RESUMEN

BACKGROUND: Healthcare worker (HCW) anxiety and depression worsened during the pandemic, prompting the expansion of digital mental health platforms as potential solutions offering online assessments, access to resources and counselling. The use of these digital engagement tools may reflect tendencies and trends for the mental health needs of HCWs. OBJECTIVES: This retrospective, cross-sectional study investigated the association between the use of an online mental health platform within a large academic health system and measures of that system's COVID-19 burden during the first 3 years of the pandemic. METHODS: The study investigated the use of Cobalt, an online mental health platform, comprising deidentified mental health assessments and utilisation metrics. Cobalt, serves as an online mental health resource broadly available to health system employees, offering online evidence-based tools, coaching, therapy options and asynchronous content (podcasts, articles, videos and more). The analyses use validated mental health assessments (Generalised Anxiety Disorder-7 (GAD-7), Patient Health Questionnaire-9 (PHQ-9) and post-traumatic stress disorder (PTSD)) alongside publicly available COVID-19 data. Statistical analyses employed univariate linear regression with Stata SE Statistical Software. RESULTS: Between March 2020 and March 2023, 43 308 independent user sessions were created on Cobalt, a majority being anonymous sessions (72%, n=31 151). Mental health assessments, including PHQ-4, PHQ-9, GAD-7 and primary care-PTSD, totalled 9462 over the time period. Risk for self-harm was noted in 17.1% of PHQ-9 assessments. Additionally, 4418 appointments were scheduled with mental health counsellors and clinicians. No significant associations were identified between COVID-19 case burden and Cobalt utilisation or assessment scores. CONCLUSION: Cobalt emerged as an important access point for assessing the collective mental health of the workforce, witnessing increased engagement over time. Notably, the study indicates the nuanced nature of HCW assessments of anxiety, depression and PTSD, with mental health scores reflecting moderate decreases in depression and anxiety but signalling potential increases in PTSD. Tailored resources are imperative, acknowledging varied mental health needs within the healthcare workforce. Ultimately, this investigation lays the groundwork for continued exploration of the impact and effectiveness of digital platforms in supporting HCW mental health.

Asunto(s)

COVID-19 , Personal de Salud , Salud Mental , SARS-CoV-2 , Humanos , Estudios Transversales , COVID-19/psicología , COVID-19/epidemiología , Estudios Retrospectivos , Personal de Salud/psicología , Personal de Salud/estadística & datos numéricos , Masculino , Salud Mental/estadística & datos numéricos , Adulto , Femenino , Servicios de Salud Mental/estadística & datos numéricos , Persona de Mediana Edad , Depresión/epidemiología , Telemedicina/estadística & datos numéricos , Pandemias , Ansiedad/epidemiología , Ansiedad/psicología

RESUMEN

BACKGROUND: Internationally, over one-third of women experience birth trauma, leading to adverse mental health outcomes. Poor communication with healthcare professionals is a primary contributing factor. Paramedics attend various clinical presentations, including childbirth, yet their potential impact on women's birth experiences has been largely overlooked. METHODS: A systematic literature search was conducted following the Joanna Briggs Institute methodological framework. The search identified 1015 potentially suitable articles, and 5 articles met the inclusion criteria. Data was analysed using reflexive thematic analysis from a feminist standpoint. RESULTS: Three themes were generated: 1. First Impressions Count: paramedic demeanour impacted the woman's sense of safety and perception of paramedic clinical competence. 2. Choice as a Pathway to Control: when paramedics involved women in decision-making, it led to empowerment, while non-involvement led to women becoming passive participants. 3. Exposed, Violated and Disempowered: some paramedics disrespected and abused women, treating them solely as objects for the purpose of producing a baby. CONCLUSIONS: This review highlights the influence of paramedic communication on women's birth experiences. While some paramedics communicated respectfully, other paramedics were the perpetrators of Obstetric Violence. Future research should inform paramedic education and improve outcomes for birthing women.

Asunto(s)

Técnicos Medios en Salud , Comunicación , Humanos , Femenino , Técnicos Medios en Salud/psicología , Técnicos Medios en Salud/estadística & datos numéricos , Embarazo , Relaciones Profesional-Paciente , Parto/psicología , Paramédico

RESUMEN

Canine carcinomatosis (CC) and mesothelioma (CM) are rare but aggressive neoplasms that historically have been associated with poor prognoses. There is limited information regarding treatment for CC and CM. The purpose of this retrospective study was to evaluate the efficacy and tolerability of toceranib phosphate (Palladia) in dogs with CC and CM. Cases were solicited from the American College of Veterinary Internal Medicine (ACVIM) Oncology listserv and retrospectively reviewed. For eligibility, a cytologic and/or histopathologic diagnosis of CC or CM was required. A total of 23 cases were included (CC = 14, CM = 8, both = 1). Eighty-two percent (19/23) of dogs presented with effusion. The best overall response rate (BORR) was 30.4% (13% complete response [CR], 17.3% partial response [PR]). Stable disease (SD) was appreciated in 14 dogs (60.8%) including the four dogs without effusion. The most common toceranib-related adverse events were either Grade 1 and 2 diarrhea or hyporexia. The median progression-free survival (PFS) was 171 days (range, 7-519 days) and overall median survival time (MST) was 301 days (range, 49-875 days) for all dogs. When evaluating dogs solely with effusion, the median PFS and overall MST were 171 days (range, 7-519 days) and 285 days (range, 49-875 days), respectively. This report demonstrates that toceranib is both well tolerated and a potential treatment for CC and CM. A randomised, controlled, prospective study would be needed to objectively assess the survival benefit of toceranib in the management of CC and CM, with and without effusion.

Asunto(s)

Antineoplásicos , Enfermedades de los Perros , Indoles , Mesotelioma , Pirroles , Perros , Animales , Enfermedades de los Perros/tratamiento farmacológico , Estudios Retrospectivos , Indoles/uso terapéutico , Indoles/administración & dosificación , Masculino , Femenino , Pirroles/uso terapéutico , Pirroles/administración & dosificación , Antineoplásicos/uso terapéutico , Mesotelioma/tratamiento farmacológico , Mesotelioma/veterinaria , Mesotelioma/patología , Carcinoma/tratamiento farmacológico , Carcinoma/veterinaria , Resultado del Tratamiento

RESUMEN

Gene expression is known to be affected by interactions between local genetic variation and DNA accessibility, with the latter organized into three-dimensional chromatin structures. Analyses of these interactions have previously been limited, obscuring their regulatory context, and the extent to which they occur throughout the genome. Here, we undertake a genome-scale analysis of these interactions in a genetically diverse population to systematically identify global genetic-epigenetic interaction, and reveal constraints imposed by chromatin structure. We establish the extent and structure of genotype-by-epigenotype interaction using embryonic stem cells derived from Diversity Outbred mice. This mouse population segregates millions of variants from eight inbred founders, enabling precision genetic mapping with extensive genotypic and phenotypic diversity. With 176 samples profiled for genotype, gene expression, and open chromatin, we used regression modeling to infer genetic-epigenetic interactions on a genome-wide scale. Our results demonstrate that statistical interactions between genetic variants and chromatin accessibility are common throughout the genome. We found that these interactions occur within the local area of the affected gene, and that this locality corresponds to topologically associated domains (TADs). The likelihood of interaction was most strongly defined by the three-dimensional (3D) domain structure rather than linear DNA sequence. We show that stable 3D genome structure is an effective tool to guide searches for regulatory elements and, conversely, that regulatory elements in genetically diverse populations provide a means to infer 3D genome structure. We confirmed this finding with CTCF ChIP-seq that revealed strain-specific binding in the inbred founder mice. In stem cells, open chromatin participating in the most significant regression models demonstrated an enrichment for developmental genes and the TAD-forming CTCF-binding complex, providing an opportunity for statistical inference of shifting TAD boundaries operating during early development. These findings provide evidence that genetic and epigenetic factors operate within the context of 3D chromatin structure.

Asunto(s)

Cromatina , Epigénesis Genética , Genoma , Animales , Ratones , Cromatina/metabolismo , Cromatina/genética , Variación Genética , Células Madre Embrionarias/metabolismo

RESUMEN

The aim of this study was to determine the impact of accelerated aging (AA) on shelf stability, product loss, sensory and biochemical characteristics of 2 lower quality beef cuts. Triceps brachii (TB) and semimembranosus (SM) were collected and fabricated from 10 USDA Choice beef carcasses and assigned to 1 of 6 treatments: 3 d cooler aged (control), 21 d cooler aged, AA 49 °C for 2 h, AA 49 °C for 3 h, AA 54 °C for 2 h, and AA 54 °C for 3 h. The results showed that AA can decrease APC counts on steak surface and in purge and redness, but increase lightness and product loss of the steaks (P < 0.01). Lower shear force was also found for AA steaks compared to those from the control (P < 0.01), with the AA 54 °C treatments being comparable to 21 d cooler aging. However, the trained sensory panel determined AA steaks were less juicy and flavorful than those from the control and 21 d cooler aged samples (P < 0.05). There was no off-flavor detected in AA steaks though lipid oxidation was higher in AA samples than those in the control steaks (P < 0.01). The AA treatments stimulated cathepsin activity (P < 0.05), which may have enhanced the solubilization of stromal proteins and led to a different troponin-T degradation pattern compared to those from the 21 d aged samples (P < 0.01). Although AA is an economical and time-efficient method to increase tenderness of lower-quality beef cuts, further research is needed to determine strategies to mitigate the decrease in juiciness from AA treatments.

Asunto(s)

Color , Almacenamiento de Alimentos , Músculo Esquelético , Carne Roja , Gusto , Animales , Carne Roja/análisis , Bovinos , Músculo Esquelético/química , Almacenamiento de Alimentos/métodos , Humanos , Resistencia al Corte , Manipulación de Alimentos/métodos , Catepsinas/metabolismo , Masculino

RESUMEN

With ascent to high altitude (HA), compensatory increases in cerebral blood flow and oxygen delivery must occur to preserve cerebral metabolism and consciousness. We hypothesized that this compensation in cerebral blood flow and oxygen delivery preserves tolerance to simulated hemorrhage (via lower body negative pressure, LBNP), such that tolerance is similar during sustained exposure to HA vs. low altitude (LA). Healthy humans (4F/4 M) participated in LBNP protocols to presyncope at LA (1130 m) and 5-7 days following ascent to HA (3800 m). Internal carotid artery (ICA) blood flow, cerebral delivery of oxygen (CDO2) through the ICA, and cerebral tissue oxygen saturation (ScO2) were determined. LBNP tolerance was similar between conditions (LA: 1276 ± 304 s vs. HA: 1208 ± 306 s; P = 0.58). Overall, ICA blood flow and CDO2 were elevated at HA vs. LA (P ≤ 0.01) and decreased with LBNP under both conditions (P < 0.0001), but there was no effect of altitude on ScO2 responses (P = 0.59). Thus, sustained exposure to hypobaric hypoxia did not negatively impact tolerance to simulated hemorrhage. These data demonstrate the robustness of compensatory physiological mechanisms that preserve human cerebral blood flow and oxygen delivery during sustained hypoxia, ensuring cerebral tissue metabolism and neuronal function is maintained.

Asunto(s)

Altitud , Circulación Cerebrovascular , Humanos , Circulación Cerebrovascular/fisiología , Masculino , Adulto , Femenino , Hipoxia/fisiopatología , Hipoxia/metabolismo , Hemorragia/fisiopatología , Oxígeno/metabolismo , Consumo de Oxígeno/fisiología , Arteria Carótida Interna/fisiopatología , Saturación de Oxígeno/fisiología , Presión Negativa de la Región Corporal Inferior

RESUMEN

INTRODUCTION: There are known disparities in the treatment of infectious diseases. However, disparities in treatment of complicated urinary tract infections (UTIs) are largely uninvestigated. OBJECTIVES: We characterized UTI treatment among males in Veterans Affairs (VA) outpatient settings by age, race, and ethnicity and identified demographic characteristics predictive of recommended first-choice antibiotic therapy. METHODS: We conducted a national, retrospective cohort study of male VA patients diagnosed with a UTI and dispensed an outpatient antibiotic from January 2010 through December 2020. Recommended first-choice therapy for complicated UTI was defined as use of a recommended first-line antibiotic drug choice regardless of area of involvement (ciprofloxacin, levofloxacin, or sulfamethoxazole/trimethoprim) and a recommended duration of 7 to 10 days of therapy. Multivariable models were used to identify demographic predictors of recommended first-choice therapy (adjusted odds ratio [aOR] > 1). RESULTS: We identified a total of 157,898 males diagnosed and treated for a UTI in the outpatient setting. The average antibiotic duration was 9.4 days (±standard deviation [SD] 4.6), and 47.6% of patients were treated with ciprofloxacin, 25.1% with sulfamethoxazole/trimethoprim, 7.6% with nitrofurantoin, and 6.6% with levofloxacin. Only half of the male patients (50.6%, n = 79,928) were treated with recommended first-choice therapy (first-line drug choice and appropriate duration); 77.6% (n = 122,590) were treated with a recommended antibiotic choice and 65.9% (n = 104,070) with a recommended duration. Age 18-49 years (aOR 1.07, 95% confidence interval [CI] 1.03-1.11) versus age ≥65 years was the only demographic factor predictive of recommended first-choice therapy. CONCLUSIONS: Nearly half of the patients included in this study did not receive recommended first-choice therapies; however, racial and ethnic disparities were not identified. Underutilization of recommended first-choice antibiotic therapy in complicated UTIs continues to be an area of focus for antimicrobial stewardship programs.

Asunto(s)

Antibacterianos , Infecciones Urinarias , Adulto , Anciano , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Factores de Edad , Atención Ambulatoria , Antibacterianos/uso terapéutico , Estudios de Cohortes , Etnicidad , Disparidades en Atención de Salud/etnología , Grupos Raciales , Estudios Retrospectivos , Estados Unidos , United States Department of Veterans Affairs , Infecciones Urinarias/tratamiento farmacológico , Adolescente

RESUMEN

Metastatic castration-resistant prostate cancer remains incurable regardless of recent therapeutic advances. Prostate cancer tumors display highly glycolytic phenotypes as the cancer progresses. Nonspecific inhibitors of glycolysis have not been utilized successfully for chemotherapy, because of their penchant to cause systemic toxicity. This study reports the preclinical activity, safety, and pharmacokinetics of a novel small-molecule preclinical candidate, BKIDC-1553, with antiglycolytic activity. We tested a large battery of prostate cancer cell lines for inhibition of cell proliferation, in vitro. Cell-cycle, metabolic, and enzymatic assays were used to demonstrate their mechanism of action. A human patient-derived xenograft model implanted in mice and a human organoid were studied for sensitivity to our BKIDC preclinical candidate. A battery of pharmacokinetic experiments, absorption, distribution, metabolism, and excretion experiments, and in vitro and in vivo toxicology experiments were carried out to assess readiness for clinical trials. We demonstrate a new class of small-molecule inhibitors where antiglycolytic activity in prostate cancer cell lines is mediated through inhibition of hexokinase 2. These compounds display selective growth inhibition across multiple prostate cancer models. We describe a lead BKIDC-1553 that demonstrates promising activity in a preclinical xenograft model of advanced prostate cancer, equivalent to that of enzalutamide. BKIDC-1553 demonstrates safety and pharmacologic properties consistent with a compound that can be taken into human studies with expectations of a good safety margin and predicted dosing for efficacy. This work supports testing BKIDC-1553 and its derivatives in clinical trials for patients with advanced prostate cancer.

Asunto(s)

Proliferación Celular , Glucólisis , Ensayos Antitumor por Modelo de Xenoinjerto , Masculino , Humanos , Animales , Ratones , Glucólisis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Línea Celular Tumoral , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico

RESUMEN

OBJECTIVE: The only commercially available thoracic branched endoprosthesis (TBE) for treatment of the aortic arch was released in 2022. Limited data outside of clinical trial results have been reported. This study describes the demographics, anatomic details, and outcomes for patients treated for zone 0 to 2 using TBEs outside of a clinical trial. METHODS: All patients treated using TBEs for zone 0 to 2 were included. Patients treated as part of the clinical trial for zone 0 to 1 (n = 6) were excluded. Patient demographics, comorbidities, anatomic and operative details, and outcomes were reported. Outcomes and survival were then compared between groups. RESULTS: Of 40 patients, six patients underwent repair of zone 0, three of zone 1, and 31 of zone 2. There were no differences in demographics, comorbidities, or operative details by zone of treatment; however, the frequency of genetic aortopathy differed (zone 0: 0%; zone 1: 67%; and zone 2: 6.4%; P < .01). Seventy-three percent of patients were treated for dissection vs 27% with isolated aneurysms. Of the patients, 2.5% were treated for rupture, 22% were treated for symptomatic aneurysms, and 75% were treated electively. Forty-eight percent of repairs included a proximal cuff, and 83% received distal extension. Technical success was achieved in 100% of patients. Mean fluoroscopy time was 18 minutes, and median fluoroscopy dose was 416 mGy. Sixty percent of patients had prior aortic ascending/arch repair. TBE was planned as part of a complete thoracoabdominal repair in 45% of patients. Thirty-day mortality was 2.5% overall, with a single death in a zone 0 patient that occurred at day 1 due to a myocardial infarction. There were no reinterventions within 30 days. All other outcomes were similar. The 30-day stroke rate was 5.0%. The strokes occurred at day 6 (zone 1) and day 15 (zone 2); however, both were due to occlusion of a prior proximal surgical bypass and unrelated to the TBE side branch or embolization. Specifically, both patients had occlusion of a branch of their prior zone 1 or zone 2 arch replacement. An endoleak occurred in 7.5% of patients at 30-day follow-up (type II: 5.0%; unknown: 2.5%). At a mean follow-up of 6.6 months, 100% of side branches were patent. CONCLUSIONS: Repair of the aortic arch including TBE can be performed electively and urgently with acceptable stroke and death rates. TBE provides a valuable tool for patients requiring complete repair of a thoracoabdominal aneurysm. Continued investigation is underway to assess long-term safety and efficacy outside of the clinical trial.

Asunto(s)

Aorta Torácica , Aneurisma de la Aorta Torácica , Implantación de Prótesis Vascular , Prótesis Vascular , Procedimientos Endovasculares , Complicaciones Posoperatorias , Diseño de Prótesis , Humanos , Procedimientos Endovasculares/efectos adversos , Procedimientos Endovasculares/mortalidad , Procedimientos Endovasculares/instrumentación , Masculino , Femenino , Resultado del Tratamiento , Anciano , Implantación de Prótesis Vascular/efectos adversos , Implantación de Prótesis Vascular/mortalidad , Implantación de Prótesis Vascular/instrumentación , Aorta Torácica/cirugía , Aorta Torácica/diagnóstico por imagen , Persona de Mediana Edad , Factores de Tiempo , Estudios Retrospectivos , Aneurisma de la Aorta Torácica/cirugía , Aneurisma de la Aorta Torácica/diagnóstico por imagen , Aneurisma de la Aorta Torácica/mortalidad , Complicaciones Posoperatorias/etiología , Factores de Riesgo , Stents , Disección Aórtica/cirugía , Disección Aórtica/diagnóstico por imagen , Disección Aórtica/mortalidad , Anciano de 80 o más Años

RESUMEN

PURPOSE: Multidrug-resistant (MDR) infections are challenging to treat due to underlying patient conditions, pathogen characteristics, and high antibiotic resistance rates. As newer antibiotic therapies come to market, limited data exist about their real-world utilization. METHODS: This was a national retrospective cohort study of ceftazidime/avibactam (approved in 2015) utilization among inpatients from the Veterans Affairs (VA) Healthcare System, from 2015 through 2021. Joinpoint regression was used to estimate time trends in utilization. RESULTS: Ceftazidime/avibactam use increased by 52.3% each year (days of therapy per 1,000 bed days; 95% confidence interval, 12.4%-106.4%). We identified 1,048 unique predominantly male (98.3%) and white (66.2%; Black, 27.7%) patients treated with ceftazidime/avibactam, with a mean (SD) age of 71.5 (11.9) years. The most commonly isolated organisms were Pseudomonas aeruginosa (36.3%; carbapenem resistant, 80.6%; MDR, 65.0%) and Klebsiella species (34.1%; carbapenem resistant, 78.4%; extended-spectrum cephalosporin resistant, 90.7%). Common comorbid conditions included hypertension (74.8%), nervous system disorders (60.2%), diabetes mellitus (48.7%), and cancer (45.1%). Median time to ceftazidime/avibactam initiation from admission was 6 days, with a median of 3 changes in therapy before ceftazidime/avibactam initiation and a subsequent median length of inpatient stay of 14 days (median of 8 days of ceftazidime/avibactam therapy). Treatment heterogeneity was high, both before ceftazidime/avibactam initiation (89.6%) and during ceftazidime/avibactam treatment (85.6%), and common concomitant antibiotics included vancomycin (41.4%), meropenem (24.1%), cefepime (15.2%), and piperacillin/tazobactam (15.2%). The inpatient mortality rate was 23.6%, and 20.8% of patients had a subsequent admission with ceftazidime/avibactam treatment. CONCLUSION: Utilization of ceftazidime/avibactam increased from 2015 to 2021 in the national VA Healthcare System. Ceftazidime/avibactam was utilized in complex, difficult-to-treat patients, with substantial treatment heterogeneity and variation in the causative organism and culture sites.

Asunto(s)

Antibacterianos , Compuestos de Azabiciclo , Ceftazidima , Combinación de Medicamentos , United States Department of Veterans Affairs , Humanos , Ceftazidima/uso terapéutico , Ceftazidima/administración & dosificación , Masculino , Estudios Retrospectivos , Femenino , Compuestos de Azabiciclo/uso terapéutico , Anciano , Persona de Mediana Edad , Estados Unidos , Antibacterianos/uso terapéutico , Farmacorresistencia Bacteriana Múltiple , Pacientes Internos , Anciano de 80 o más Años , Estudios de Cohortes , Veteranos

RESUMEN

INTRODUCTION: Many evidence-based tools exist to address pain and distress associated with injections; however, there remains a large gap between the knowledge of these tools and their utilization. Our hospital began a quality improvement (QI) project prior to COVID-19, with the goal of increasing the utilization of Comfort Promise measures during needle procedures. When COVID-19 vaccinations were approved, our mass vaccination clinics provided an opportunity to rapidly increase utilization across the institution. The primary aim was to increase the percentage of comfort measures (CM) offered with COVID-19 vaccinations. METHODS: Through this QI project, nurses and other professionals implemented CMs during COVID mass vaccination clinics. Clinics occurred in 3 age-based waves. Waves served as Plan-Do-Study-Act (PDSA) cycles. Families completed post-vaccination surveys to determine what CMs were offered and intention for future use with vaccinations. RESULTS: Uptake of CMs (PainEase, ShotBlockers, Comfort Positioning, Alternative Focus, Topical Lidocaine, and Breastfeeding/Sucrose) throughout the waves increased and generally remained stable. CMs also seemed to decrease pain/distress with vaccinations (70.5 to 88.7%), and children/caregivers intended to use some combination for future vaccinations (82.5 to 98.5%). CONCLUSIONS: Fast-paced mass vaccination clinics provided an ideal opportunity to significantly increase utilization of CMs. Across age groups CMs yielded high satisfaction and interest in future utilization. Clinic nurses returned to their own sub-specialties and became change agents. IMPLICATIONS: If all healthcare providers can work together to achieve consensus while incorporating comfort measures into daily practice, sustained change with incorporation of these evidence-based tools can be achieved. Future directions are discussed.

Asunto(s)

COVID-19 , Mejoramiento de la Calidad , Humanos , COVID-19/prevención & control , Niño , Femenino , Masculino , Vacunación Masiva , Manejo del Dolor/métodos , Preescolar , Vacunas contra la COVID-19/administración & dosificación , SARS-CoV-2 , Dolor/prevención & control , Comodidad del Paciente , Lactante , Adolescente

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White-nose syndrome is a fungal disease that has decimated hibernating bats from multiple North American species. In 2014, the invasive fungus arrived at a hibernaculum of little brown bats (Myotis lucifugus) inside the spillway of Tippy Dam, located near Wellston, Michigan, USA, yet surprisingly, this population has not experienced the declines seen elsewhere. Unlike a typical subterranean hibernaculum, light enters the spillway through small ventilation holes. We hypothesized that this light causes the hibernating bats to maintain a circadian rhythm, thereby saving energy via social thermoregulation during synchronous arousals. To test this idea, we used high-resolution thermal cameras to monitor arousals from October 2019 to April 2020. We found that arousals followed a circadian rhythm, peaking after sunset, and that most observed arousals (>68%) occurred within a cluster of bats allowing for social thermoregulation. These findings are consistent with the hypothesis that light-induced synchronized arousals contribute to the unprecedented absence of mass mortality from white-nose syndrome in this large population. Using light to maintain a circadian rhythm in bats should be tested as a potential tool for mitigating mortality from white-nose syndrome. More generally, studying populations that have been largely unaffected by white-nose syndrome may provide insight into mitigation strategies for protecting the remaining populations.

Asunto(s)

Quirópteros , Hibernación , Animales , Hibernación/fisiología , Quirópteros/fisiología , Regulación de la Temperatura Corporal , Hongos , Nivel de Alerta/fisiología

RESUMEN

Dogs diagnosed with multicentric lymphoma often relapse following induction therapy within the first year of treatment. The primary aim of this study was to evaluate the tolerability of a novel drug combination using melphalan, vincristine, and cytarabine (MOC) for the treatment of relapsed lymphoma. On day 1, dogs were treated with vincristine (0.5-0.6 mg/m2 IV) and cytarabine (300 mg/m2 IV over 4-6 hr or subcutaneously over 2 days). On day 7, dogs were treated with melphalan (20 mg/m2per os). This 2 wk protocol was repeated for at least three cycles or until treatment failure. Twenty-six dogs were treated with MOC and met the inclusion criteria. Twenty-three dogs had toxicity data, and all experienced adverse events with the majority graded as mild. The overall response rate was 38%, which included 19% of dogs who achieved a complete response. The median progression-free survival was 29 days (range 1-280 days). The overall clinical benefit was 65% for a median of 37 days (range 33-280 days). MOC is a safe treatment option for relapsed lymphoma in dogs.

Asunto(s)

Enfermedades de los Perros , Linfoma , Animales , Perros , Melfalán/uso terapéutico , Melfalán/efectos adversos , Citarabina/uso terapéutico , Vincristina/uso terapéutico , Estudios Retrospectivos , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/veterinaria , Enfermedades de los Perros/etiología , Linfoma/tratamiento farmacológico , Linfoma/veterinaria , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico

RESUMEN

INTRODUCTION: Limited data exist regarding real-world utilization of nirmatrelvir/ritonavir. We identified predictors of nirmatrelvir/ritonavir use among Veterans Affairs (VA) outpatients nationally. METHODS: We conducted a retrospective cohort study among outpatients with coronavirus disease 2019 (COVID-19) who were eligible to receive nirmatrelvir/ritonavir between January and December of 2022, to identify factors associated with nirmatrelvir/ritonavir use (i.e., demographics, medical history, prior medication and healthcare exposures, frailty, and other clinical characteristics) using multivariable logistic regression. RESULTS: We included 309,755 outpatients with COVID-19 who were eligible for nirmatrelvir/ritonavir, of whom 12.2% received nirmatrelvir/ritonavir. Nirmatrelvir/ritonavir uptake increased from 1.1% to 23.2% over the study period. Factors associated with nirmatrelvir/ritonavir receipt included receiving a COVID-19 booster vs. none (adjusted odds ratio [aOR] 2.19 [95% confidence interval [CI] 2.12-2.26]), age ≥ 50 vs. 18-49 years (aORs > 1.5 for all age groups ≥ 50 years), having HIV (aOR 1.36 [1.22-1.51]), being non-frail vs. severely frail (aOR 1.22 [1.13-1.33]), and having rheumatoid arthritis (aOR 1.12 [1.04-1.21). Those with concomitant use of potentially interacting antiarrhythmics (aOR 0.35 [0.28-0.45]), anticoagulants/antiplatelets (aOR 0.42 [0.40-0.45]), and/or psychiatric/sedatives (aOR 0.84 [0.81-0.87]) were less likely to receive nirmatrelvir/ritonavir. CONCLUSIONS: Despite increases over time, overall utilization of nirmatrelvir/ritonavir was low. Predictors of nirmatrelvir/ritonavir utilization were consistent with known risk factors for progression to severe COVID-19, including older age and underlying medical conditions. Unvaccinated and undervaccinated patients and those receiving potentially interacting medications for cardiovascular or mental health conditions (antiarrhythmic, alpha-1 antagonist, anticoagulant/antiplatelet, sedative/hypnotic/psychiatric) were less likely to receive nirmatrelvir/ritonavir. Further education of prescribers and patients about nirmatrelvir/ritonavir treatment guidelines is needed to improve overall uptake and utilization in certain high-risk subpopulations.

RESUMEN

Here, we characterize the DNA methylation phenotypes of bone marrow cells from mice with hematopoietic deficiency of Dnmt3a or Dnmt3b (or both enzymes) or expressing the dominant-negative Dnmt3aR878H mutation [R882H in humans; the most common DNMT3A mutation found in acute myeloid leukemia (AML)]. Using these cells as substrates, we defined DNA remethylation after overexpressing wild-type (WT) DNMT3A1, DNMT3B1, DNMT3B3 (an inactive splice isoform of DNMT3B), or DNMT3L (a catalytically inactive "chaperone" for DNMT3A and DNMT3B in early embryogenesis). Overexpression of DNMT3A for 2 weeks reverses the hypomethylation phenotype of Dnmt3a-deficient cells or cells expressing the R878H mutation. Overexpression of DNMT3L (which is minimally expressed in AML cells) also corrects the hypomethylation phenotype of Dnmt3aR878H/+ marrow, probably by augmenting the activity of WT DNMT3A encoded by the residual WT allele. DNMT3L reactivation may represent a previously unidentified approach for restoring DNMT3A activity in hematopoietic cells with reduced DNMT3A function.

Asunto(s)

ADN (Citosina-5-)-Metiltransferasas , Leucemia Mieloide Aguda , Humanos , Ratones , Animales , ADN (Citosina-5-)-Metiltransferasas/genética , ADN Metiltransferasa 3A , ADN , Mutación , Metilación de ADN , Leucemia Mieloide Aguda/genética

RESUMEN

Purpose: Metastatic castration-resistant prostate cancer remains incurable regardless of recent therapeutic advances. Prostate cancer tumors display highly glycolytic phenotypes as the cancer progresses. Non-specific inhibitors of glycolysis have not been utilized successfully for chemotherapy, because of their penchant to cause systemic toxicity. This study reports the preclinical activity, safety, and pharmacokinetics of a novel small molecule preclinical candidate, BKIDC-1553, with antiglycolytic activity. Experimental design: We tested a large battery of prostate cancer cell lines for inhibition of cell proliferation, in vitro. Cell cycle, metabolic and enzymatic assays were used to demonstrate their mechanism of action. A human PDX model implanted in mice and a human organoid were studied for sensitivity to our BKIDC preclinical candidate. A battery of pharmacokinetic experiments, absorption, distribution, metabolism, and excretion experiments, and in vitro and in vivo toxicology experiments were carried out to assess readiness for clinical trials. Results: We demonstrate a new class of small molecule inhibitors where antiglycolytic activity in prostate cancer cell lines is mediated through inhibition of hexokinase 2. These compounds display selective growth inhibition across multiple prostate cancer models. We describe a lead BKIDC-1553 that demonstrates promising activity in a preclinical xenograft model of advanced prostate cancer, equivalent to that of enzalutamide. BKIDC-1553 demonstrates safety and pharmacologic properties consistent with a compound that can be taken into human studies with expectations of a good safety margin and predicted dosing for efficacy. Conclusion: This work supports testing BKIDC-1553 and its derivatives in clinical trials for patients with advanced prostate cancer.

RESUMEN

The profound impact of the human microbiome on health and disease has captivated the interest of clinical and scientific communities. The human body hosts a vast array of microorganisms collectively forming the human microbiome, which significantly influences various physiological processes and profoundly shapes overall well-being. Notably, the gut stands out as an exceptional reservoir, harboring the most significant concentration of microorganisms, akin to an organ in itself. The gut microbiome's composition and function are influenced by genetics, environment, age, underlying conditions, and antibiotic usage, leading to dysbiosis and pathogenesis, such as Clostridioides difficile infection (CDI). Conventional CDI treatment, involving antibiotics like oral vancomycin and fidaxomicin, fails to address dysbiosis and may further disrupt gut microbial communities. Consequently, emerging therapeutic strategies are focused on targeting dysbiosis and restoring gut microbiota to advance CDI therapeutics. Fecal microbiota transplantation (FMT) has demonstrated remarkable efficacy in treating recurrent CDI by transferring processed stool from a healthy donor to a recipient, restoring gut dysbiosis and enhancing bacterial diversity. Moreover, 2 newer Food and Drug Administration (FDA)-approved live biotherapeutic products (LBP), namely, Fecal Microbiota Live-JSLM and Fecal Microbiota Spores Live-BRPK, have shown promise in preventing CDI recurrence. This review explores the role of the gut microbiota in preventing and treating CDI, with an emphasis on gut-based interventions like FMT and fecal microbiota-based products that hold potential for gut restoration and prevention of CDI recurrence. Understanding the microbiome's impact on CDI prevention and treatment offers valuable insights for advancing future CDI therapeutics.

Asunto(s)

Clostridioides difficile , Infecciones por Clostridium , Humanos , Disbiosis/terapia , Trasplante de Microbiota Fecal , Infecciones por Clostridium/prevención & control , Infecciones por Clostridium/tratamiento farmacológico , Heces/microbiología , Antibacterianos/uso terapéutico

RESUMEN

Personalized medicine efforts are focused on identifying biomarkers to guide individualizing neoadjuvant therapy regimens. In this work, we aim to validate a previously developed image data-driven mathematical modeling approach for dynamic characterization of breast cancer response to neoadjuvant therapy using a large, multi-site cohort. We retrospectively analyzed patients enrolled in the BMMR2 ACRIN 6698 subset at 10 institutions. Patients enrolled received four MRI examinations during neoadjuvant therapy with acquisitions at baseline (T 0 ), 3-weeks/early-treatment (T 1 ), 12-weeks/mid-treatment (T 2 ), and completion of therapy prior to surgery (T 3 ). A biophysical mathematical model of tumor growth is used extract metrics to characterize the dynamics of treatment response. Using predicted response at therapy conclusion and histogram summary metrics to quantify estimated tumor proliferation maps, we found univariate model-based metrics able to predict pathological response, with area under the receiver operating characteristic curve (AUC) ranging from 0.58 and 0.69 analyzing between T 0 and T 1 , and AUCs ranging from 0.72-0.76 analyzing between T 0 and T 2 . For hormone receptor (HR)-negative, human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients our model-based metrics achieved an AUC of 0.9 analyzing between T 0 and T 1 and AUC of 1.0 analyzing between T 0 and T 2 . This data shows the significant promise in developing these imaging-based biophysical mathematical modeling methods of dynamic characterization into a clinical decision support tool for individualizing treatment regimens based on patient-specific response.

RESUMEN

PURPOSE: Previous work shows that linguistic features (e.g., word length, word frequency) impact the predictability of stuttering events. Most of this work has been conducted using reading tasks. Our study examined how linguistic features impact the predictability of stuttering events during spontaneous speech. METHODS: The data were sourced from the FluencyBank database and consisted of interviews with 35 adult stutterers (27,009 words). Three logistic regression mixed models were fit as the primary analyses: one model with four features (i.e., initial phoneme, grammatical function, word length, and word position within a sentence), a second model with six features (i.e., the features from the previous model plus word frequency and neighborhood density), and a third model with nine features (i.e., the features from the previous model plus bigram frequency, word concreteness, and typical age of word acquisition). We compared our models using the Area Under the Curve statistic. RESULTS: The four-feature model revealed that initial phoneme, grammatical function, and word length were predictive of stuttering events. The six-feature model revealed that initial phoneme, word length, word frequency, and neighborhood density were predictive of stuttering events. The nine-feature model was not more predictive than the six-feature model. CONCLUSION: Linguistic features that were previously found to be predictive of stuttering during reading were predictive of stuttering during spontaneous speech. The results indicate the influence of linguistic processes on the predictability of stuttering events such that words associated with increased planning demands (e.g., longer words, low frequency words) were more likely to be stuttered.

Asunto(s)

Habla , Tartamudeo , Adulto , Humanos , Tartamudeo/diagnóstico , Medición de la Producción del Habla/métodos , Lingüística/métodos , Lenguaje

RESUMEN

Gender-stereotyped beliefs develop early in childhood and are thought to increase with age based on prior research that was primarily carried out in Western cultures. Little research, however, has examined cross-cultural (in)consistencies in the developmental trajectory of gender-stereotyped beliefs. The present study examined implicit gender-toy stereotypes among 4- to 9-year-olds (N = 1,013; 49.70% girls) in Canada, China, and Thailand. Children from all three cultures evidenced implicit gender-toy stereotypes over this developmental period, but cultural differences in the developmental pattern and strength of these stereotypes were apparent. Gender-toy stereotypes were relatively strong and stable across age groups among Thai children and relatively weak and stable across age groups among Chinese children. Canadian 4- to 5-year-old children displayed weaker stereotypes, whereas 6- to 9-year-olds displayed stronger stereotypes. These findings highlight the contribution of culture to children's gender stereotype development. Although gender-toy stereotypes were found among 4- to 9-year-olds in all three cultures examined here, the strength of these stereotypes varies by culture. Furthermore, the previously described increase in gender stereotyping over this developmental period appears to not apply across cultures, thus challenging the conventional view on development in this domain based on prior, mainly Western, research. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Asunto(s)

Estereotipo , Femenino , Humanos , Preescolar , Masculino , Canadá , China