Noncanonical role of singleminded-2s in mitochondrial respiratory chain formation in breast cancer.

Dysregulation of cellular metabolism is a hallmark of breast cancer progression and is associated with metastasis and therapeutic resistance. Here, we show that the breast tumor suppressor gene SIM2 promotes mitochondrial oxidative phosphorylation (OXPHOS) using breast cancer cell line models. Mechanistically, we found that SIM2s functions not as a transcription factor but localizes to mitochondria and directly interacts with the mitochondrial respiratory chain (MRC) to facilitate functional supercomplex (SC) formation. Loss of SIM2s expression disrupts SC formation through destabilization of MRC Complex III, leading to inhibition of electron transport, although Complex I (CI) activity is retained. A metabolomic analysis showed that knockout of SIM2s leads to a compensatory increase in ATP production through glycolysis and accelerated glutamine-driven TCA cycle production of NADH, creating a favorable environment for high cell proliferation. Our findings indicate that SIM2s is a novel stabilizing factor required for SC assembly, providing insight into the impact of the MRC on metabolic adaptation and breast cancer progression.

SIM2s directed Parkin-mediated mitophagy promotes mammary epithelial cell differentiation.

The functionally differentiated mammary gland adapts to extreme levels of stress from increased demand for energy by activating specific protective mechanisms to support neonatal health. Here, we identify the breast tumor suppressor gene, single-minded 2 s (SIM2s) as a novel regulator of mitophagy, a key component of this stress response. Using tissue-specific mouse models, we found that loss of Sim2 reduced lactation performance, whereas gain (overexpression) of Sim2s enhanced and extended lactation performance and survival of mammary epithelial cells (MECs). Using an in vitro model of MEC differentiation, we observed SIM2s is required for Parkin-mediated mitophagy, which we have previously shown as necessary for functional differentiation. Mechanistically, SIM2s localizes to mitochondria to directly mediate Parkin mitochondrial loading. Together, our data suggest that SIM2s regulates the rapid recycling of mitochondria via mitophagy, enhancing the function and survival of differentiated MECs.

Evaluation of Loop Diuretic Dosing Following Sodium-Glucose Cotransporter 2 Inhibitor Initiation in Patients With Heart Failure.

Introduction: Sodium-glucose cotransporter 2 inhibitors (SGLT2is) have demonstrated cardiovascular benefits in patients with heart failure, many of which take loop diuretics. There are no evidence-based recommendations identifying which patients may require loop diuretic dose decreases or how to adjust loop diuretic doses when SGLT2is are initiated. Objectives: The main objective of this study was to investigate the frequency and degree of adjustments in loop diuretic doses after SGLT2i initiation in patients with heart failure. Methods: In this retrospective evaluation, patients seen in the UCHealth system with a diagnosis of heart failure who were prescribed a loop diuretic before initiation of SGLT2i were identified. We described loop diuretic dose changes at the time of SGLT2i initiation, at 6 months after initiation, and at 1 year after initiation. We also described de-escalation of maintenance medications that can contribute to hypotension at these time points. Data were evaluated using descriptive statistics. Results: A total of 100 patients were included. Loop diuretic dose was reduced empirically upon SGLT2i initiation in 2.0% of patients. Reduction of loop diuretic dose within the first 6 months of starting an SGLT2i occurred in 8.0% of patients. From baseline to 12 months after starting SGLT2i therapy, 14.0% of patients had loop diuretic dose reduction. Conclusions: Most of our patients with HF did not have change in loop diuretic dose after initiation of an SGLT2i. In patients who did have loop diuretic dose reduction, most occurred within 6 months after starting SGLT2i therapy rather than empirically at time of initiation.

Non-breeding changes in at-sea distribution and abundance of the threatened marbled murrelet (Brachyramphus marmoratus) in a portion of its range exhibiting long-term breeding season declines.

The marbled murrelet (Brachyramphus marmoratus) is classified as a threatened species under the US Endangered Species Act in Washington, Oregon, and California USA due to population declines, loss of breeding habitat, and other factors. To date, population assessments have focused on breeding season at-sea surveys. Consequently, there is little information on this species' distribution, abundance, and population trends during the non-breeding season, when murrelets are found exclusively in the marine environment. To address this information need, we assessed non-breeding (Sep-Mar) at-sea murrelet abundance patterns and population trends over 8 years, in a portion of its range where breeding season surveys indicate a 20-year population decline, Puget Sound, Washington, USA. This allowed us to assess whether non-breeding population trends mirrored those observed during the breeding season suggesting regional year-round conservation concerns and to also identify important over-wintering areas (areas of high abundance). We integrated our non-breeding abundance information with breeding season information to assess year-round patterns of abundance. This allowed us to test the prediction that murrelets move into the relatively protected inner marine waters of Puget Sound from harsher outer coastal habitats during the non-breeding season to molt and over-winter. Similar to trends from the breeding season, we observed strong murrelet density declines across the entire non-breeding period (Sep and Apr) with declines most pronounced in the fall and early winter (lateSep-Dec) survey windows when birds molt and in the spring just prior to breeding (Mar-Apr). Despite these declines, there was essentially no change in murrelet density in mid-winter (January-February) when overall density was lower. Puget Sound murrelet density exhibited a strong north-south gradient with relatively high densities to the north and low densities to the south; murrelets were largely absent from Central Puget Sound. For strata other than Central Puget Sound, density varied seasonally with birds more evenly distributed among strata between September and December but in the late winter/early spring period (Jan-Apr), murrelets were largely absent from all strata except the most northerly Admiralty Inlet Stratum, which appears to be important to murrelets year-round. Depending on the year, non-breeding season densities were nearly the same or higher than breeding season densities indicate that murrelets were not moving into the relatively protected inner marine waters of Puget Sound from more outer coastal environments during the non-breeding season as predicted.

Data on the diets of Salish Sea harbour seals from DNA metabarcoding.

Marine trophic ecology data are in high demand as natural resource agencies increasingly adopt ecosystem-based management strategies that account for complex species interactions. Harbour seal (Phoca vitulina) diet data are of particular interest because the species is an abundant predator in the northeast Pacific Ocean and Salish Sea ecosystem that consumes Pacific salmon (Oncorhynchus spp.). A multi-agency effort was therefore undertaken to produce harbour seal diet data on an ecosystem scale using, 1) a standardized set of scat collection and analysis methods, and 2) a newly developed DNA metabarcoding diet analysis technique designed to identify prey species and quantify their relative proportions in seal diets. The DNA-based dataset described herein contains records from 4,625 harbour seal scats representing 52 haulout sites, 7 years, 12 calendar months, and a total of 11,641 prey identifications. Prey morphological hard parts analyses were conducted alongside, resulting in corresponding hard parts data for 92% of the scat DNA samples. A custom-built prey DNA sequence database containing 201 species (192 fishes, 9 cephalopods) is also provided.

Potentially Inappropriate Medication Usage in Older Adults in a Tertiary Academic Medical Center Emergency Department.

BACKGROUND: The Beers Criteria® medications are potentially inappropriate medications (PIMs) recommended by the American Geriatric Society to be avoided or used with caution in adults 65 years and older. The usage of PIMs in the emergency department (ED) setting is not well characterized. OBJECTIVES: The purpose of this study is to evaluate the usage of PIMS in the ED. METHODS: This is a single center retrospective observational study of a random sample of patients aged 65 and older who presented to the ED during a 6-month timeframe. The primary outcome was the incidence of ED readmissions in patients administered or prescribed a PIM compared with patients who were not prescribed or administered a PIM. Secondary outcomes included ED length of stay (LOS) and hospital admission. RESULTS: Out of 192 patients, there was a total of 58 patients (30.2%) in the PIM group and 134 patients (69.8%) in the No PIM group. ED re-presentation within 30 days occurred in 10 patients (17%) in the PIM group vs 26 patients (19%) in the No PIM group (p = 0.88). The median ED LOS was 227 minutes vs 208 minutes (p = 0.1679). Hospital admission within 30 days occurred in 4 patients (7%) in the PIM group and 13 patients (10%) in the No PIM group (p = 0.725). CONCLUSIONS: This analysis did not show statistically significant differences between patients who received a PIM compared to those who received an alternative medication with regard to re-presentation, admission, and ED LOS. ED LOS trended towards being longer in the PIM group.

Interprofessional student-led outreach to high-risk older adults during the COVID-19 pandemic.

In response to a statewide stay-at-home order during the COVID-19 pandemic, the Seniors Clinic launched an interprofessional student-led, telephone-based outreach initiative targeting older adults deemed high risk for social isolation. The initiative primarily aimed to enhance students' geriatric and interprofessional education during a time when clinical learning opportunities were limited, as well as supporting geriatric patients and providers through outreach during the COVID-19 quarantine period. Nurse practitioner, medical, and pharmacy students participated in virtual patient contact, geriatric case-based learning, and team-based interprofessional development. We conducted pre-and post-outreach assessments with students and geriatric providers to determine the effects of this initiative. After participating in the 3-month outreach initiative, interprofessional students reported increased confidence in conducting outreach calls, participating in interdisciplinary team discussions, and reviewing geriatric cases. This student-led telephone-based outreach to older adults improved students' exposure to and confidence with interprofessional teamwork and geriatric medicine. Our experience can inform future interprofessional initiatives to improve outreach to populations affected by public health emergencies.

Presentation, Treatment and Long-Term Outcomes of a Multidisciplinary Acute Atrial Fibrillation Pathway: A 12-Month Follow-Up Study.

AIM: Atrial fibrillation/flutter (AF/AFL) is associated with high rates of emergency department (ED) visits and acute hospitalisation. A recently established multidisciplinary acute AF treatment pathway seeks to avoid hospital admissions by early discharge of haemodynamically stable, low risk patients from the ED with next-working-day return to a ward-based AF clinic for further assessment. We conducted a preliminary analysis of the clinical outcomes of this pathway. METHODS: We retrospectively reviewed clinical records of all patients assessed at the AF clinic at Christchurch Hospital, New Zealand, over a 12-month period. Data related to presentation, patient characteristics, treatment, and 12-month outcomes were analysed. RESULTS: A total of 143 patients (median age 65, interquartile range: 57-74 years, 59% male, 87% European) were assessed. Of these, 87 (60.8%) presented with their first episode of AF/AFL. Spontaneous cardioversion occurred in 41% at ED discharge, and this increased to 73% at AF clinic review. Electrical cardioversion was subsequently performed in 16 patients (11.2%), and 16 (11.2%) ultimately required hospital admission (eight to facilitate electrical cardioversion). At a median of 1 day, 83.9% were discharged from the AF clinic in sinus rhythm. During 12-month follow-up, there were 25 AF-related hospitalisations (20 patients, 14%) and one patient underwent electrical cardioversion; additionally, one patient had had a stroke and eight had bleeding complications giving a combined outcome rate of 6.3%. CONCLUSION: Utilising a rate-control strategy with ED discharge and early return to a dedicated AF clinic can safely prevent the majority of hospitalisations, avert unnecessary procedures, and facilitate longitudinal care.

Sensitivity of modern multislice CT for subarachnoid haemorrhage at incremental timepoints after headache onset: a 10-year analysis.

BACKGROUND: CT performed within 6 hours of headache onset is highly sensitive for the detection of subarachnoid haemorrhage (SAH). Beyond this time frame, if the CT is negative for blood, a lumbar puncture is often performed. Technology improvements in image noise reduction, resolution and motion artefact have enhanced the performance of multislice CT (MSCT) and may have further improved sensitivity. We aimed to describe how the sensitivity to SAH of modern MSCT changes with time from headache onset. METHODS: This was a retrospective analysis of electronic data collected as part of routine care among all patients presenting to Christchurch Hospital diagnosed with a SAH between 1 January 2008 and 31 December 2017. Patients were imaged with MSCT. The primary outcome was the proportion of patients with spontaneous aneurysmal SAH (identified via coding and confirmed by clinical and radiological records) that had a positive MSCT. The secondary outcome was the proportion of patients with any type of spontaneous SAH that had a positive MSCT. RESULTS: There were 347 patients with an SAH of whom 260 were aneurysmal SAH. MSCT identified 253 (97.3%) of all aneurysmal SAH and 332 (95.7%) of all SAH. The sensitivity of MSCT was 99.6% (95% CI 97.6 to 100) for aneurysmal SAH and 99.0% (95% CI 97.1 to 99.8) for all SAH at 48 hours after headache onset. At 24 hours after headache onset, the sensitivity for aneurysmal SAH was 100% (95% CI 98.3 to 100). CONCLUSION: These data suggest that it may be possible to extend the timeframe from headache onset within which modern MSCT can be used to rule out aneurysmal SAH.

Implementation of Pharmacist Reviews to Screen for Potentially Inappropriate Medications in Patients With Cognitive Impairment.

Objective: To describe two pharmacist-led initiatives aimed to reduce potentially inappropriate medication (PIM) use in community-dwelling patients with dementia or cognitive impairment. Design: Retrospective, descriptive analysis of two clinical initiatives. Setting: Academic geriatric primary care clinics. Participants: Patients were included if they received a Memory Clinic pharmacist review May 1, 2017, to December 31, 2019, or a Living with Dementia (LWD) program pharmacist review November 15, 2018 to December 31, 2019 with provider follow-up within 6 months. Interventions: Both initiatives involved medication review by a clinical pharmacist to identify and make recommendations regarding medications that may contribute to cognitive impairment. The Memory Clinic served patients with concerns of cognitive impairment; whereas, the LWD program enrolled patients with an established diagnosis of dementia. Main Outcome Measure: Number of PIMs that could negatively impact cognition within each cohort. Additionally, 6-month implementation rates were analyzed for actionable pharmacist recommendations. RESULTS: Memory Clinic patients (n = 110) were taking an average of 2.4 PIMs; whereas, LWD patients (n = 40) were taking an average of 1.5 PIMs. Six-month implementation rates for all actionable pharmacist recommendations were 61.0% for the Memory Clinic and 42.4% for the LWD program. Specifically evaluating deprescribing recommendations, the 6-month PIM discontinuation rate was 63.6% for the Memory Clinic group and 60.0% for the LWD group. Conclusion: Pharmacists routinely identified PIMs during medication reviews, which led to successful recommendation implementation throughout multiple stages of cognitive decline. Both programs will continue to be adapted to ensure maximal impact.

A case of venlafaxine-induced angioedema in an older adult.

Angioedema is a serious adverse event that can manifest as lower extremity edema, face swelling, rash, hives, and a swollen tongue, which can sometimes lead to airway constriction and death. It is a well-documented reaction within the angiotensin-converting enzyme inhibitor drug class, where the bradykinin pathway leads to angioedema. We report a case where a patient experienced angioedema after taking venlafaxine. We evaluated other antidepressants as potential treatment options for the patient. We further examined potential cross-reactivity between antidepressants in order to find alternative medications for patients that experience serious adverse effects.

The REDCap Mobile Application: a data collection platform for research in regions or situations with internet scarcity.

OBJECTIVES: To share our approach for designing, developing, and deploying the Research Electronic Data Capture (REDCap) Mobile Application, details about its dissemination and support through the REDCap Consortium, and a set of lessons learned and guidance recommendations for others developing mobile platforms to support research in regions or situations with internet scarcity. MATERIALS AND METHODS: We defined minimum viable product requirements centered around Android and iOS platform availability, data capture specifications and project initiation workflow, study data synchronization, and data security. After launch, we added features based on feedback from end-users and REDCap administrators. We prioritized new features based on expected impact, difficulty, and anticipated long-term cost for sustainability. RESULTS: We chose Apache Cordova, a combined iOS and Android development framework, based on targeted end-user technology expectations, available programmer resources, and the need to provide solutions for resource-limited settings. The REDCap Mobile Application was launched in 2015, has been enabled at over 800 REDCap Consortium partner organizations, and has supported diverse scientific studies around the world. DISCUSSION: Apache Cordova enabled early software releases for both iOS and Android, but required ongoing optimization efforts to improve software responsiveness. Developing a robust and efficient mobile device synchronization architecture was difficult without direct access to global network infrastructures for testing. Research teams in sub-Saharan Africa helped our development team understand and simulate real-world scenarios of intermittent internet connectivity. CONCLUSION: Guidance recommendations based on designing, developing, deploying, and disseminating the REDCap Mobile Application may help other teams looking to develop clinical research informatics applications.

Continent-wide tree fecundity driven by indirect climate effects.

Indirect climate effects on tree fecundity that come through variation in size and growth (climate-condition interactions) are not currently part of models used to predict future forests. Trends in species abundances predicted from meta-analyses and species distribution models will be misleading if they depend on the conditions of individuals. Here we find from a synthesis of tree species in North America that climate-condition interactions dominate responses through two pathways, i) effects of growth that depend on climate, and ii) effects of climate that depend on tree size. Because tree fecundity first increases and then declines with size, climate change that stimulates growth promotes a shift of small trees to more fecund sizes, but the opposite can be true for large sizes. Change the depresses growth also affects fecundity. We find a biogeographic divide, with these interactions reducing fecundity in the West and increasing it in the East. Continental-scale responses of these forests are thus driven largely by indirect effects, recommending management for climate change that considers multiple demographic rates.

Autophagy regulates functional differentiation of mammary epithelial cells.

Mitochondria operate as a central hub for many metabolic processes by sensing and responding to the cellular environment. Developmental cues from the environment have been implicated in selective autophagy, or mitophagy, of mitochondria during cell differentiation and tissue development. Mitophagy occurring in this context, termed programmed mitophagy, responds to cell state rather than mitochondrial damage and is often accompanied by a metabolic transition. However, little is known about the mechanisms that engage and execute mitophagy under physiological or developmental conditions. As the mammary gland undergoes post-natal development and lactation challenges mitochondrial homeostasis, we investigated the contribution of mitochondria to differentiation of mammary epithelial cells (MECs). Using lactogenic differentiation of the HC11 mouse MEC line, we demonstrated that HC11 cells transition to a highly energetic state during differentiation by engaging both oxidative phosphorylation and glycolysis. Interestingly, this transition was lost when autophagy was inhibited with bafilomycin A1 or knockdown of Atg7 (autophagy related 7). To evaluate the specific targeting of mitochondria, we traced mitochondrial oxidation and turnover in vitro with the fluorescent probe, pMitoTimer. Indeed, we found that differentiation engaged mitophagy. To further evaluate the requirement of mitophagy during differentiation, we knocked down the expression of Prkn/parkin in HC11 cells. We found that MEC differentiation was impaired in shPrkn cells, implying that PRKN is required for MEC differentiation. These studies suggest a novel regulation of MEC differentiation through programmed mitophagy and provide a foundation for future studies of development and disease associated with mitochondrial function in the mammary gland.Abbreviations: AA: antimycin A; ATG5: autophagy related 5; BAF: bafilomycin A1; BNIP3: BCL2 interacting protein 3; BNIP3L/NIX: BCL2 interacting protein 3 like; COX8A: cytochrome c oxidase subunit 8A; CQ: chloroquine; CSN2: casein beta; ECAR: extracellular acidification rate; FCCP: trifluoromethoxy carbonylcyanide phenylhydrazone; FUNDC1: FUN14 domain containing 1; HIF1A: hypoxia inducible factor 1 subunit alpha; L1: lactation day 1; MAP1LC3B: microtubule associated protein 1 light chain 3 beta; MEC: mammary epithelial cell; mitoQ: mitoquinol; mROS: mitochondrial reactive oxygen species; OCR: oxygen consumption rate; P: priming; P16: pregnancy day 16; PARP1: poly(ADP-ribose) polymerase 1; PINK1: PTEN induced kinase 1; PPARGC1A: PPARG coactivator 1 alpha; PRKN: parkin RBR E3 ubiquitin protein ligase; shNT: short hairpin non-targeting control; SQSTM1: sequestosome 1; STAT3: signal transducer and activator of transcription 3; TEM: transmission electron microscopy; TFAM: transcription factor A, mitochondrial; U: undifferentiated.

Cognitive effects of vortioxetine in older adults: a systematic review.

Many older adults experience a deterioration in cognitive function with aging, and this can have a negative impact on quality of life. Late-life depression has been linked to mild cognitive impairment and dementia, and treating depression with an agent that has procognitive effects could be beneficial. Vortioxetine is a novel antidepressant with a multimodal mechanism of action that works primarily via serotonin transporter inhibition, 5-HT1A receptor agonism and 5-HT3 receptor antagonism. A recent systematic review demonstrated procognitive effects of vortioxetine when indirectly compared with selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors in adults aged 18-65 years with major depressive disorder. While this systematic review demonstrated promising procognitive effects from vortioxetine, the included studies did not enroll older adults, who are at the highest risk of cognitive impairment. Therefore, our systematic review sought to investigate the effects of vortioxetine on cognitive functioning in patients over the age of 65 years. Three studies met the prespecified search criteria and were evaluated. Overall, these preliminary data suggest that vortioxetine has promising effects in improving cognition in older adults with depressive symptoms and may have a place in therapy in older adults with depression and/or cognitive impairment, including Alzheimer's disease. Additional long-term studies that include more diverse populations with comorbidities and direct comparisons with other antidepressants are needed to fully understand the potential cognitive benefits in older adults.

Geolocator tagging links distributions in the non-breeding season to population genetic structure in a sentinel North Pacific seabird.

We tested the hypothesis that segregation in wintering areas is associated with population differentiation in a sentinel North Pacific seabird, the rhinoceros auklet (Cerorhinca monocerata). We collected tissue samples for genetic analyses on five breeding colonies in the western Pacific Ocean (Japan) and on 13 colonies in the eastern Pacific Ocean (California to Alaska), and deployed light-level geolocator tags on 12 eastern Pacific colonies to delineate wintering areas. Geolocator tags were deployed previously on one colony in Japan. There was strong genetic differentiation between populations in the eastern vs. western Pacific Ocean, likely due to two factors. First, glaciation over the North Pacific in the late Pleistocene might have forced a southward range shift that historically isolated the eastern and western populations. And second, deep-ocean habitat along the northern continental shelf appears to act as a barrier to movement; abundant on both sides of the North Pacific, the rhinoceros auklet is virtually absent as a breeder in the Aleutian Islands and Bering Sea, and no tagged birds crossed the North Pacific in the non-breeding season. While genetic differentiation was strongest between the eastern vs. western Pacific, there was also extensive differentiation within both regional groups. In pairwise comparisons among the eastern Pacific colonies, the standardized measure of genetic differentiation (FꞌST) was negatively correlated with the extent of spatial overlap in wintering areas. That result supports the hypothesis that segregation in the non-breeding season is linked to genetic structure. Philopatry and a neritic foraging habit probably also contribute to the structuring. Widely distributed, vulnerable to anthropogenic stressors, and exhibiting extensive genetic structure, the rhinoceros auklet is fully indicative of the scope of the conservation challenges posed by seabirds.

Pharmacist-Led Transition of Care Pilot Targeting Older People After Emergency Department Discharge.

OBJECTIVE: To evaluate the impact of a pharmacist-led transitional care intervention targeting high-risk older people after an emergency department (ED) visit.
DESIGN: Retrospective cohort study of older people with ED visits prior to and during a pharmacist-led intervention.
SETTING: Patients receiving primary care from the University of Colorado Health Seniors Clinic.
PARTICIPANTS: The intervention cohort comprised 170 patients with an ED visit between August 18, 2018, and February 19, 2019, and the historical cohort included 166 patients with an ED visit between August 18, 2017, and February 19, 2018. All included patients either had a historical diagnosis of heart failure or chronic obstructive pulmonary disease, or they had an additional ED visit in the previous six months.
INTERVENTIONS: The pilot intervention involved postED discharge telephonic outreach and assessment by a clinical pharmacist, with triaging to other staff if necessary.
MAIN OUTCOME MEASURE: The primary outcome was the proportion of patients with at least one repeat ED visit, hospitalization, or death within 30 days of ED discharge. Outcome rates were also assessed at 90 days postdischarge.
RESULTS: The primary outcome occurred in 21% of the historical cohort and 25% of the intervention cohort (adjusted P-value = 0.48). The incidence of the composite outcome within 90 days of ED discharge was 43% in the historical group compared with 38% in the intervention group (adjusted P-value = 0.29).
CONCLUSION: A pharmacist-led telephonic intervention pilot targeting older people did not appear to have a significant effect on the composite of repeat ED visit, hospitalization, or death within 30 or 90 days of ED discharge. A limited sample size may hinder the ability to make definitive conclusions based on these findings.