Distinct p53 transcriptional programs dictate acute DNA-damage responses and tumor suppression.

The molecular basis for p53-mediated tumor suppression remains unclear. Here, to elucidate mechanisms of p53 tumor suppression, we use knockin mice expressing an allelic series of p53 transcriptional activation mutants. Microarray analysis reveals that one mutant, p53(25,26), is severely compromised for transactivation of most p53 target genes, and, moreover, p53(25,26) cannot induce G(1)-arrest or apoptosis in response to acute DNA damage. Surprisingly, p53(25,26) retains robust activity in senescence and tumor suppression, indicating that efficient transactivation of the majority of known p53 targets is dispensable for these pathways. In contrast, the transactivation-dead p53(25,26,53,54) mutant cannot induce senescence or inhibit tumorigenesis, like p53 nullizygosity. Thus, p53 transactivation is essential for tumor suppression but, intriguingly, in association with a small set of novel p53 target genes. Together, our studies distinguish the p53 transcriptional programs involved in acute DNA-damage responses and tumor suppression-a critical goal for designing therapeutics that block p53-dependent side effects of chemotherapy without compromising p53 tumor suppression.

Examining aid fragmentation and collaboration opportunities in Cambodia's health sector.

BACKGROUND: Cambodia's health sector faces significant challenges exacerbated by aid fragmentation, where development aid is dispersed among numerous small, uncoordinated projects. This study examines the distribution of health sector aid among Cambodia's principal donors to identify priorities, overlaps, and potential collaboration opportunities, addressing the urgent need for aid efficiency and alignment with national health priorities. METHODS: Utilizing OECD datasets and the Herfindahl-Hirschman Index (HHI) for the years 2010-2021, this study quantifies aid fragmentation within Cambodia's health sector. It analyzes aid allocations from the top five donors-United States, Australia, South Korea, Japan, and Germany-across various health projects and initiatives, evaluating the extent of fragmentation and identifying areas for potential donor collaboration. RESULTS: This study's findings highlight a pervasive issue of aid fragmentation within Cambodia's health sector, evident through the sector's low HHI score. This indicates a widespread distribution of aid across numerous small-scale initiatives, rather than targeted, unified efforts. A notable example includes Japan and Korea, which exhibit lower HHI scores, indicating a more pronounced fragmentation in their aid allocation. These countries' contributions are spread across various sectors without a dominant focus, contrasting with the United States' significant dedication to infectious disease control. However, beyond this specific area, the US's aid distribution across other priority health areas shows signs of fragmentation. This scattered approach to aid allocation, even amidst instances of focused support, illustrates the overarching challenge of aligning donor contributions with the holistic needs of Cambodia's health infrastructure. CONCLUSIONS: This investigation highlights the critical need for enhanced collaboration and strategic harmonization among international donors to mitigate aid fragmentation in Cambodia's health sector. It underscores the importance of adopting integrated and priority-aligned aid strategies to improve the efficiency and impact of health aid. By fostering synergistic partnerships and harmonizing donor efforts, there is a potential to create a more cohesive support framework that resonates with Cambodia's comprehensive health requirements and contributes to sustainable health outcomes. Such harmonization not only aligns with Sustainable Development Goal 3 by optimizing health services and outcomes but also strengthens global partnerships under Sustainable Development Goal 17, fostering a unified approach to international development.

Seasonal COVID-19 surge related hospital volumes and case fatality rates.

BACKGROUND: Seasonal and regional surges in COVID-19 have imposed substantial strain on healthcare systems. Whereas sharp inclines in hospital volume were accompanied by overt increases in case fatality rates during the very early phases of the pandemic, the relative impact during later phases of the pandemic are less clear. We sought to characterize how the 2020 winter surge in COVID-19 volumes impacted case fatality in an adequately-resourced health system. METHODS: We performed a retrospective cohort study of all adult diagnosed with COVID-19 in a large academic healthcare system between August 25, 2020 to May 8, 2021, using multivariable logistic regression to examine case fatality rates across 3 sequential time periods around the 2020 winter surge: pre-surge, surge, and post-surge. Subgroup analyses of patients admitted to the hospital and those receiving ICU-level care were also performed. Additionally, we used multivariable logistic regression to examine risk factors for mortality during the surge period. RESULTS: We studied 7388 patients (aged 52.8 ± 19.6 years, 48% male) who received outpatient or inpatient care for COVID-19 during the study period. Patients treated during surge (N = 6372) compared to the pre-surge (N = 536) period had 2.64 greater odds (95% CI 1.46-5.27) of mortality after adjusting for sociodemographic and clinical factors. Adjusted mortality risk returned to pre-surge levels during the post-surge period. Notably, first-encounter patient-level measures of illness severity appeared higher during surge compared to non-surge periods. CONCLUSIONS: We observed excess mortality risk during a recent winter COVID-19 surge that was not explained by conventional risk factors or easily measurable variables, although recovered rapidly in the setting of targeted facility resources. These findings point to how complex interrelations of population- and patient-level pandemic factors can profoundly augment health system strain and drive dynamic, if short-lived, changes in outcomes.

Identification of Functional Limitations and Discharge Destination in Patients With COVID-19.

OBJECTIVES: The objectives of this study were to identify functional limitations in patients with coronavirus 2019 (COVID-19) admitted to acute care hospitals; to evaluate functional limitations by demographic, medical, and encounter characteristics; and to examine functional limitations in relation to discharge destination. DESIGN: and Setting:This is a cross-sectional, retrospective study of adult patients with COVID-19 who were discharged from 2 different types of hospitals (academic medical center and a community hospital) within 1 health care system from January 1 to April 30, 2020. PARTICIPANTS: Patients were identified from the Cedars-Sinai COVID-19 data registry who had a new-onset positive test for severe acute respiratory syndrome coronavirus 2. A total of 273 patients were identified, which included 230 patients who were discharged alive and 43 patients who died and were excluded from the study sample. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Functional limitations in patients with COVID-19 in acute care hospitals and the predictors for discharge disposition. RESULTS: A total of 230 records were analyzed including demographic, encounter, medical, and functional variables. In a propensity score-matched cohort based on age and comorbidity, 88.2% had functional physical health deficits, 72.5% had functional mental health deficits, and 17.6% experienced sensory deficits. In the matched cohort, individuals discharged to an institution experienced greater physical (62.7% vs 25.5%, P<.001) and mental health (49.0% vs 23.5%, P=.006) deficits than patients discharged home. Marital status (odds ratio, 3.17; P=.011) and physical function deficits (odds ratio, 3.63; P=.025) were associated with an increase odds ratio of discharge to an institution. CONCLUSIONS: This research highlights that functional status is a strong predictor for discharge destination to an institution for patients with COVID-19. Patients who were older, in the acute care hospital longer, and with comorbidities were more likely to be discharged to an institution. Rehabilitation is a significant aspect of the health care system for these vulnerable patients. The challenges of adjusting the role of rehabilitation providers and systems during the pandemic needs further exploration. Moreover, additional research is needed to look more closely at the many facets and timing of functional status needs, to shed light in use of interdisciplinary rehabilitation services, and to guide providers and health care systems in facilitating optimal recovery and patient outcomes.

Ca2+/calmodulin-dependent regulation of polycystic kidney disease 2-like-1 by binding at C-terminal domain.

Polycystic kidney disease 2-like-1 (PKD2L1), also known as polycystin-L or TRPP3, is a non-selective cation channel that regulates intracellular calcium concentration. Calmodulin (CaM) is a calcium binding protein, consisting of N-lobe and C-lobe with two calcium binding EF-hands in each lobe. In previous study, we confirmed that CaM is associated with desensitization of PKD2L1 and that CaM N-lobe and PKD2L1 EF-hand specifically are involved. However, the CaM-binding domain (CaMBD) and its inhibitory mechanism of PKD2L1 have not been identified. In order to identify CaM-binding anchor residue of PKD2L1, single mutants of putative CaMBD and EF-hand deletion mutants were generated. The current changes of the mutants were recorded with whole-cell patch clamp. The calmidazolium (CMZ), a calmodulin inhibitor, was used under different concentrations of intracellular. Among the mutants that showed similar or higher basal currents with that of the PKD2L1 wild type, L593A showed little change in current induced by CMZ. Co-expression of L593A with CaM attenuated the inhibitory effect of PKD2L1 by CaM. In the previous study it was inferred that CaM C-lobe inhibits channels by binding to PKD2L1 at 16 nM calcium concentration and CaM N-lobe at 100 nM. Based on the results at 16 nM calcium concentration condition, this study suggests that CaM C-lobe binds to Leu-593, which can be a CaM C-lobe anchor residue, to regulate channel activity. Taken together, our results provide a model for the regulation of PKD2L1 channel activity by CaM.

The role of calmodulin in regulating calcium-permeable PKD2L1 channel activity.

Polycystic kidney disease 2-like-1 (PKD2L1), polycystin-L or transient receptor potential polycystin 3 (TRPP3) is a TRP superfamily member. It is a calcium-permeable non-selective cation channel that regulates intracellular calcium concentration and thereby calcium signaling. Although the calmodulin (CaM) inhibitor, calmidazolium, is an activator of the PKD2L1 channel, the activating mechanism remains unclear. The purpose of this study is to clarify whether CaM takes part in the regulation of the PKD2L1 channel, and if so, how. With patch clamp techniques, we observed the current amplitudes of PKD2L1 significantly reduced when coexpressed with CaM and CaMΔN. This result suggests that the N-lobe of CaM carries a more crucial role in regulating PKD2L1 and guides us into our next question on the different functions of two lobes of CaM. We also identified the predicted CaM binding site, and generated deletion and truncation mutants. The mutants showed significant reduction in currents losing PKD2L1 current-voltage curve, suggesting that the C-terminal region from 590 to 600 is crucial for maintaining the functionality of the PKD2L1 channel. With PKD2L1608Stop mutant showing increased current amplitudes, we further examined the functional importance of EF-hand domain. Along with co-expression of CaM, ΔEF-hand mutant also showed significant changes in current amplitudes and potentiation time. Our findings suggest that there is a constitutive inhibition of EF-hand and binding of CaM C-lobe on the channel in low calcium concentration. At higher calcium concentration, calcium ions occupy the N-lobe as well as the EF-hand domain, allowing the two to compete to bind to the channel.

Englerin A-sensing charged residues for transient receptor potential canonical 5 channel activation.

The transient receptor potential canonical (TRPC) 5 channel, known as a nonselective cation channel, has a crucial role in calcium influx. TRPC5 has been reported to be activated by muscarinic receptor activation and extracellular pH change and inhibited by the protein kinase C pathway. Recent studies have also suggested that TRPC5 is extracellularly activated by englerin A (EA), but the mechanism remains unclear. The purpose of this study is to identify the EA-interaction sites in TRPC5 and thereby clarify the mechanism of TRPC5 activation. TRPC5 channels are over-expressed in human embryonic kidney (HEK293) cells. TRPC5 mutants were generated by site-directed mutagenesis. The whole-cell patch-clamp configuration was used to record TRPC5 currents. Western analysis was also performed to observe the expression of TRPC5 mutants. To identify the EA-interaction site in TRPC5, we first generated pore mutants. When screening the mutants with EA, we observed the EA-induced current increases of TRPC5 abolished in K554N, H594N, and E598Q mutants. The current increases of other mutants were reduced in different levels. We also examined the functional intactness of the mutants that had no effect by EA with TRPC5 agonists, such as carbachol or GTPγS. Our results suggest that the three residues, Lys-554, His-594, and Glu-598, in TRPC5 might be responsible for direct interaction with EA, inducing the channel activation. We also suggest that although other pore residues are not critical, they could partly contribute to the EA-induced channel activation.

Identification of clustered phosphorylation sites in PKD2L1: how PKD2L1 channel activation is regulated by cyclic adenosine monophosphate signaling pathway.

Polycystic kidney disease 2-like-1 (PKD2L1), or polycystin-L or TRPP2, formerly TRPP3, is a transient receptor potential (TRP) superfamily member. It is a calcium-permeable non-selective cation channel that regulates intracellular calcium concentration and thereby calcium signaling. PKD2L1 has been reported to take part in hedgehog signaling in renal primary cilia and sour tasting coupling with PKD1L3. In addition to the previous reports, PKD2L1 is recently found to play a crucial role in localization with ß2-adrenergic receptor (ß2AR) on the neuronal primary cilia. The disruption of PKD2L1 leads to the loss of ß2AR on the primary cilia and reduction in intracellular concentration of cyclic adenosine monophosphate (cAMP). Since the role of cAMP and PKA is frequently mentioned in the studies of PKD diseases, we investigated on the mechanism of cAMP regulation in relation to the function of PKD2L1 channel. In this study, we observed the activity of PKD2L1 channel increased by the downstream cascades of ß2AR and found the clustered phosphorylation sites, Ser-682, Ser-685, and Ser-686 that are significant in the channel regulation by phosphorylation.

Full p53 transcriptional activation potential is dispensable for tumor suppression in diverse lineages.

Over half of all human cancers, of a wide variety of types, sustain mutations in the p53 tumor suppressor gene. Although p53 limits tumorigenesis through the induction of apoptosis or cell cycle arrest, its molecular mechanism of action in tumor suppression has been elusive. The best-characterized p53 activity in vitro is as a transcriptional activator, but the identification of numerous additional p53 biochemical activities in vitro has made it unclear which mechanism accounts for tumor suppression. Here, we assess the importance of transcriptional activation for p53 tumor suppression function in vivo in several tissues, using a knock-in mouse strain expressing a p53 mutant compromised for transcriptional activation, p53(25,26). p53(25,26) is severely impaired for the transactivation of numerous classical p53 target genes, including p21, Noxa, and Puma, but it retains the ability to activate a small subset of p53 target genes, including Bax. Surprisingly, p53(25,26) can nonetheless suppress tumor growth in cancers derived from the epithelial, mesenchymal, central nervous system, and lymphoid lineages. Therefore, full transactivation of most p53 target genes is dispensable for p53 tumor suppressor function in a range of tissue types. In contrast, a transcriptional activation mutant that is completely defective for transactivation, p53(25,26,53,54), fails to suppress tumor development. These findings demonstrate that transcriptional activation is indeed broadly critical for p53 tumor suppressor function, although this requirement reflects the limited transcriptional activity observed with p53(25,26) rather than robust transactivation of a full complement of p53 target genes.

Escalation of genome defense capacity enables control of an expanding meiotic driver.

From RNA interference to chromatin silencing, diverse genome defense pathways silence selfish genetic elements to safeguard genome integrity1,2. Despite their diversity, different defense pathways share a modular organization, where numerous specificity factors identify diverse targets and common effectors silence them. In the PIWI-interacting RNA (piRNA) pathway, which controls selfish elements in the metazoan germline, diverse target RNAs are first identified by complementary base pairing with piRNAs and then silenced by PIWI-clade nucleases via enzymatic cleavage1,3. Such a binary architecture allows the defense systems to be readily adaptable, where new targets can be captured via the innovation of new specificity factors4,5. Thus, our current understanding of genome defense against lineage-specific selfish genes has been largely limited to the evolution of specificity factors, while it remains poorly understood whether other types of innovations are required. Here, we describe a new type of innovation, which escalates the defense capacity of the piRNA pathway to control a recently expanded selfish gene in Drosophila melanogaster. Through an in vivo RNAi screen for repressors of Stellate-a recently evolved and expanded selfish meiotic driver6-8-we discovered a novel defense factor, Trailblazer. Trailblazer is a transcription factor that promotes the expression of two PIWI-clade nucleases, Aub and AGO3, to match Stellate in abundance. Recent innovation in the DNA-binding domain of Trailblazer enabled it to drastically elevate Aub and AGO3 expression in the D. melanogaster lineage, thereby escalating the silencing capacity of the piRNA pathway to control expanded Stellate and safeguard fertility. As copy-number expansion is a recurrent feature of diverse selfish genes across the tree of life9-12, we envision that augmenting the defense capacity to quantitatively match selfish genes is likely a repeatedly employed defense strategy in evolution.

Self-reported hearing loss and health during a pandemic: Findings from a cross-sectional analysis using a 2021 household survey.

BACKGROUND: The COVID-19 pandemic differentially impacted individuals with hearing loss, likely in part due to increased communication difficulties from masking, a commonly implemented protective measure. OBJECTIVE: This study examines the association between self-reported hearing loss and health during the pandemic. METHODS: This study uses data from the COVID-19 Survey collected by the Survey of the Health of Wisconsin from February to March 2021. Hearing loss was defined as self-reported fair or poor hearing. The outcomes were self-reported symptoms of anxiety and depression, separately, and self-reported general health. Multivariable models adjusted for age, gender, and race/ethnicity were used to examine the associations between hearing loss with each outcome. Results are presented as prevalence ratios (PR) with corresponding 95 % confidence intervals (CI). RESULTS: There were 1857 participants (60.3 % female, 12.9 % non-white) with a mean age of 57.1 years in this cross-sectional study. In multivariable models, individuals with hearing loss (versus none) had higher prevalence of depression (PR: 1.22, 95 % CI: 1.06, 1.39), anxiety (PR: 1.13, 95 % CI: 1.02, 1.27), and self-reported fair or poor health (PR: 2.61, 95 % CI: 1.89, 3.61). CONCLUSION: Hearing loss was associated with poorer self-reported health during winter 2021 of the COVID-19 pandemic, when mask use in public was newly mandated and vaccines were not widely available to the general public. Further research on the impact of public health policies on vulnerable populations, including those with hearing loss, is warranted. Such research could inform policy decisions that accommodate these populations.

Mechanistic insights into a heterobifunctional degrader-induced PTPN2/N1 complex.

PTPN2 (protein tyrosine phosphatase non-receptor type 2, or TC-PTP) and PTPN1 are attractive immuno-oncology targets, with the deletion of Ptpn1 and Ptpn2 improving response to immunotherapy in disease models. Targeted protein degradation has emerged as a promising approach to drug challenging targets including phosphatases. We developed potent PTPN2/N1 dual heterobifunctional degraders (Cmpd-1 and Cmpd-2) which facilitate efficient complex assembly with E3 ubiquitin ligase CRL4CRBN, and mediate potent PTPN2/N1 degradation in cells and mice. To provide mechanistic insights into the cooperative complex formation introduced by degraders, we employed a combination of structural approaches. Our crystal structure reveals how PTPN2 is recognized by the tri-substituted thiophene moiety of the degrader. We further determined a high-resolution structure of DDB1-CRBN/Cmpd-1/PTPN2 using single-particle cryo-electron microscopy (cryo-EM). This structure reveals that the degrader induces proximity between CRBN and PTPN2, albeit the large conformational heterogeneity of this ternary complex. The molecular dynamic (MD)-simulations constructed based on the cryo-EM structure exhibited a large rigid body movement of PTPN2 and illustrated the dynamic interactions between PTPN2 and CRBN. Together, our study demonstrates the development of PTPN2/N1 heterobifunctional degraders with potential applications in cancer immunotherapy. Furthermore, the developed structural workflow could help to understand the dynamic nature of degrader-induced cooperative ternary complexes.

Early detection of recurrent disease by FDG-PET/CT leads to management changes in patients with squamous cell cancer of the head and neck.

OBJECTIVE: The objective of this study was to compare the efficacy of surveillance high-resolution computed tomography (HRCT) and physical examination/endoscopy (PE/E) with the efficacy of fluorodeoxyglucose (FDG)-positron emission tomography (PET)/HRCT for the detection of relapse in head and neck squamous cell carcinoma (HNSCC) after primary treatment. METHODS: This is a retrospective analysis of contemporaneously performed FDG-PET/HRCT, neck HRCT, and PE/E in 99 curatively treated patients with HNSCC during post-therapy surveillance to compare performance test characteristics in the detection of early recurrence or second primary cancer. RESULTS: Relapse occurred in 19 of 99 patients (20%) during a median follow-up of 21 months (range: 9-52 months). Median time to first PET/HRCT was 3.5 months. The median time to radiological recurrence was 6 months (range: 2.3-32 months). FDG-PET/HRCT detected more disease recurrences or second primary cancers and did so earlier than HRCT or PE/E. The sensitivity, specificity, and positive and negative predictive values for detecting locoregional and distant recurrence or second primary cancer were 100%, 87.3%, 56.5%, and 100%, respectively, for PET/HRCT versus 61.5%, 94.9%, 66.7%, and 93.8%, respectively, for HRCT versus 23.1%, 98.7%, 75%, and 88.6%, respectively, for PE/E. In 19 patients with true positive PET/HRCT findings, a significant change in the management of disease occurred, prompting either salvage or systemic therapy. Of the 14 curatively treated patients, 11 were alive with without disease at a median follow-up of 31.5 months. CONCLUSION: FDG-PET/HRCT has a high sensitivity in the early detection of relapse or second primary cancer in patients with HNSCC, with significant management implications. Given improvements in therapy and changes in HNSCC biology, appropriate modifications in current post-therapy surveillance may be required to determine effective salvage or definitive therapies.

Loss of the p53/p63 regulated desmosomal protein Perp promotes tumorigenesis.

Dysregulated cell-cell adhesion plays a critical role in epithelial cancer development. Studies of human and mouse cancers have indicated that loss of adhesion complexes known as adherens junctions contributes to tumor progression and metastasis. In contrast, little is known regarding the role of the related cell-cell adhesion junction, the desmosome, during cancer development. Studies analyzing expression of desmosome components during human cancer progression have yielded conflicting results, and therefore genetic studies using knockout mice to examine the functional consequence of desmosome inactivation for tumorigenesis are essential for elucidating the role of desmosomes in cancer development. Here, we investigate the consequences of desmosome loss for carcinogenesis by analyzing conditional knockout mice lacking Perp, a p53/p63 regulated gene that encodes an important component of desmosomes. Analysis of Perp-deficient mice in a UVB-induced squamous cell skin carcinoma model reveals that Perp ablation promotes both tumor initiation and progression. Tumor development is associated with inactivation of both of Perp's known functions, in apoptosis and cell-cell adhesion. Interestingly, Perp-deficient tumors exhibit widespread downregulation of desmosomal constituents while adherens junctions remain intact, suggesting that desmosome loss is a specific event important for tumorigenesis rather than a reflection of a general change in differentiation status. Similarly, human squamous cell carcinomas display loss of PERP expression with retention of adherens junctions components, indicating that this is a relevant stage of human cancer development. Using gene expression profiling, we show further that Perp loss induces a set of inflammation-related genes that could stimulate tumorigenesis. Together, these studies suggest that Perp-deficiency promotes cancer by enhancing cell survival, desmosome loss, and inflammation, and they highlight a fundamental role for Perp and desmosomes in tumor suppression. An understanding of the factors affecting cancer progression is important for ultimately improving the diagnosis, prognostication, and treatment of cancer.

Sense of community and mental health: a cross-sectional analysis from a household survey in Wisconsin.

BACKGROUND: In the USA, one in five adults live with a mental illness, and researchers have estimated that nearly half of the population will have a mental illness over the course of their lifetime. Research has shown significant associations between social relationships and mental health outcomes at the individual and population levels. This study aims to examine whether sense of community, a type of social capital, is associated with mental health. METHODS: In a cross-sectional analysis, multiple logistic regression models were used to examine whether sense of community was associated with symptoms of depression, anxiety and stress reported over the last week. The analysis used data from the Survey of the Health of Wisconsin collected between 2014 and 2016. A total of 1647 observations are included in the analyses. RESULTS: Compared with those who report a positive sense of community, those with a negative sense of community had a significantly higher odds of reporting depression, anxiety and stress symptoms. Socioeconomic status is negatively associated with depression and anxiety, but not with stress. Women were more likely to experience moderate, severe, or extremely severe anxiety and stress, compared with men. CONCLUSION: This study extends current understanding of health benefits of social capital and found that individuals' sense of community is associated with reduced symptoms of depression, anxiety and stress. Further research examining mechanisms to support improved sense of community and other types of social capital could benefit health equity research.

Religion, Spirituality, and Coping During the Pandemic: Perspectives of Dementia Caregivers.

Religious and spiritual (R/S) practices support individuals during difficult situations. The COVID-19 social distancing restrictions may have limited access to R/S practices for older adults with Alzheimer's disease related dementia (ADRD) and their caregivers, affecting coping and well-being. This qualitative study explored the impact of social distancing on R/S practices and coping in ADRD-caregiver dyads from the perspective of caregivers. Interviews were conducted with 11 family caregivers of older adults with ADRD residing in nursing homes (n = 4) or private homes (n = 7). Caregivers continued individual and started virtual R/S practices which improved their ability to cope. However, organized R/S practices were unavailable for those with ADRD, but they used prayer and read religious texts which noticeably improved their mood. Healthcare professionals' sharing of individual and community R/S resources available for ADRD-caregiver dyads could decrease anxiety and agitation, while improving their ability to cope with increased isolation.

Harnessing the Electronic Medical Record to Improve the Utilization of Ultrasound Screening for Abdominal Aortic Aneurysms.

PURPOSE: The US Preventive Services Task Force recommends one-time ultrasound screening to detect abdominal aortic aneurysms (AAAs) in male smokers. Despite this recommendation, AAA screening is still underutilized. The aim of this study was to determine the effectiveness of an electronic medical record (EMR) automated ordering program in increasing AAA screening at an integrated health care system. METHODS: This study was a retrospective chart review of patients who underwent ultrasound screening for AAA from January 1, 2016, to December 31, 2021, at a geographically isolated integrated health care system. An automated ordering system was implemented in a stepwise fashion within our EMR beginning in March 2019. The number of ultrasound studies and the incidence of AAA were compared between manual referral and EMR automated ordering periods. RESULTS: A total of 4,176 patients met the inclusion criteria for this study, among whom 148 aneurysms were identified. There was an increase in the average number of monthly screening ultrasound studies performed during the automated ordering period compared with the manual referral period (105 vs 16.3 studies, P < .001). The incidence of AAA was lower in the automated ordering period compared with the manual referral period (3.2% vs 5.3%, P = .013). CONCLUSIONS: An EMR automated ordering program can increase the number of screening ultrasound studies performed for AAA, which may help clinicians identify more high-risk aneurysms requiring urgent repair.

"Please Don't Forget Us": A Descriptive Qualitative Study of Caregivers of Older Adults With Alzheimer's Disease and Related Dementias During the COVID-19 Pandemic.

The current descriptive qualitative study explored the perceived impact of the coronavirus disease 2019 pandemic on sleep disturbances and nighttime agitation; the reported use of antipsychotics and other sedating medications; and the overall well-being of older adults with Alzheimer's disease and related dementias (ADRD) and their caregivers. One investigator conducted in-depth, phone interviews with caregivers of nursing home residents with ADRD (four family caregivers [FCs], three nurse practitioners [NPs]) and seven FCs of older adults with ADRD who lived with them at home. Caregivers described multiple sleep disturbances. Nighttime agitation symptoms were perceived to continue or worsen, and sedating medications and nonpharmacological interventions were required. Adverse impacts on reported well-being were significant, and impacts were grouped into emotional, social, and physical themes. Caregivers said, "Please don't forget us," and requested telehealth support for those at home and technology and human resources for nursing homes to reduce adverse impacts. [Research in Gerontological Nursing, 15(5), 217-228.].

Draft Genome Sequences of Three Antibiotic-Producing Soil Bacteria, Staphylococcus pasteuri WAM01, Peribacillus butanolivorans WAM04, and Micrococcus yunnanensis WAM06, with Growth-Inhibiting Effects against Commensal Neisseria Strains.

We report the isolation, identification, and assemblies of three antibiotic-producing soil bacteria (Staphylococcus pasteuri, Peribacillus butanolivorans, and Micrococcus yunnanensis) that inhibit the growth of Neisseria commensals in coculture. With pathogenic Neisseria strains becoming increasingly resistant to antibiotics, bioprospecting for novel antimicrobials using commensal relatives may facilitate discovery of clinically useful drugs.