fit the data from all the treatment groups. Absorption was essentially complete for all three injection sites in non-lymph-cannulated s.c. groups, but the rates of absorption differed significantly. Based on the modeling results for the lymph-cannulated groups, the lymphatics represented the predominant absorption route for both the interdigital (90 +/- 1%) and the abdomen (67 +/- 9%) injection sites. Fluorescein isothiocyanate dextran visualization studies revealed that the lymph draining the shoulder injection site entered the thoracic lymph duct distal to the point of cannulation, effectively precluding collection of thoracic lymph from this site. For that reason, the contribution of the lymphatics following injection in the shoulder could not be determined using these cannulation procedures.

The absorption of darbepoetin alfa occurs predominantly via the lymphatics following subcutaneous administration to sheep.

PURPOSE: To determine the contribution of the lymphatics to the systemic availability of darbepoetin alfa (DA) using an established sheep model. MATERIALS AND METHODS: DA was administered either by intravenous (IV) injection (0.2, 0.5 or 2 microg/kg) or by subcutaneous (SC) administration (2 microg/kg) into the interdigital space of the hind leg. A SC control group was used to determine the absolute bioavailability (F (sys)). Cannulation of the peripheral lymphatics in a parallel SC group allowed the continuous collection of lymph draining the injection site and determination of the cumulative amount of DA absorbed via the lymphatics. Serum and lymph concentrations of DA were determined by ELISA. The fraction of the dose absorbed into the lymphatics (F (lymph)) relative to the fraction absorbed directly into the blood (F (blood)) was determined using a compartmental approach. RESULTS: Dose-linear pharmacokinetics was observed within the dose range investigated. The bioavailability was virtually complete following SC injection into the interdigital space (88.4 +/- 15.7%). A high proportion of the administered dose was recovered in peripheral lymph (90.2 +/- 4.4%) resulting in a substantial reduction in the systemic availability in lymph cannulated animals (3.7%). CONCLUSION: The high recovery of DA in the peripheral lymph demonstrated near complete absorption of this recombinant protein via the lymphatics in a lymph cannulated sheep model.

Lymphatic absorption is the primary contributor to the systemic availability of epoetin Alfa following subcutaneous administration to sheep.

The contribution of the lymphatics to the absorption and systemic availability of recombinant human epoetin alfa (rHuEPO) following s.c. injection was examined using a cannulated sheep model. Parallel studies were conducted in sheep where a single bolus dose was administered either by i.v. (10, 100, or 1000 IU/kg) or s.c. (400 IU/kg) injection. The first s.c. group served as a control for the calculation of absolute bioavailability. In the second group, the efferent popliteal lymphatic duct was cannulated and peripheral lymph draining the injection site was continuously collected. In the third group, the thoracic duct was cannulated to allow collection of central lymph just prior to entry into the systemic circulation. Blood was periodically sampled from all animals, and concentrations in serum and lymph were determined by enzyme-linked immunosorbent assay. The cumulative amount of rHuEPO recovered in peripheral and central lymph was 83.9 +/- 6.6% and 75.3 +/- 3.9% of the administered dose, respectively, indicating almost complete absorption from the s.c. injection site and minimal clearance during transit through the lymphatic system. After i.v. administration, the systemic clearance of rHuEPO decreased with increasing dose, reflecting capacity-limited elimination kinetics. A pharmacokinetic model was developed to simultaneously fit experimental data for all treatment groups and estimate bioavailability. The direct measurement of >75% of the dose in peripheral and central lymph independently verifies the calculated bioavailability of 87% and demonstrates the major role of the lymphatic route in the overall s.c. bioavailability of rHuEPO after s.c. administration with this animal model.

Subcutaneous drug delivery and the role of the lymphatics.

Subcutaneous injections are widely utilised as a delivery route for compounds with limited oral bioavailability or as a means to modify or extend the release profile. In this review, factors affecting absorption from the subcutaneous space are discussed with particular emphasis on differential drug absorption into either the underlying blood or lymphatic capillaries. Formulation and targeted delivery approaches, which utilise the subcutaneous administration route, are reviewed with reference to associated technologies and future challenges.:

Pharmacokinetic model to describe the lymphatic absorption of r-metHu-leptin after subcutaneous injection to sheep.

PURPOSE: The purpose of this work was to develop a pharmacokinetic model to describe the contribution of the lymphatics to the absorption and bioavailability of r-metHu-Leptin administered by subcutaneous (SC) injection to sheep. METHODS: r-metHu-Leptin was administered either by bolus intravenous injection (0.1 mg/kg) into the jugular vein or by SC injection (0.15 mg/kg) into the interdigital space of the hind leg. The SC groups included a non-cannulated control group and a lymph-cannulated group, in which peripheral lymph was continuously collected from a cannula in the efferent popliteal lymph duct. Serum and lymph concentrations were determined by enzyme-linked immunosorbent assay and profiles were modeled using compartmental pharmacokinetic methods. The fraction of the dose reaching the systemic circulation (Fsys) and the proportions of the absorbed dose taken up via the blood (Fblood) and lymph (Flymph) were determined. RESULTS: Serum and lymph concentration vs. time profiles were well described by a two compartment model with parallel first order absorption into blood and lymph. Fsys for the SC control group was 60.4 +/- 8.4%. In the lymph-cannulated group, 21.7 +/- 6.4% of the dose was recovered in serum and 34.4 +/- 9.7% was recovered in peripheral lymph giving a total fraction absorbed (Fabs) of 56.0 +/- 10.3%. Fsys for the SC control group was not significantly different to Fabs in the lymph-cannulated group. CONCLUSION: This study has shown that the lymph represents the predominant pathway for absorption of r-metHu-Leptin after SC administration.