Implementing Strengths-Based Nursing and Healthcare: A Decade of Leadership and Learning in a Canadian Pediatric Rehabilitation Setting.

The nursing context in pediatric rehabilitation is that of caring for children with disabilities and complex developmental differences and health conditions in an ever-changing and demanding environment. Rehabilitation nurses aim to continuously advance nursing leadership, practice, education and research to meet service needs. Strengths-Based Nursing and Healthcare (SBNH) is a philosophy and value-driven approach that aligns with and enables the advancement of strengths-based rehabilitation nursing and family-centred care. This paper describes the leadership approach undertaken to implement SBNH in a Canadian pediatric rehabilitation hospital context over a 10-year period. We will share what we did and what we learned.

Pervasive aggregation and depletion of host and viral proteins in response to cysteine-reactive electrophilic compounds.

Protein homeostasis is tightly regulated, with damaged or misfolded proteins quickly eliminated by the proteasome and autophagosome pathways. By co-opting these processes, targeted protein degradation technologies enable pharmacological manipulation of protein abundance. Recently, cysteine-reactive molecules have been added to the degrader toolbox, which offer the benefit of unlocking the therapeutic potential of 'undruggable' protein targets. The proteome-wide impact of these molecules remains to be fully understood and given the general reactivity of many classes of cysteine-reactive electrophiles, on- and off-target effects are likely. Using chemical proteomics, we identified a cysteine-reactive small molecule degrader of the SARS-CoV-2 nonstructural protein 14 (nsp14), which effects degradation through direct modification of cysteines in both nsp14 and in host chaperones together with activation of global cell stress response pathways. We find that cysteine-reactive electrophiles increase global protein ubiquitylation, trigger proteasome activation, and result in widespread aggregation and depletion of host proteins, including components of the nuclear pore complex. Formation of stress granules was also found to be a remarkably ubiquitous cellular response to nearly all cysteine-reactive compounds and degraders. Collectively, our study sheds light on complexities of covalent target protein degradation and highlights untapped opportunities in manipulating and characterizing proteostasis processes via deciphering the cysteine-centric regulation of stress response pathways.

Probe-based quantitative PCR and RPA-Cas12a molecular diagnostics for detection of the tomato pest Phthorimaea absoluta (Lepidoptera: Gelechiidae).

The tomato pest Phthorimaea absoluta Meyrick is highly invasive but has not yet invaded North America. However, several morphologically similar species are already present, making detection of P. absoluta presence and invasion challenging. We designed a quantitative PCR molecular diagnostic to differentiate P. absoluta, P. operculella (Zeller), or Keiferia lycopersicella (Walsingham) (Lepidoptera: Gelechiidae) DNA. Additionally, we developed an RPA-Cas12a molecular diagnostic that allows for the isothermal detection of P. absoluta DNA, eliminating the need for a thermocycler. The results of the RPA-Cas12a diagnostic can be visualized simply using a UV light source and cell phone camera. We expect these diagnostics to improve quarantine and prevention measures against this serious agricultural threat.

Current State of Knowledge on Digital Rectal Stimulation in Individuals With Traumatic and Nontraumatic Spinal Cord Injury: A Scoping Review.

OBJECTIVES: To map and characterize the nature of the evidence on the use of digital rectal stimulation for bowel management in individuals with spinal cord injury (SCI). DATA SOURCES: Five electronic databases were searched (ie, MEDLINE, EMBASE, CINAHL, Cochrane CENTRAL, and Cochrane Incontinence Group) from 1990 to November 2019. STUDY SELECTION: Articles that provided information on the use of digital rectal stimulation either alone or in combination with treatments were included. Title and abstract screening was split between 2 reviewers after reaching consensus on the first 100 studies screened. Full-texts were reviewed independently by 2 reviewers. Discrepancies were resolved by a third reviewer. DATA EXTRACTION: The data extraction form was developed by 2 reviewers and piloted. Data were extracted by one reviewer and checked for accuracy by a second reviewer. DATA SYNTHESIS: A total of 4841 studies were screened, including 425 full text articles; 33 articles were identified. Thirty-two studies focused solely on individuals with SCI and 1 study explored the experiences of caregivers of individuals with SCI. The majority of participants were aged between 30 and 59 years old. Most studies used quantitative methods (n=30, 91%). Fourteen of the studies (42%) were cross-sectional. Within experimental or quasiexperimental designs, digital rectal stimulation was commonly studied as an adjunct to other methods such as suppositories or enemas. Incontinence and defecation time were the most commonly examined outcomes. CONCLUSION: There were few studies found that focus on digital rectal stimulation. Further studies examining experience, effectiveness, complications, and long-term outcomes are warranted.

CK2 Inhibits TIMELESS Nuclear Export and Modulates CLOCK Transcriptional Activity to Regulate Circadian Rhythms.

Circadian clocks orchestrate daily rhythms in organismal physiology and behavior to promote optimal performance and fitness. In Drosophila, key pacemaker proteins PERIOD (PER) and TIMELESS (TIM) are progressively phosphorylated to perform phase-specific functions. Whereas PER phosphorylation has been extensively studied, systematic analysis of site-specific TIM phosphorylation is lacking. Here, we identified phosphorylation sites of PER-bound TIM by mass spectrometry, given the importance of TIM as a modulator of PER function in the pacemaker. Among the 12 TIM phosphorylation sites we identified, at least two of them are critical for circadian timekeeping as mutants expressing non-phosphorylatable mutations exhibit altered behavioral rhythms. In particular, we observed that CK2-dependent phosphorylation of TIM(S1404) promotes nuclear accumulation of PER-TIM heterodimers by inhibiting the interaction of TIM and nuclear export component, Exportin 1 (XPO1). We propose that proper level of nuclear PER-TIM accumulation is necessary to facilitate kinase recruitment for the regulation of daily phosphorylation rhythm and phase-specific transcriptional activity of CLOCK (CLK). Our results highlight the contribution of phosphorylation-dependent nuclear export of PER-TIM heterodimers to the maintenance of circadian periodicity and identify a new mechanism by which the negative elements of the circadian clock (PER-TIM) regulate the positive elements (CLK-CYC). Finally, because the molecular phenotype of tim(S1404A) non-phosphorylatable mutant exhibits remarkable similarity to that of a mutation in human timeless that underlies familial advanced sleep phase syndrome (FASPS), our results revealed an unexpected parallel between the functions of Drosophila and human TIM and may provide new insights into the molecular mechanisms underlying human FASPS.

The ß2-adrenoceptor agonist bronchodilators terbutaline and orciprenaline are also weak α1-adrenoceptor antagonists.

Recently, the ß2-adrenoceptor agonist terbutaline was shown to have α1-adrenolytic activity in mouse isolated pulmonary arteries in vitro and to lower pulmonary artery pressure in anaesthetised mice. The aim of our study was to determine the α1-adrenoceptor antagonist activity of terbutaline and its structurally close resorcinol, orciprenaline, in rat isolated small mesenteric arteries set up for myography. Their α1-adrenoceptor antagonist potency was then compared with their potency as ß2-adrenoceptor agonists. Concentration-response curves to methoxamine were competitively antagonised by terbutaline (30-300 µM) or orciprenaline (30-300 µM) with a pKB of 4.70 ± 0.09 or 4.79 ± 0.17, respectively. Both terbutaline and orciprenaline fulfilled the criteria for simple, silent competitive antagonism. Terbutaline (30-300 µM) had no effect on endothelin-1 concentration-contraction curves. Our findings suggest that after oral dosing of terbutaline, the maximum plasma levels would NOT reach levels to show α1-adrenoceptor antagonist activity. In conclusion, our work has provided additional quantitative evidence that terbutaline and orciprenaline are weak competitive α1-adrenoceptor antagonists, but this additional property is probably not therapeutically important in the clinical treatment of asthma or pulmonary artery hypertension with these more potent ß2-adrenoceptor agonists.

Patient-Reported Usability of Positive Airway Pressure Equipment Is Associated With Adherence in Older Adults.

Study objectives: To examine the usability of positive airway pressure (PAP) devices and its association with PAP adherence among older adults with sleep-disordered breathing. Methods: We mailed questionnaires to patients aged ≥65 years prescribed PAP therapy during the prior 36 months from two large healthcare systems. Survey participants completed the Usability of Sleep Apnea Equipment-Positive Airway Pressure (USE-PAP) questionnaire, which assessed the usability of their PAP device. Other questionnaire items included demographics and self-rated health. We also abstracted adherence data (mean nightly hours of PAP use available from one site) and interface type from the electronic health record. Results: Five hundred sixty-four patients completed the survey (response rate = 33%). The mean USE-PAP score (0 = best to 100 = worst) was 20 (SD ± 20). Mean duration of PAP use (available in 189 respondents) was 5.2 hours per night (SD ± 2.0). In a nested regression model predicting nightly hours of PAP use, a 10-point (0.5 SD) increase in USE-PAP score corresponded to a 0.37 hour/night reduction in PAP use. The model including the USE-PAP score explained a significant proportion (R2 = 15%) of the variation in nightly hours of PAP use above and beyond demographics, self-reported health, and interface type (∆R2 = 12%). Conclusions: Our results demonstrate that PAP usability varies among older patients and is associated with PAP adherence, above and beyond other predictors of adherence. These results support measuring and improving PAP usability to further improve PAP adherence for older patients.

Patient-Provider Communication With Older Adults About Sleep Apnea Diagnosis and Treatment.

Patient-provider communication impacts adherence to therapy. We explored older adults' communication with their providers, preferences for communication, and views on communication attributes and decision aid characteristics, by conducting four focus groups. Several participants reported they had received insufficient information about their sleep apnea diagnosis and treatment options. Most participants felt that it would be helpful to have treatment information tailored to their needs, including information on the negative impact of treatment on comfort and convenience and disclosure about common barriers to adherence. Participants provided desired characteristics for a decision aid, including their preferred delivery method, content, and format. These findings have implications for how to design useful decision aids for older adults with newly diagnosed sleep apnea.