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1.
Am J Physiol Heart Circ Physiol ; 326(3): H752-H759, 2024 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-38214902

RESUMEN

Sleep disturbance, one of the most common menopausal symptoms, contributes to autonomic dysfunction and is linked to hypertension and cardiovascular risk. Longitudinal studies suggest that hyperreactivity of blood pressure (BP) to a stressor can predict the future development of hypertension. It remains unknown if postmenopausal females who experience sleep disturbance (SDG) demonstrate greater hemodynamic and sympathetic neural hyperreactivity to a stressor. We hypothesized that postmenopausal females with reported sleep disturbance would exhibit increased hemodynamic and sympathetic reactivity to a stressor compared with postmenopausal females without sleep disturbance (non-SDG). Fifty-five postmenopausal females (age, 62 ± 4 yr old; SDG, n = 36; non-SDG; n = 19) completed two study visits. The Menopause-Specific Quality of Life Questionnaire (MENQOL) was used to assess the presence of sleep disturbance (MENQOL sleep scale, ≥2 units). Beat-to-beat BP (finger plethysmography), heart rate (HR; electrocardiogram), and muscle sympathetic nerve activity (MSNA; microneurography; SDG, n = 25; non-SDG, n = 15) were continuously measured during a 10-min baseline and 2-min stressor (cold pressor test; CPT) in both groups. Menopause age and body mass index were similar between groups (P > 0.05). There were no differences between resting BP, HR, or MSNA (P > 0.05). HR and BP reactivity were not different between SDG and non-SDG (P > 0.05). In contrast, MSNA reactivity had a more rapid increase in the first 30 s of the CPT in the SDG (burst incidence, Δ10.2 ± 14.8 bursts/100 hb) compared with the non-SDG (burst incidence, Δ4.0 ± 14.8 bursts/100 hb, time × group, P = 0.011). Our results demonstrate a more rapid sympathetic neural reactivity to a CPT in postmenopausal females with perceived sleep disturbance, a finding that aligns with and advances recent evidence that sleep disturbance is associated with sympathetic neural hyperactivity in postmenopausal females.NEW & NOTEWORTHY This is the first study to demonstrate that muscle sympathetic nerve activity (MSNA) to a cold pressor test is augmented in postmenopausal females with perceived sleep disturbance. The more rapid increase in MSNA reactivity during the cold pressor test in the sleep disturbance group was present despite similar increases in the perceived pain levels between groups. Baseline MSNA burst incidence and burst frequency, as well as blood pressure and heart rate, were similar between the sleep disturbance and nonsleep disturbance groups.


Asunto(s)
Hipertensión , Trastornos del Sueño-Vigilia , Humanos , Femenino , Persona de Mediana Edad , Anciano , Posmenopausia , Calidad de Vida , Músculo Esquelético/inervación , Presión Sanguínea/fisiología , Sistema Nervioso Simpático , Frecuencia Cardíaca/fisiología , Sueño , Trastornos del Sueño-Vigilia/diagnóstico
2.
Am J Physiol Regul Integr Comp Physiol ; 327(4): R379-R388, 2024 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-39034814

RESUMEN

Oral contraceptive (OC) use can increase resting blood pressure (BP) in females as well as contribute to greater activation of group III/IV afferents during upper body exercise. It is unknown, however, whether an exaggerated BP response occurs during lower limb exercise in OC users. We sought to elucidate the group III/IV afferent activity-mediated BP and heart rate responses while performing lower extremity tasks during early and late follicular phases in young, healthy females. Females not taking OCs (NOC: n = 8; age: 25 ± 4 yr) and those taking OCs (OC: n = 10; age: 23 ± 2 yr) completed a continuous knee extension/flexion passive stretch (mechanoreflex) and cycling exercise with subsystolic cuff occlusion (exercise pressor reflex), which was followed by a 2-min postexercise circulatory occlusion (PECO) (metaboreflex). Data collection occurred on two occasions: once during the early follicular phase (days 1-4) and once during the late follicular phase (days 10-14) of their menstrual cycle (NOC) or during the placebo and active pill phases (OC). Resting mean arterial BP and heart rate were not different between phases in NOC and OC participants (P > 0.05). Hemodynamic responses to metaboreflex, mechanoreflex, and collective exercise pressor reflex activation were not different between phases in both groups (P > 0.05). In conclusion, although OCs are known to increase BP at rest, our findings indicate that neither endogenous nor exogenous (OC) sex hormones modulate BP during large, lower limb muscle exercise with or without group III/IV afferent activation in young, healthy females.NEW & NOTEWORTHY Sex differences in the cardiovascular response to exercise have been demonstrated and may be dependent on sex hormone levels. Furthermore, oral contraceptives (OCs) have been shown to exaggerate the blood pressure response to upper extremity exercise. The results of this study indicate that neither endogenous nor exogenous (OC) sex hormones modulate BP during lower extremity dynamic exercise or with group III/IV afferent activation in young, healthy females.


Asunto(s)
Ejercicio Físico , Frecuencia Cardíaca , Extremidad Inferior , Humanos , Femenino , Adulto , Adulto Joven , Frecuencia Cardíaca/efectos de los fármacos , Ejercicio Físico/fisiología , Presión Sanguínea/efectos de los fármacos , Músculo Esquelético , Reflejo , Fase Folicular , Anticonceptivos Hormonales Orales/farmacología , Anticonceptivos Hormonales Orales/administración & dosificación
3.
J Intensive Care Med ; : 8850666241291524, 2024 Oct 24.
Artículo en Inglés | MEDLINE | ID: mdl-39444331

RESUMEN

IMPORTANCE: Extubation Advisor (EA) is a novel software tool that generates a synoptic report for each Spontaneous Breathing Trial (SBT) conducted to inform extubation decision-making. OBJECTIVES: To assess bedside EA implementation, perceptions of utility, and identify barriers and facilitators of use. DESIGN, SETTING AND PARTICIPANTS: We conducted a phase I mixed-methods interventional study in three mixed intensive care unit (ICUs) in two academic hospitals. We interviewed critical care physicians (MDs) and respiratory therapists (RTs) regarding user-centered design principles and usability. ANALYSIS: We evaluated our ability to consent participants (feasibility threshold 50%), capture complete data (threshold 90%), generate and review EA reports in real-time (thresholds 75% and 80%, respectively), and MD perception of tool usefulness (6-point Likert scale). We analyzed interview transcripts using inductive coding to identify facilitators and barriers to EA implementation and perceived benefit of tool use. RESULTS: We enrolled 31 patients who underwent 70 SBTs. Although consent rates [31/31 (100%], complete data capture [68/68 (100%)], and EA report generation [68/70 (97.1%)] exceeded feasibility thresholds, reports were reviewed by MDs for [55/70 (78.6%)] SBTs. Mean MD usefulness score was 4.0/6. Based on feedback obtained from 36 interviews (15 MDs, 21 RTs), we revised the EA report twice and identified facilitators (ability to track patient progress, enhance extubation decision-making, and provide support in resource-limited settings) and barriers (resource constraints, need for education) to tool implementation. Half of respondents (9 MDs, 9 RTs; combined 50%) perceived definite or potential benefit to EA tool use. CONCLUSION: This is the first study of a waveform-based variability-derived, predictive clinical decision support tool evaluated in adult ICUs. Our findings support the feasibility of integrating the EA tool into bedside workflow. Clinical trials are needed to assess the utility of the EA tool in practice and its impact on extubation decision-making and outcomes. TRIAL REGISTRATION: NCT04708509.

4.
Mycoses ; 67(9): e13800, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39307841

RESUMEN

BACKGROUND: Blastomycosis is a pulmonary disease caused by Blastomyces spp., a group of pathogenic dimorphic fungi endemic to a number of geographic regions, specifically Manitoba and northwestern Ontario, Canada. Immunosuppression is a major risk factor affecting disease susceptibility, yet host immunity is not well understood. Genetic immunodeficiencies can also influence disease, with variants in IL6, GATA2 and VDBP shown to influence susceptibility. Additional genetic factors in disease susceptibility and severity remain undetected. Our study seeks to identify potential genetic risk factors in a blastomycosis case-control cohort from Manitoba and northwestern Ontario, Canada. METHODS: Exomes from 18 blastomycosis cases and 9 controls were sequenced, variants were identified and filtered for accuracy and quality. We performed candidate gene prioritisation and variant aggregation to identify genetic associations and explored the full exome dataset. RESULTS: Ninety-nine genetic variants in 42 candidate genes were identified in the exome dataset. No variants associated with susceptibility were identified in a single-variant analysis although two non-synonymous variants in TYK2 were enriched among cases suggesting a possible role in susceptibility. Gene-based association analysis found variants in TLR1 enriched in controls (p = 0.024) suggesting a possible protective effect. Gene cluster analysis identified genetic variants in genes of chromatin remodelling, proteasome and intraflagellar transport significantly enriched in cases (false discovery rates < 14%). CONCLUSIONS: The findings in this study show novel associations with blastomycosis susceptibility. A better understanding of host immunity and genetic predisposition to Blastomyces infection can help to inform clinical practice for improved outcomes.


Asunto(s)
Blastomicosis , Secuenciación del Exoma , Humanos , Blastomicosis/genética , Blastomicosis/microbiología , Blastomicosis/epidemiología , Estudios de Casos y Controles , Masculino , Femenino , Ontario/epidemiología , Persona de Mediana Edad , Manitoba/epidemiología , Adulto , Predisposición Genética a la Enfermedad , Anciano , Blastomyces/genética , Estudios de Cohortes , Exoma/genética , Adulto Joven
5.
Pediatr Res ; 94(1): 222-230, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-36418484

RESUMEN

BACKGROUND: The uncertainties surrounding the COVID-19 pandemic have been associated with increased parental concern. The aim of this study is to explore if this increased level of concern is associated with certain individual/household characteristics or if parents adapted to the ever-changing realities of the COVID-19 pandemic over time. METHODS: This prospective study explored COVID-19 concern trajectories and associated family characteristics of 765 UK parents caring for an immunosuppressed child during the first 18 months of the pandemic using growth mixture modelling. Qualitative analysis was performed to examine in more detail the source of concern. RESULTS: Four different trajectories of parental COVID-19 concern were identified. Ongoing very high concern was associated with caring for children with nephrotic or respiratory disease; having a child on an organ transplant waiting list; residency in the North of England; or parental vocational inactivity. Explicit concerns voiced by the parents generally followed national trends, but vulnerable status specific concerns were also reported. CONCLUSION: Diagnosis and prescribed medication of the immunosuppressed child, geographical location, household composition, and employment status of parent were associated with the different concern trajectories. This information can be helpful in targeting psychological family care where it is most needed. IMPACT: Many British parents caring for a clinically vulnerable child during the first 18 months of the COVID-19 pandemic showed high levels of concern with little sign of psychological adaptation. Consistent with findings from non-vulnerable populations, parents mentioned the impact of shielding and repeated isolation on their child's education, social life, and mental health. Unique to the clinically vulnerable population, parents were worried about child's health status, impact of delayed healthcare, and were confused by the contradictory information received from government, doctors, and media. Psychological family care can be targeted to those parents at greater risk for high levels of concern.


Asunto(s)
COVID-19 , Pandemias , Humanos , Niño , Estudios Prospectivos , Estudios Longitudinales , Estado de Salud
6.
Am J Physiol Heart Circ Physiol ; 323(6): H1270-H1280, 2022 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-36367692

RESUMEN

Cardiovascular disease (CVD), the leading cause of death among US adults, is more prevalent in menopausal females compared with age-matched males. Vasomotor symptoms of menopause (VMS; hot flashes/flushes and night sweats) are common among females undergoing menopausal transition and have been associated with elevated blood pressure (BP) and increased CVD risk. Autonomic dysregulation of BP has been posited as a contributing factor to the elevated CVD risk in menopausal females with VMS. This review includes 1) a brief overview of the relationship between VMS and CVD, 2) mechanisms of hot flushes and their potential impact on short- and long-term BP regulation, and 3) how the disruption of autonomic function associated with VMS might provide a mechanistic pathway to CVD development. Finally, this review will highlight knowledge gaps and future directions toward better understanding of hot flush physiology and VMS contributions to CVD.


Asunto(s)
Enfermedades del Sistema Nervioso Autónomo , Enfermedades Cardiovasculares , Adulto , Femenino , Humanos , Sudoración , Menopausia/fisiología , Sofocos/complicaciones , Sistema Vasomotor
7.
Ann Am Acad Pol Soc Sci ; 702(1): 206-223, 2022 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-36474772

RESUMEN

Single-parent families have historically faced greater economic precarity relative to other family types in the United States. We investigate how and whether those disparities widened after the onset of the COVID-19 pandemic. Using data on exposure to school and childcare center closures, unemployment, poverty, food hardship, and frequent worrying among single-parent families versus two-parent families throughout 2020 and 2021, we find that the challenges that single parents faced prior to the pandemic generally magnified after the arrival of COVID-19. In April 2020, one in four single parents was unemployed, and unemployment rates recovered more slowly for single parents throughout 2021, perhaps in part due to their unequal exposure to school and childcare closures. The expansion of income transfers largely buffered against potential increases in poverty and hardship, but levels of worrying among single parents continued to worsen throughout 2021.

10.
FASEB J ; 31(10): 4382-4395, 2017 10.
Artículo en Inglés | MEDLINE | ID: mdl-28615325

RESUMEN

During sepsis and shock states, mitochondrial dysfunction occurs. Consequently, adaptive mechanisms, such as fission, fusion, and mitophagy, are induced to eliminate damaged portions or entire dysfunctional mitochondria. The regulatory PINK1/Parkin and DJ-1 pathways are strongly induced by mitochondrial depolarization, although a direct link between loss of mitochondrial membrane potential (ΔΨ) and mitophagy has not been identified. Mitochondria also buffer Ca2+, and their buffering capacity is dependent on ΔΨ Here, we characterize a role for calcium/calmodulin-dependent protein kinase (CaMK) I in the regulation of these mechanisms. Loss of ΔΨ with either pharmacologic depolarization or LPS leads to Ca2+-dependent mitochondrial recruitment and activation of CaMKI that precedes the colocalization of PINK1/Parkin and DJ-1. CaMKI is required and serves as both a PINK1 and Parkin kinase. The mechanisms operate in both immune and nonimmune cells and are induced in in vivo models of endotoxemia, sepsis, and hemorrhagic shock. These data support the idea that CaMKI links mitochondrial stress with the PINK1/Parkin and DJ-1 mechanisms of mitophagy.-Zhang, X., Yuan, D., Sun, Q., Xu, L., Lee, E., Lewis, A. J., Zuckerbraun, B. S., Rosengart, M. R. Calcium/calmodulin-dependent protein kinase regulates the PINK1/Parkin and DJ-1 pathways of mitophagy during sepsis.


Asunto(s)
Proteínas Quinasas Dependientes de Calcio-Calmodulina/metabolismo , Mitocondrias/metabolismo , Proteína Desglicasa DJ-1/metabolismo , Proteínas Quinasas/metabolismo , Sepsis/metabolismo , Animales , Modelos Animales de Enfermedad , Lipopolisacáridos/farmacología , Masculino , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones Endogámicos C57BL , Mitofagia/efectos de los fármacos , Proteínas Serina-Treonina Quinasas/metabolismo , Transporte de Proteínas/efectos de los fármacos
11.
Vet Ophthalmol ; 21(5): 459-463, 2018 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-29251393

RESUMEN

Objectives To report the incidence and evaluate the clinical significance of goniolens bacterial contamination in clinical use in dogs with three different usage protocols and one with an added cleaning protocol. Animals Studied and Methods Three groups of twenty dogs undergoing gonioscopy at a private practice in the UK had the goniolenses swabbed for bacteriology culture and identification prior to placement on the cornea. Three protocols of lens use, with 2 different types of goniolens, were studied. One protocol was then repeated with 21 dogs with a lens cleaning protocol prior to storage. Results Low levels of bacterial contamination were found in all 3 initial groups (10-15%). No correlation was found between usage protocol used and rate of contamination and no correlation was found between length of storage between use and contamination. All bacteria cultured were considered naturally occurring commensals for the canine eye and environment. The group with a cleaning protocol had a 4.7% contamination rate. This was not statistically different from the non-cleaning groups. Conclusions The rate of bacterial contamination of goniolenses in clinical practice is low and the bacterial contaminants consist of commensal bacteria, unlikely to be of detriment to the eye. Minimal contamination of the goniolenses was found and this did not appear to be of clinical significance. The introduction of a simple cleaning protocol did not produce a statistically significant reduction in bacterial contamination.


Asunto(s)
Enfermedades de los Perros/diagnóstico por imagen , Contaminación de Equipos , Gonioscopía/veterinaria , Lentes/microbiología , Animales , Perros , Femenino , Gonioscopía/instrumentación , Masculino , Medicina Veterinaria/instrumentación
13.
Lancet Oncol ; 15(11): 1263-8, 2014 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-25242048

RESUMEN

BACKGROUND: In the final analysis of the phase 3 COU-AA-301 study, abiraterone acetate plus prednisone significantly prolonged overall survival compared with prednisone alone in patients with metastatic castration-resistant prostate cancer progressing after chemotherapy. Here, we present the final analysis of an early-access protocol trial that was initiated after completion of COU-AA-301 to enable worldwide preapproval access to abiraterone acetate in patients with metastatic castration-resistant prostate cancer progressing after chemotherapy. METHODS: We did a multicentre, open-label, early-access protocol trial in 23 countries. We enrolled patients who had metastatic castration-resistant prostate cancer progressing after taxane chemotherapy. Participants received oral doses of abiraterone acetate (1000 mg daily) and prednisone (5 mg twice a day) in 28-day cycles until disease progression, development of sustained side-effects, or abiraterone acetate becoming available in the respective country. The primary outcome was the number of adverse events arising during study treatment and within 30 days of discontinuation. Efficacy measures (time to prostate-specific antigen [PSA] progression and time to clinical progression) were gathered to guide treatment decisions. We included in our analysis all patients who received at least one dose of abiraterone acetate. This study is registered with ClinicalTrials.gov, number NCT01217697. FINDINGS: Between Nov 17, 2010, and Sept 30, 2013, 2314 patients were enrolled into the early-access protocol trial. Median follow-up was 5·7 months (IQR 3·5-10·6). 952 (41%) patients had a grade 3 or 4 treatment-related adverse event, and grade 3 or 4 serious adverse events were recorded in 585 (25%) people. The most common grade 3 and 4 adverse events were hepatotoxicity (188 [8%]), hypertension (99 [4%]), cardiac disorders (52 [2%]), osteoporosis (31 [1%]), hypokalaemia (28 [1%]), and fluid retention or oedema (23 [1%]). 172 (7%) patients discontinued the study because of adverse events (64 [3%] were drug-related), as assessed by the investigator, and 171 (7%) people died. The funder assessed causes of death, which were due to disease progression (85 [4%]), an unrelated adverse experience (72 [3%]), and unknown reasons (14 [1%]). Of the 86 deaths not attributable to disease progression, 18 (<1%) were caused by a drug-related adverse event, as assessed by the investigator. Median time to PSA progression was 8·5 months (95% CI 8·3-9·7) and median time to clinical progression was 12·7 months (11·8-13·8). INTERPRETATION: No new safety signals or unexpected adverse events were found in this early-access protocol trial to assess abiraterone acetate for patients with metastatic castration-resistant prostate cancer who progressed after chemotherapy. Future work is needed to ascertain the most effective regimen of abiraterone acetate to optimise patients' outcomes. FUNDING: Janssen Research & Development.


Asunto(s)
Androstenoles/administración & dosificación , Recurrencia Local de Neoplasia/tratamiento farmacológico , Prednisolona/administración & dosificación , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Administración Oral , Adulto , Anciano , Anciano de 80 o más Años , Antagonistas de Andrógenos/administración & dosificación , Androstenos , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Quimioterapia Combinada , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Invasividad Neoplásica/patología , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Pronóstico , Neoplasias de la Próstata Resistentes a la Castración/mortalidad , Neoplasias de la Próstata Resistentes a la Castración/patología , Análisis de Supervivencia , Resultado del Tratamiento
14.
Nat Hum Behav ; 8(4): 657-667, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38374443

RESUMEN

The COVID-19 pandemic put families in the United States under financial stress. The federal government's largest response in 2021 was the American Rescue Plan Act, which temporarily expanded the Child Tax Credit (CTC) into a large, unconditional child allowance providing monthly payments to families with children. This study investigates consumption responses to the CTC expansion using anonymized mobile-location data and debit/credit card data that track visits and spending at 1.3 million establishments across US counties. For identification, we exploit variation in the size of households' income gains due to the CTC across counties in a difference-in-differences framework spanning January 2021 to May 2022. Counties benefiting most from the CTC expansion experienced larger increases in visits to childcare centres and health- and personal-care establishments, and increased visits to and spending per transaction at grocery and general stores. These findings suggest that the CTC expansion increased household consumption and spending on children.


Asunto(s)
COVID-19 , Humanos , Estados Unidos , COVID-19/epidemiología , COVID-19/economía , Niño , Renta/estadística & datos numéricos , Impuestos/economía , Composición Familiar , Preescolar , Estrés Financiero
15.
J Am Geriatr Soc ; 72(4): 1234-1241, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38147454

RESUMEN

BACKGROUND: Older adults are commonly prescribed long-term benzodiazepines for anxiety and insomnia despite evidence of risks and limited evidence of long-term benefits. Recent quality measures and guidelines have recommended benzodiazepine deprescribing, yet there is little real-world data on clinic-based deprescribing programs. METHODS: We developed a benzodiazepine deprescribing quality improvement program for older adults at a large US academic medical center. The program targeted adults aged 65 years and older who were prescribed chronic benzodiazepines by their primary care physician (PCP). PCPs were contacted to opt-out patients not suitable for deprescribing; then eligible patients were mailed a letter discussing patient-specific risks and advising them to discuss deprescribing with their PCP or a pharmacist who was available to support tapering. The primary outcomes were the number of patients who discussed deprescribing and who initiated a taper within 90 days of outreach. RESULTS: Of 504 older adults prescribed benzodiazepines, 133 (26%) were opted out by their PCPs leaving a cohort of 371 (median age 71 years [IQR 68-75], 58% female, 82% White). The median daily diazepam milligram equivalent was 5 mg (IQR 3-6 mg) and 30% were prescribed long-acting benzodiazepines. Three months following patient outreach, 97 patients (26%) had a documented discussion of benzodiazepines with their PCP or clinic pharmacist. Of these patients, 35 (36%) had documentation of a deprescribing discussion and 25 (26%) initiated a taper. At 12 months, 16 patients (64%) were tapered successfully, with nine (36%) patients taking a lower benzodiazepine dose and seven (28%) discontinuing benzodiazepines completely. CONCLUSIONS: A low-intensity benzodiazepine deprescribing outreach program led to deprescribing conversations for a minority of patients, but one-quarter of older adults who engaged in a conversation chose to taper and nearly two-thirds sustained reduced use. Incorporating benzodiazepine deprescribing into routine care may require more intensive population-health efforts to engage patients and clinicians.


Asunto(s)
Benzodiazepinas , Deprescripciones , Humanos , Femenino , Anciano , Masculino , Benzodiazepinas/uso terapéutico , Mejoramiento de la Calidad , Ansiedad , Atención Primaria de Salud
16.
Protein Sci ; 33(2): e4860, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38149326

RESUMEN

Cystathionine- ß $$ \beta $$ -synthase (CBS)-pair domain divalent metal cation transport mediators (CNNMs) are an evolutionarily conserved family of magnesium transporters. They mediate magnesium homeostasis directly by transport of Mg2+ ions and indirectly by regulation of the transient receptor potential ion channel subfamily M member 7 (TRPM7). Here, we report the crystal structure of the extracellular domain of tapeworm CNNM4. The domain forms a dimer of immunoglobulin-like (Ig-like) folds with electron density observed for three glycosylation sites. Analytical ultracentrifugation confirms that mutations in the extracellular domain of human CNNM4 prevent its dimerization. An analogous mutation in mouse CNNM2 impairs its activity in a cellular assay of Mg2+ transport.


Asunto(s)
Proteínas de Transporte de Catión , Canales Catiónicos TRPM , Humanos , Ratones , Animales , Dimerización , Magnesio/química , Mutación , Proteínas de Transporte de Membrana , Homeostasis , Proteínas Serina-Treonina Quinasas/genética , Canales Catiónicos TRPM/genética , Proteínas de Transporte de Catión/química
17.
J Virol Methods ; 327: 114939, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38604585

RESUMEN

Despite increasing scale-up of antiretroviral therapy (ART) coverage, challenges related to adherence and HIV drug resistance (HIVDR) remain. The high cost of HIVDR surveillance is a persistent challenge with implementation in resource-constrained settings. Dried blood spot (DBS) specimens have been demonstrated to be a feasible alternative to plasma or serum for HIVDR genotyping and are more suitable for lower resource settings. There is a need for affordable HIVDR genotyping assays which can amplify HIV-1 sequences from DBS specimens, particularly those with low viral loads, at a low cost. Here, we present an in-house assay capable of reliably amplifying HIV-1 protease and partial reverse transcriptase genes from DBS specimens, which covers the complete World Health Organization 2009 list of drug resistance mutations under surveillance. DBS specimens were prepared using whole blood spiked with HIV-1 at concentrations of 10,000, 5000, 1000, and 500 copies/mL (n=30 for each concentration). Specimens were tested in triplicate. A two-step approach was used consisting of cDNA synthesis followed by nested PCR. The limit of detection of the assay was calculated to be approximately 5000 (95% CI: 3200-10,700) copies/mL for the protease gene and 3600 (95% CI: 2200-10,000) copies/mL for reverse transcriptase. The assay was observed to be most sensitive with higher viral load specimens (97.8% [95% CI: 92.2-99.7]) for both protease and reverse transcriptase at 10,000 copies/mL with performance decreasing with the use of specimens with lower viral loads (46.7% [36.1-57.5] and 60.0% [49.1-70.2] at 500 copies/mL for protease and reverse transcriptase, respectively). Ultimately, this assay presents a promising opportunity for use in resource-constrained settings. Future work should involve validation under field conditions including sub-optimal storage conditions and preparation of DBS with fingerprick blood in order to accurately reflect real-world collection scenarios.


Asunto(s)
Farmacorresistencia Viral , Infecciones por VIH , Proteasa del VIH , Transcriptasa Inversa del VIH , VIH-1 , Mutación , Humanos , VIH-1/genética , VIH-1/efectos de los fármacos , VIH-1/aislamiento & purificación , Farmacorresistencia Viral/genética , Infecciones por VIH/virología , Infecciones por VIH/tratamiento farmacológico , Transcriptasa Inversa del VIH/genética , Proteasa del VIH/genética , Pruebas con Sangre Seca/métodos , Manejo de Especímenes/métodos , Carga Viral , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/uso terapéutico , Técnicas de Genotipaje/métodos , Genotipo , Sensibilidad y Especificidad
18.
JAMA Netw Open ; 7(2): e2355301, 2024 02 05.
Artículo en Inglés | MEDLINE | ID: mdl-38353954

RESUMEN

Importance: Unmet social needs in local populations may hinder the development of targeted cancer control interventions aimed at improving screening utilization and early-stage breast cancer diagnosis to ultimately improve breast cancer survival disparities. Objective: To evaluate if (1) city-funded screening mammography is associated with utilization of screening mammography, (2) unmet social needs are associated with utilization of screening mammography, and (3) unmet social needs are associated with later-stage disease at diagnosis. Design, Setting, and Participants: This cohort study included patients with stages I-IV invasive ductal or lobular carcinoma treated at an academic medical center (including both an underserved safety-net hospital [SNH] and a National Cancer Institute-designated academic cancer center [ACC]) from 2020 to 2023. Eligible patients were aged 18 years or older and able to consent. Data were analyzed between July 2023 and September 2023. Exposure: The Health Leads Social Needs Screening Toolkit, a screening tool that gathers information on the most common social need domains affecting patient health. Main Outcomes and Measures: Univariable and multivariable logistic regression was utilized to evaluate the following primary outcomes: (1) routine screening mammography and (2) American Joint Committee on Cancer 8th edition clinical stage at presentation. Results: Of the 322 women who completed the Health Leads Social Needs Screening Toolkit, 201 (62%) self-identified as Hispanic, 63 (19%) as non-Hispanic Black, and 63 (19%) as non-Hispanic White. Two hundred fifty-five (76%) patients with access to city-funded screening mammography completed a screening mammogram. Patients who presented to the SNH were more likely to present with late-stage disease compared with early-stage disease (15 of 48 [31%] vs 50 of 274 [18%]; P = .04). On multivariable logistic regression, not completing a screening mammography was associated with having an increasing number of unmet social needs (OR, 0.74; 95% CI, 0.55-0.99; P = .047) and an increasing age at diagnosis (OR, 0.92; 95% CI, 0.89-0.96; P < .001). Moreover, increasing unmet social needs was significantly associated with late-stage diagnosis above and beyond screening mammography (OR, 1.38; 95% CI, 1.01-1.89; P = .04). Conclusions and Relevance: In this cohort study, access to screening mammography did not translate to utilization of screening mammography, increasing unmet social needs were significantly associated with lower rates of screening mammography, and those with increasing unmet social needs were more likely to present with late-stage disease. This association transcended recruitment site (SNH vs ACC), indicating that patients in either hospital setting may benefit from unmet social needs screening to overcome access to care barriers associated with late-stage disease at diagnosis.


Asunto(s)
Neoplasias de la Mama , Detección Precoz del Cáncer , Humanos , Femenino , Neoplasias de la Mama/diagnóstico , Mamografía , Estudios de Cohortes , Mama
19.
Womens Health Rep (New Rochelle) ; 4(1): 136-147, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37008184

RESUMEN

Background: Menopause symptoms can be debilitating, and the use of menopausal hormone therapy (MHT) has declined significantly since the Women's Health Initiative. Materials and Methods: We surveyed 508 peri- and postmenopausal females to determine (1) the use of complementary and integrative therapies (CIT), MHT; and pharmacotherapies; (2) the perceptions, perceived benefits/risks of CIT, MHT; and pharmacotherapy use; and (3) factors associated with CIT and MHT use for menopause symptom treatment. Results: The majority of respondents used CIT to treat menopause symptoms based on physician recommendation and research studies. Treatments that were perceived as most beneficial included exercise, mind-body therapies, diet, and spiritual practices, with exercise and mind-body therapies chosen to treat the most common symptoms of sleep disturbances, depressive mood, and anxiety. Higher education level was the main predictive variable for choosing exercise (odds ratio [OR] = 1.27, p = 0.02) and mind-body therapies (OR = 1.57, p = 0.02) to treat menopausal symptoms. Perceptions, beliefs, and use of different CIT by primarily white, affluent, and educated peri- and postmenopausal females to treat menopause symptoms, including sleep disturbances, depression, and anxiety, are driven by conversations with physicians and evidence-based research. Conclusion: These findings reinforce the necessity for both additional research in more diverse populations, as well as comprehensive, individualized personalized care from an interdisciplinary team that considers the best options available for all female patients.

20.
J Psychiatr Res ; 161: 273-281, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-36947958

RESUMEN

The COVID-19 pandemic has proved unique in both its unpredictability and the extent to which it has continued to impact on daily life since March 2020. Among the immunosuppressed population the challenges of the COVID-19 pandemic are cumulative to the ever-present challenges of living with a long-term condition. This prospective longitudinal study explored patterns of concern experienced by 467 British parents caring for an immunosuppressed child during the first 2 years of the COVID-19 pandemic and related this to parental mental wellbeing. Most parents slowly adapted or were resilient to the ever-changing stressors of the COVID-19 pandemic. However, 12% experienced high levels of concern throughout the first 2 years of the pandemic. This group was also more likely to report emotional mental health problems towards the end of this period. The experience of emotional mental health problems among parents caring for an immunosuppressed child was related to low household income, single parenting, difficult access to greenspace, and higher level of exposure to COVID positive cases and COVID restrictions (North of England). Parents reported that optimism, reduction of isolation, and support promoted coping and management of the challenges of the COVID-19 pandemic. More reliable COVID information and periodic medical-condition-specific guidance would have been appreciated. These findings can increase clinical awareness of high-risk parental groups and make an important contribution to the planning of appropriate targeted psychological family interventions.


Asunto(s)
COVID-19 , Distrés Psicológico , Niño , Humanos , Pandemias , Estudios Longitudinales , Estudios Prospectivos , Padres
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