Comparing Unmet Service Needs Between Rural and Urban Family Caregivers of People Living with Alzheimer's Disease and Related Dementias: A Multi-Site Study.

BACKGROUND AND OBJECTIVES: The scarcity of resources and available caregiving services in rural areas in the United States has been well-documented. However, less research has compared unmet service needs between caregivers of people with Alzheimer's disease and related dementias (ADRD) in rural versus urban areas. RESEARCH DESIGN AND METHODS: Using semi-structured interviews guided by theories of health service use and dependent care, we interviewed 20 family caregivers residing in rural areas of Western North Carolina and 18 caregivers within the urban setting of Houston, Texas, and compared their unmet service needs and contextual factors that facilitate their service use. RESULTS: Thematic analyses revealed similar unmet service needs among rural and urban caregivers; however, the ways they approached and solved their challenges differed. Caregivers in rural areas wished for more information and caregiver support whereas urban caregivers looked for information they needed until they found the answers. Rural caregivers expressed guilt about using services because they felt they were limited and zero-sum whereas urban caregivers shared available resources so that other caregivers could use them as well. Unmet service needs for urban caregivers included more racially and ethnically specific services for people with ADRD in their ethnic-specific languages and foods while rural caregivers' cultural needs were not racially and ethnically specific but for more place-specific services. DISCUSSION AND IMPLICATIONS: Recommendations for rural caregivers included utilizing online and virtual opportunities and expanding their reach across the United States. For urban caregivers, increasing culturally tailored service options would likely increase access and use.

A cross sectional pilot study utilising STrain Analysis and Mapping of the Plantar Surface (STAMPS) to measure plantar load characteristics within a healthy population.

BACKGROUND: No in-shoe systems, measuring both components of plantar load (plantar pressure and shear stress) are available for use in patients with diabetes. The STAMPS (STrain Analysis and Mapping of the Plantar Surface) system utilises digital image correlation (DIC) to determine the strain sustained by a deformable insole, providing a more complete understanding of plantar shear load at the foot-surface interface. RESEARCH QUESTIONS: What is the normal range and pattern of strain at the foot-surface interface within a healthy population as measured by the STAMPS system? Is STAMPS a valid tool to measure the effects of plantar load? METHODS: A cross-sectional study of healthy participants was undertaken. Healthy adults without foot pathology or diabetes were included. Participants walked 20 steps with the STAMPS insole in a standardised shoe. Participants also walked 10 m with the Novel Pedar® plantar pressure measurement insole within the standardised shoe. Both measurements were repeated three times. Outcomes of interest were global and regional values for peak resultant strain (SMAG) and peak plantar pressure (PPP). RESULTS: In 18 participants, median peak SMAG and PPP were 35.01 % and 410.6kPa respectively. The regions of the hallux and heel sustained the highest SMAG (29.31 % (IQR 24.56-31.39) and 20.50 % (IQR 15.59-24.12) respectively) and PPP (344.8kPa (IQR 268.3 - 452.5) and 279.3kPa (IQR 231.3-302.1) respectively). SMAG was moderately correlated with PPP (r= 0.65, p < 0.001). Peak SMAG was located at the hallux in 55.6 % of participants, at the 1st metatarsal head (MTH) in 16.7 %, the heel in 16.7 %, toes 3-5 in 11.1 % and the MTH2 in 5.6 %. SIGNIFICANCE: The results demonstrate the STAMPS system is a valid tool to measure plantar strain. Further studies are required to investigate the effects of elevated strain and the relationship with diabetic foot ulcer formation.

Native mass spectrometry of membrane protein-lipid interactions in different detergent environments.

Native mass spectrometry (MS) is revealing the role of specific lipids in modulating membrane protein structure and function. Membrane proteins solubilized in detergents are often introduced into the mass spectrometer; however, commonly used detergents for structural studies, such as dodecylmaltoside, tend to generate highly charged ions, leading to protein unfolding, thereby diminishing their utility for characterizing protein-lipid interactions. Thus, there is a critical need to develop approaches to investigate protein-lipid interactions in different detergents. Here, we demonstrate how charge-reducing molecules, such as spermine and trimethylamine-N-oxide, enable characterization of lipid binding to the bacterial water channel (AqpZ) and ammonia channel (AmtB) in complex with regulatory protein GlnK in different detergent environments. We find protein-lipid interactions are not only protein-dependent but can also be influenced by the detergent and type of charge-reducing molecule. AqpZ-lipid interactions are enhanced in LDAO (n-dodecyl-N,N-dimethylamine-N-oxide), whereas the interaction of AmtB-GlnK with lipids is comparable among different detergents. A fluorescent lipid binding assay also shows detergent dependence for AqpZ-lipid interactions, consistent with results from native MS. Taken together, native MS will play a pivotal role in establishing optimal experimental parameters that will be invaluable for various applications, such as drug discovery, as well as biochemical and structural investigations.

Clinical perspectives on sampling and processing approaches for the management of infection in diabetic foot ulceration: A qualitative study.

Diabetic foot ulcers (DFUs) often become infected and are treated with antimicrobials, with samples collected to inform care. Swab samples are easier than tissue sampling but report fewer organisms. Compared with culture and sensitivity (C&S) methods, molecular microbiology identifies more organisms. Clinician perspectives on sampling and processing are unknown. We explored clinician perspectives on DFU sampling-tissue samples/wound swabs-and on processing techniques, culture and sensitivity or molecular techniques. The latter provides information on organisms which have not survived transport to the laboratory for culture. We solicited feedback on molecular microbiology reports. Qualitative study using semi-structured interview, with analysis using a Framework approach. CODIFI2 clinicians from UK DFU clinics. Seven consultants agreed to take part. They reported, overall, a preference for tissue samples over swabbing. Clinicians were not confident replacing C&S with molecular microbiology as the approach to reporting was unfamiliar. The study was small and did not recruit any podiatrists or nurses, who may have discipline-specific attitudes or perspectives on DFU care. Both sampling approaches appear to be used by clinicians. Molecular microbiology reports would not be, at present, suitable for replacement of traditional culture and sensitivity.

Variation in Systemic Antibiotic Treatment for Diabetic Foot Osteomyelitis in England and Wales: A Multi-Centre Case Review.

Background: Diabetic foot osteomyelitis (DFO) is a major complication and can lead to significant morbidity and mortality. Systemic antibiotic therapy is often initiated first line to achieve quiescence of infection. To perform a multi-centre case review of systemic antibiotic intervention to treat adults with DFO in England and Wales and compare with national guidelines 'Diabetic foot problems: prevention and management'. Methods: Eight centres from England and Wales retrospectively collated data from a minimum of five adults (aged ≥ 18 years) from electronic case records. All patients were treated with systemic antibiotics following a new diagnosis of DFO (1 June 2021-31 December 2021). Results: 40 patients (35 males and 5 females) were included; the mean age was 62.3 years (standard deviation (SD) 13.0). Patients commenced systemic oral 14 (35%) or intravenous 26 (65%) antibiotic therapy following a new diagnosis of DFO. Twenty-seven (67.5%) patients were medically or surgically managed in the 12-week period with clinical quiescence of infection. Twenty-one patients (52.5%) had no recurrence of DFO infection within 12 weeks; seventeen (42.5%) of these patients had clinical quiescence of infection with systemic antibiotics alone without surgical intervention and nine (22.5%) of these cases had no recurrence of DFO. There were no cases of major amputation or death. All centres showed significant in-centre variability in systemic antibiotic management; variability was reported in the clinical and quantity indicators specifically to antibiotic selection, single versus dual therapy, mode of delivery and duration of treatment. Conclusions: This case review identifies there is existing variation when treating adults with systemic antibiotics for DFO. Further national guidance is required to standardise service delivery and care to improve patient outcomes.

Minimal clinically important differences in patient-reported outcomes after coronary artery bypass surgery in the arterial revascularization trial.

OBJECTIVES: This article identifies minimal clinically important differences (MCIDs) in quality of life (QoL) measures among patients who had coronary artery bypass grafting (CABG) and were enrolled in the arterial revascularization trial (ART). METHODS AND RESULTS: The European Quality of Life-5 Dimensions (EQ-5D) and the Short Form Health Survey 36-Item (SF-36) physical component (PC) and mental component (MC) scores were recorded at baseline, 5 years and 10 years in ART. The MCIDs were calculated as changes in QoL scores anchored to 1-class improvement in the New York Heart Association functional class and Canadian Cardiovascular Society scale at 5 years. Cox proportional hazard models were used to evaluate associations between MCIDs and mortality. Patient cohorts were examined for the SF-36 PC (N = 2671), SF-36 MC (N = 2815) and EQ-5D (N = 2943) measures, respectively. All QoL scores significantly improved after CABG compared to baseline. When anchored to the New York Heart Association, the MCID at 5 years was 17 (95% confidence interval: 17-20) for SF-36 PC, 14 (14-17) for the SF-36 MC and 0.12 (0.12-0.15) for EQ-5D. Using the Canadian Cardiovascular Society scale as an anchor, the MCID at 5 years was 15 (15-17) for the SF-36 PC, 12 (13-15) for the SF-36 MC and 0.12 (0.11-0.14) for the EQ-5D. The MCIDs for SF-36 PC and EQ-5D at 5 years were associated with a lower risk of mortality at the 10-year follow-up point after surgery. CONCLUSIONS: MCIDs for CABG patients have been identified. These thresholds may have direct clinical applications in monitoring patients during follow-up and in designing new trials that include QoL as a primary study outcome. CLINICAL TRIAL REGISTRATION NUMBER: ISRCTN46552265.

Host stress drives tolerance and persistence: The bane of anti-microbial therapeutics.

Antibiotic resistance, typically associated with genetic changes within a bacterial population, is a frequent contributor to antibiotic treatment failures. Antibiotic persistence and tolerance, which we collectively term recalcitrance, represent transient phenotypic changes in the bacterial population that prolong survival in the presence of typically lethal concentrations of antibiotics. Antibiotic recalcitrance is challenging to detect and investigate-traditionally studied under in vitro conditions, our understanding during infection and its contribution to antibiotic failure is limited. Recently, significant progress has been made in the study of antibiotic-recalcitrant populations in pathogenic species, including Mycobacterium tuberculosis, Staphylococcus aureus, Salmonella enterica, and Yersiniae, in the context of the host environment. Despite the diversity of these pathogens and infection models, shared signals and responses promote recalcitrance, and common features and vulnerabilities of persisters and tolerant bacteria have emerged. These will be discussed here, along with progress toward developing therapeutic interventions to better treat recalcitrant pathogens.

Genome-wide screen of Mycobacterium tuberculosis- infected macrophages identified the GID/CTLH complex as a determinant of intracellular bacterial growth.

The eukaryotic GID/CTLH complex is a highly conserved E3 ubiquitin ligase involved in a broad range of biological processes. However, a role of this complex in host antimicrobial defenses has not been described. We exploited Mycobacterium tuberculosis ( Mtb ) induced cytotoxicity in macrophages in a FACS based CRISPR genetic screen to identify host determinants of intracellular Mtb growth restriction. Our screen identified 5 ( GID8 , YPEL5 , WDR26 , UBE2H , MAEA ) of the 10 predicted members of the GID/CTLH complex as determinants of intracellular growth of both Mtb and Salmonella serovar Typhimurium. We show that the antimicrobial properties of the GID/CTLH complex knockdown macrophages are mediated by enhanced GABAergic signaling, activated AMPK, increased autophagic flux and resistance to cell death. Meanwhile, Mtb isolated from GID/CTLH knockdown macrophages are nutritionally starved and oxidatively stressed. Our study identifies the GID/CTLH complex activity as broadly suppressive of host antimicrobial responses against intracellular bacterial infections.

Bortezomib Inhibits Open Configurations of the 20S Proteasome.

Bortezomib, a small dipeptide-like molecule, is a proteasome inhibitor used widely in the treatment of myeloma and lymphoma. This molecule reacts with threonine side chains near the center of the 20S proteasome and disrupts proteostasis by blocking enzymatic sites that are responsible for protein degradation. In this work, we use novel mass-spectrometry-based techniques to examine the influence of bortezomib on the structures and stabilities of the 20S core particle. These studies indicate that bortezomib binding dramatically favors compact 20S structures (in which the axial gate is closed) over larger structures (in which the axial gate is open)─suppressing gate opening by factors of at least ∼400 to 1300 over the temperature range that is studied. Thus, bortezomib may also restrict degradation in the 20S proteasome by preventing substrates from entering the catalytic pore. That bortezomib influences structures at the entrance region of the pore at such a long distance (∼65 to 75 Å) from its binding sites raises a number of interesting biophysical issues.

Emerging racial disparities among Medicare beneficiaries and Veterans with metastatic castration-sensitive prostate cancer.

BACKGROUND: Previous studies have shown that Black men receive worse prostate cancer care than White men. This has not been explored in metastatic castration-sensitive prostate cancer (mCSPC) in the current treatment era. METHODS: We evaluated treatment intensification (TI) and overall survival (OS) in Medicare (2015-2018) and Veterans Health Administration (VHA; 2015-2019) patients with mCSPC, classifying first-line mCSPC treatment as androgen deprivation therapy (ADT) + novel hormonal therapy; ADT + docetaxel; ADT + first-generation nonsteroidal antiandrogen; or ADT alone. RESULTS: We analyzed 2226 Black and 16,071 White Medicare, and 1020 Black and 2364 White VHA patients. TI was significantly lower for Black vs White Medicare patients overall (adjusted odds ratio [OR] 0.68; 95% confidence interval [CI] 0.58-0.81) and without Medicaid (adjusted OR 0.70; 95% CI 0.57-0.87). Medicaid patients had less TI irrespective of race. OS was worse for Black vs White Medicare patients overall (adjusted hazard ratio [HR] 1.20; 95% CI 1.09-1.31) and without Medicaid (adjusted HR 1.13; 95% CI 1.01-1.27). OS was worse in Medicaid vs without Medicaid, with no significant OS difference between races. TI was significantly lower for Black vs White VHA patients (adjusted OR 0.75; 95% CI 0.61-0.92), with no significant OS difference between races. CONCLUSIONS: Guideline-recommended TI was low for all patients with mCSPC, with less TI in Black patients in both Medicare and the VHA. Black race was associated with worse OS in Medicare but not the VHA. Medicaid patients had less TI and worse OS than those without Medicaid, suggesting poverty and race are associated with care and outcomes.

2024 Australia-New Zealand Expert Consensus Statement on Cardiac Amyloidosis.

Over the past 5 years, early diagnosis of and new treatments for cardiac amyloidosis (CA) have emerged that hold promise for early intervention. These include non-invasive diagnostic tests and disease modifying therapies. Recently, CA has been one of the first types of cardiomyopathy to be treated with gene editing techniques. Although these therapies are not yet widely available to patients in Australia and New Zealand, this may change in the near future. Given the rapid pace with which this field is evolving, it is important to view these advances within the Australian and New Zealand context. This Consensus Statement aims to update the Australian and New Zealand general physician and cardiologist with regards to the diagnosis, investigations, and management of CA.

Transcriptome-Based Prognostic and Predictive Biomarker Analysis of ENACT: A Randomized Controlled Trial of Enzalutamide in Men Undergoing Active Surveillance.

PURPOSE: Few studies have explored the potential for pharmacological interventions to delay disease progression in patients undergoing active surveillance (AS). This preplanned transcriptomic analysis of patient samples from the ENACT trial aims to identify biomarkers in patients on AS who are at increased risk for disease progression or who may derive the greatest benefit from enzalutamide treatment. PATIENTS AND METHODS: In the phase II ENACT (ClinicalTrials.gov identifier: NCT02799745) trial, patients on AS were randomly assigned 1:1 to 160 mg orally once daily enzalutamide monotherapy or continued AS for 1 year. Transcriptional analyses were conducted on biopsies collected at trial screening, year 1, and year 2. Three gene expression signatures were evaluated in samples collected at screening and in available samples from patients on AS at any time during surveillance (expanded cohort): Decipher genomic classifier, androgen receptor activity (AR-A) score, and Prediction Analysis of Microarray 50 (PAM50) cell subtype signature. RESULTS: The Decipher genomic classifier score was prognostic; higher scores were associated with disease progression in the expanded cohort and AS arm of the expanded cohort. Patients with higher Decipher scores had greater positive treatment effect from enzalutamide as measured by time to secondary rise in prostate-specific antigen >25% above baseline. In patients treated with enzalutamide, higher AR-A scores and PAM50 luminal subtypes were associated with a greater likelihood of negative biopsy incidence at year 2. CONCLUSION: This analysis suggests that the Decipher genomic classifier may be prognostic for disease progression in AS patients with low- to intermediate-risk prostate cancer. Higher Decipher and AR-A scores, as well as PAM50 luminal subtypes, may also serve as biomarkers for treatment response.

Increasing Isolation Efficiency Using a Segmented Quadrupole Mass Filter Operated with Rectangular Waveforms.

The performance of a segmented quadrupole mass filter operated with rectangular waveforms and capacitively coupled rectangular waveforms applied to the prefilters was examined on a home-built quadrupole-Orbitrap platform. For peak widths of 50 m/z, 100% isolation efficiency was achieved, which fell to approximately 20% for 5 m/z peak width for a rectangular waveform of 150 V0-p. Due to a small exit aperture following the mass filter, peak structure was observed in both experimental peak shapes and those simulated using SIMION. A larger radius quadrupole was examined and achieved similar performance. While the segmented quadrupole does remove the defocusing effects of the fringing fields, the ion beam is only slightly refocused due to the low RF voltage which limits achievable gains in isolation efficiency.

Home Care Worker Continuity in Home-Based Long-Term Care: Associated Factors and Relationships With Client Health and Well-Being.

Background and Objectives: Despite the importance of provider continuity across healthcare settings, continuity among home care workers who provide hands-on long-term care is understudied. This project describes home care worker continuity, identifies factors associated with increased continuity, and examines associations between continuity and client outcomes. Research Design and Methods: We conducted a retrospective cohort study of clients receiving Medicaid-funded home-based long-term care (n = 3,864) using insurance plan and home care agency data from a large nonprofit organization. We estimated home care worker continuity for clients between 6-month clinical assessments using Bice-Boxerman scores. We then used generalized estimating equations to model associations between home care worker continuity and (1) client characteristics (e.g., cognitive impairment), and (2) client functional, health, and psychosocial outcomes. Results: While home care worker continuity was lowest for clients receiving the most weekly care hours, a range of continuity existed across all levels of care need. Those who were male, older, Asian/Pacific Islander/Native American, cognitively impaired, and functionally impaired had lower continuity. Higher home care worker continuity was significantly associated (p < .05) with fewer falls, a higher likelihood of functional improvement/stabilization, and fewer depressive symptoms. Discussion and Implications: The finding that home care worker continuity is associated with the health and well-being of home-based long-term care clients underscores the importance of building high-quality relationships in long-term care. Continued efforts are necessary to understand and advance home care worker continuity and to identify other aspects of the home care experience that benefit those receiving long-term care at home.

EMPOWER: A Multi-Site Pilot Trial to Reduce Distress in Surrogate Decision-Makers in the ICU.

CONTEXT: Efforts to reduce the psychological distress of surrogate decision-makers of critically ill patients have had limited success, and some have even exacerbated distress. OBJECTIVES: The aim of this study was to determine the feasibility, acceptability, and preliminary efficacy of EMPOWER (Enhancing and Mobilizing the POtential for Wellness and Resilience), an ultra-brief (∼2-hour), 6-module manualized psychological intervention for surrogates. METHODS: Surrogates who reported significant anxiety and/or an emotionally close relationship with the patient (n=60) were randomized to receive EMPOWER or enhanced usual care (EUC) at one of three metropolitan hospitals. Participants completed evaluations of EMPOWER's acceptability and measures of psychological distress pre-intervention, immediately post-intervention, and at 1- and 3-month follow-up assessments. RESULTS: Delivery of EMPOWER appeared feasible, with 89% of participants completing all 6 modules, and acceptable, with high ratings of satisfaction (mean=4.5/5, SD = .90). Compared to EUC, intent-to-treat analyses showed EMPOWER was superior at reducing peritraumatic distress (Cohen's d = -0.21, small effect) immediately post-intervention and grief intensity (d = -0.70, medium-large effect), posttraumatic stress (d = -0.74, medium-large effect), experiential avoidance (d = -0.46, medium effect), and depression (d = -0.34, small effect) 3 months post-intervention. Surrogate satisfaction with overall critical care (d = 0.27, small effect) was higher among surrogates randomized to EMPOWER. CONCLUSIONS: EMPOWER appeared feasible and acceptable, increased surrogates' satisfaction with critical care, and prevented escalation of posttraumatic stress, grief, and depression 3 months later.

ARL5b inhibits human rhinovirus 16 propagation and impairs macrophage-mediated bacterial clearance.

Human rhinovirus is the most frequently isolated virus during severe exacerbations of chronic respiratory diseases, like chronic obstructive pulmonary disease. In this disease, alveolar macrophages display significantly diminished phagocytic functions that could be associated with bacterial superinfections. However, how human rhinovirus affects the functions of macrophages is largely unknown. Macrophages treated with HRV16 demonstrate deficient bacteria-killing activity, impaired phagolysosome biogenesis, and altered intracellular compartments. Using RNA sequencing, we identify the small GTPase ARL5b to be upregulated by the virus in primary human macrophages. Importantly, depletion of ARL5b rescues bacterial clearance and localization of endosomal markers in macrophages upon HRV16 exposure. In permissive cells, depletion of ARL5b increases the secretion of HRV16 virions. Thus, we identify ARL5b as a novel regulator of intracellular trafficking dynamics and phagolysosomal biogenesis in macrophages and as a restriction factor of HRV16 in permissive cells.

Nonlinear Frequency Modulation for Fourier Transform Ion Mobility Mass Spectrometry Improves Experimental Efficiency.

Through optimization of terminal frequencies and effective sampling rates, we have developed nonlinear sawtooth-shaped frequency sweeps for efficient Fourier transform ion mobility mass spectrometry (FT-IM-MS) experiments. This is in contrast to conventional FT-IM-MS experiments where ion gates are modulated according to a linear frequency sweep. Linear frequency sweeps are effective but can be hindered by the amount of useful signal obtained using a single sweep over a large frequency range imposed by ion gating inefficiencies, particularly small ion packets, and gate depletion. These negative factors are direct consequences of the inherently low gate pulse widths of high-frequency ion gating events, placing an upper bound on FT-IM-MS performance. Here, we report alternative ion modulation strategies. Sawtooth frequency sweeps may be constructed for the purpose of either extending high-SNR transients or conducting efficient signal-averaging experiments for low-SNR transients. The data obtained using this approach show high-SNR signals for a set of low-mass tetraalkylammonium salts (<1000 m/z) where resolving powers in excess of 500 are achieved. Data for low-SNR obtained for multimeric protein complexes streptavidin (53 kDa) and GroEL (800 kDa) also reveal large increases in the signal-to-noise ratio for reconstructed arrival time distributions.

Expanding Native Mass Spectrometry to the Masses.

At the 33rd ASMS Sanibel Meeting, on Membrane Proteins and Their Complexes, a morning roundtable discussion was held discussing the current challenges facing the field of native mass spectrometry and approaches to expanding the field to nonexperts. This Commentary summarizes the discussion and current initiatives to address these challenges.

BRD4354 Is a Potent Covalent Inhibitor against the SARS-CoV-2 Main Protease.

Numerous organic molecules are known to inhibit the main protease (MPro) of SARS-CoV-2, the pathogen of Coronavirus Disease 2019 (COVID-19). Guided by previous research on zinc-ligand inhibitors of MPro and zinc-dependent histone deacetylases (HDACs), we identified BRD4354 as a potent inhibitor of MPro. The in vitro protease activity assays show that BRD4354 displays time-dependent inhibition against MPro with an IC50 (concentration that inhibits activity by 50%) of 0.72 ± 0.04 µM after 60 min of incubation. Inactivation follows a two-step process with an initial rapid binding step with a KI of 1.9 ± 0.5 µM followed by a second slow inactivation step, kinact,max of 0.040 ± 0.002 min-1. Native mass spectrometry studies indicate that a covalent intermediate is formed where the ortho-quinone methide fragment of BRD4354 forms a covalent bond with the catalytic cysteine C145 of MPro. Based on these data, a Michael-addition reaction mechanism between MPro C145 and BRD4354 was proposed. These results suggest that both preclinical testing of BRD4354 and structure-activity relationship studies based on BRD4354 are warranted to develop more effective anti-COVID therapeutics.