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1.
Genet Med ; : 101231, 2024 Aug 09.
Artículo en Inglés | MEDLINE | ID: mdl-39132680

RESUMEN

PURPOSE: Pediatric cholestasis is the phenotypic expression of clinically and genetically heterogeneous disorders of bile acid synthesis and flow. Although a growing number of monogenic causes of pediatric cholestasis have been identified, the majority of cases remain undiagnosed molecularly. METHODS: In a cohort of 299 pediatric participants (279 families) with intrahepatic cholestasis, we performed exome sequencing as a first-tier diagnostic test. RESULTS: A likely causal variant was identified in 135 families (48.56%). These comprise 135 families that harbor variants spanning 37 genes with established or tentative links to cholestasis. In addition, we propose a novel candidate gene (PSKH1) (HGNC:9529) in 4 families. PSKH1 was particularly compelling because of strong linkage in three consanguineous families who shared a novel hepatorenal ciliopathy phenotype. Two of the four families shared a founder homozygous variant while the third had a different homozygous variant in PSKH1. PSKH1 encodes a putative protein serine kinase of unknown function. Patient fibroblasts displayed abnormal cilia that are long and show abnormal transport. A homozygous Pskh1 mutant mouse faithfully recapitulated the human phenotype and displayed abnormally long cilia. The phenotype could be rationalized by the loss of catalytic activity observed for each recombinant PSKH1 variant using in vitro kinase assays. CONCLUSION: Our results support the use of genomics in the workup of pediatric cholestasis and reveal PSKH1-related hepatorenal ciliopathy as a novel candidate monogenic form.

2.
Health Aff (Millwood) ; 43(8): 1180-1189, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-39102607

RESUMEN

Trauma activation fees are intended to help trauma centers cover the costs of providing lifesaving care at all times, but they have fallen under greater scrutiny because of a lack of regulation and wide variability in charges. We leveraged the federal Hospital Price Transparency rule to systematically describe trauma activation fees as captured in the Turquoise Health database for all Level I-III trauma centers nationally and across payer types. As of April 18, 2023, a total of 38 percent of US trauma centers published trauma activation fees. These fees varied widely by payer type. The minimum fee charged was $40 (for a Medicaid contract); the maximum fees charged were $28,356 (self-pay) and $28,893 (commercial payers). Trauma centers that were larger, metropolitan, located in the West, and associated with proprietary (investor-owned, for-profit) hospitals had higher trauma activation fees. Proprietary hospitals posted fees that were 60 percent higher than those published by public, nonfederal hospitals. Unmerited variation in trauma activation fees may suggest that the current funding strategy is equitable neither for trauma centers nor for the severely injured patients who rely on them for lifesaving care.


Asunto(s)
Centros Traumatológicos , Centros Traumatológicos/economía , Estados Unidos , Humanos , Honorarios y Precios , Medicaid/economía , Heridas y Lesiones/economía , Precios de Hospital/estadística & datos numéricos , Bases de Datos Factuales
3.
J Biol Chem ; : 107656, 2024 Aug 09.
Artículo en Inglés | MEDLINE | ID: mdl-39128715

RESUMEN

Adrenergic modulation of voltage gated Ca2+ currents is a context specific process. In the heart Cav1.2 channels initiate excitation-contraction coupling. This requires protein kinase A (PKA) phosphorylation of the small GTPase Rad (Ras associated with diabetes) and involves direct phosphorylation of a1 subunit of the Cav1.2 at Ser1700. A contributing factor is the proximity of PKA to the channel through association with A-kinase anchoring proteins (AKAPs). Disruption of PKA anchoring by the disruptor peptide AKAP-IS prevents up-regulation of Cav1.2 currents in tsA-201 cells. Biochemical analyses demonstrate that Rad does not function as an A-kinase anchoring protein. Electrophysiological recording shows that channel mutants lacking phosphorylation sites (Cav1.2 STAA) lose responsivity to the second messenger cAMP. Measurements in cardiomyocytes isolated from Rad-/- mice show that adrenergic activation of Cav1.2 is attenuated but not completely abolished. Whole animal electrocardiography studies reveal that cardiac selective Rad knockout mice exhibited higher baseline left-ventricular ejection fraction (EF), greater fractional shortening (FS), and increased heart rate as compared to control animals. Yet, each parameter of cardiac function was slightly elevated when Rad-/- mice were treated with the adrenergic agonist isoproterenol. Thus, phosphorylation of Cav1.2 and dissociation of phospho-Rad from the channel are local cAMP responsive events that act in concert to enhance L-type calcium currents. This convergence of local PKA regulatory events at the cardiac L-type calcium channel may permit maximal ß-adrenergic influence on the fight-or-flight response.

4.
Respir Med ; 231: 107737, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38986792

RESUMEN

BACKGROUND: Airway stenting may be needed to manage anastomotic complications in lung transplant recipients. Conventional stenting strategies may be inadequate due to anatomic variations between the recipient and donor or involvement of both the anastomosis and lobar bronchi. METHODS: We investigated the efficacy of 3D-designed patient-specific silicone Y-stents in managing this scenario. 9 patients with complex airway stenosis underwent custom stent insertion after either failing traditional management strategies or having anatomy not suitable for conventional stents. CT images were uploaded to stent design software to make a virtual stent model. 3D printing technology was then used to make a mold for the final silicone stent which was implanted via rigid bronchoscopy. Forced expiratory volume in 1 s (FEV1) was measured pre- and post-stent placement. RESULTS: 78 % of patients experienced an increase in their FEV1 after stent insertion, (p = 0.001, 0.02 at 30 and 90 days respectively). Unplanned bronchoscopies primarily occurred due to mucous plugging. 2 patients had sufficient airway remodeling allowing for stent removal. CONCLUSIONS: Personalized 3D-designed Y-stents demonstrate promising results for managing complicated airway stenosis, offering improved lung function and potential long-term benefits for lung transplant recipients.


Asunto(s)
Broncoscopía , Trasplante de Pulmón , Siliconas , Stents , Humanos , Trasplante de Pulmón/efectos adversos , Masculino , Femenino , Constricción Patológica/cirugía , Constricción Patológica/etiología , Persona de Mediana Edad , Broncoscopía/métodos , Adulto , Impresión Tridimensional , Anastomosis Quirúrgica/efectos adversos , Volumen Espiratorio Forzado , Complicaciones Posoperatorias/etiología , Tomografía Computarizada por Rayos X , Anciano , Receptores de Trasplantes
5.
J Surg Res ; 300: 448-457, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38870652

RESUMEN

INTRODUCTION: Ventilator-associated pneumonia (VAP) is associated with increased mortality, prolonged mechanical ventilation, and longer intensive care unit stays. The rate of VAP (VAPs per 1000 ventilator days) within a hospital is an important quality metric. Despite adoption of preventative strategies, rates of VAP in injured patients remain high in trauma centers. Here, we report variation in risk-adjusted VAP rates within a statewide quality collaborative. METHODS: Using Michigan Trauma Quality Improvement Program data from 35 American College of Surgeons-verified Level I and Level II trauma centers between November 1, 2020 and January 31, 2023, a patient-level Poisson model was created to evaluate the risk-adjusted rate of VAP across institutions given the number of ventilator days, adjusting for injury severity, physiologic parameters, and comorbid conditions. Patient-level model results were summed to create center-level estimates. We performed observed-to-expected adjustments to calculate each center's risk-adjusted VAP days and flagged outliers as hospitals whose confidence intervals lay above or below the overall mean. RESULTS: We identified 538 VAP occurrences among a total of 33,038 ventilator days within the collaborative, with an overall mean of 16.3 VAPs per 1000 ventilator days. We found wide variation in risk-adjusted rates of VAP, ranging from 0 (0-8.9) to 33.0 (14.4-65.1) VAPs per 1000 d. Several hospitals were identified as high or low outliers. CONCLUSIONS: There exists significant variation in the rate of VAP among trauma centers. Investigation of practices and factors influencing the differences between low and high outlier institutions may yield information to reduce variation and improve outcomes.


Asunto(s)
Neumonía Asociada al Ventilador , Mejoramiento de la Calidad , Centros Traumatológicos , Humanos , Neumonía Asociada al Ventilador/epidemiología , Neumonía Asociada al Ventilador/prevención & control , Neumonía Asociada al Ventilador/etiología , Michigan/epidemiología , Masculino , Femenino , Persona de Mediana Edad , Centros Traumatológicos/estadística & datos numéricos , Adulto , Ajuste de Riesgo/métodos , Anciano , Respiración Artificial/estadística & datos numéricos , Respiración Artificial/efectos adversos
6.
bioRxiv ; 2024 May 28.
Artículo en Inglés | MEDLINE | ID: mdl-38853984

RESUMEN

Metabolic adaptations in response to changes in energy supply and demand are essential for survival. The mitochondrial calcium uniporter coordinates metabolic homeostasis by regulating TCA cycle activation, mitochondrial fatty acid oxidation and cellular calcium signaling. However, a comprehensive analysis of uniporter-regulated mitochondrial metabolic pathways has remained unexplored. Here, we investigate the metabolic consequences of uniporter loss- and gain-of-function, and identify a key transcriptional regulator that mediates these effects. Using gene expression profiling and proteomic, we find that loss of uniporter function increases the expression of proteins in the branched-chain amino acid (BCAA) catabolism pathway. Activity is further augmented through phosphorylation of the enzyme that catalyzes this pathway's committed step. Conversely, in the liver cancer fibrolamellar carcinoma (FLC)-which we demonstrate to have high mitochondrial calcium levels- expression of BCAA catabolism enzymes is suppressed. We also observe uniporter-dependent suppression of the transcription factor KLF15, a master regulator of liver metabolic gene expression, including those involved in BCAA catabolism. Notably, loss of uniporter activity upregulates KLF15, along with its transcriptional target ornithine transcarbamylase (OTC), a component of the urea cycle, suggesting that uniporter hyperactivation may contribute to the hyperammonemia observed in FLC patients. Collectively, we establish that FLC has increased mitochondrial calcium levels, and identify an important role for mitochondrial calcium signaling in metabolic adaptation through the transcriptional regulation of metabolism.

7.
Artículo en Inglés | MEDLINE | ID: mdl-38745357

RESUMEN

BACKGROUND: Trauma patients are at increased risk for venous thromboembolism events (VTE). The decision of when to initiate VTE chemoprophylaxis (VTEP) and with what agent remains controversial in patients with severe traumatic brain injury (TBI). METHODS: This comparative effectiveness study evaluated the impact of timing and agent for VTEP on outcomes for patients with severe TBI (AIS Head = 3,4, or 5). Data was collected at 35 Level 1 and 2 trauma centers from January 1, 2017 to June 1, 2022. Patients were placed into analysis cohorts: No VTEP, low-molecular weight heparin (LMWH) ≤ 48 hours, LMWH>48 hours, Heparin≤48 hours, Heparin>48 hours. Propensity score matching accounting for patient factors and injury characteristics was used with logistic regression modeling to evaluate in-hospital mortality, VTE events, and discharge disposition. Neurosurgical intervention after initiation of VTEP was used to evaluate extension of intracranial hemorrhage. RESULTS: Of 12,879 patients, 32% had no VTEP, 36% LMWH, and 32% Heparin. Overall mortality was 8.3% and lowest among patients receiving LMWH≤48 hours (4.1%). VTE rates were lower with use of LMWH (1.6 vs 4.5%, OR 2.98, 95% CI 1.40-6.34, p = 0.005) without increasing mortality or neurosurgical interventions. VTE rates were lower with early prophylaxis (2.0 vs 3.5%, OR 1.76, 95% CI 1.15-2.71, p = 0.01) without increasing mortality (p = 1.0). Early VTEP was associated with more non-fatal intracranial operations (p < 0.001). However, patients undergoing neurosurgical intervention after VTEP initiation had no difference in rates of mortality, withdrawal of care, or unfavorable discharge disposition (p = 0.7, p = 0.1, p = 0.5). CONCLUSIONS: In patients with severe TBI, LMWH usage was associated with lower VTE incidence without increasing mortality or neurosurgical interventions. Initiation of VTEP≤48 hours decreased VTE incidence and increased non-fatal neurosurgical interventions without affecting mortality. LMWH is the preferred VTEP agent for severe TBI, and initiation ≤48 hours should be considered in relation to these risks and benefits. LEVEL OF EVIDENCE: Therapeutic/Care Management, Level III.

8.
Australas J Ageing ; 2024 May 26.
Artículo en Inglés | MEDLINE | ID: mdl-38798032

RESUMEN

OBJECTIVE: To describe the types of hospital and out-of-hospital services provided by public geriatric medicine departments in Australia and New Zealand, and to explore head of department (HOD) views on issues in current and future service provision. METHODS: An electronic survey was sent to HODs of public geriatric medicine departments. RESULTS: Seventy-six (89%) of 85 identified HODs completed the survey. Seventy-one (93%) departments admit inpatients and 51 (67%) admit acute inpatients, with variable admission criteria. Sixty-four (84%) have hospitals with an inpatient general medicine service, and 58 (91%) of these admit older patients with acute geriatric issues. Sixty (79%) departments provide inpatient rehabilitation. Forty (53%) have beds for behavioural symptoms of dementia and/or delirium. Seventy (92%) provide a proactive orthogeriatric service. In terms of out-of-hospital services, 74 (97%) departments have outpatient clinics, 59 (78%) have telehealth and 68 (89%) perform home visits. Forty-five (59%) provide an inreach/outreach service to nursing homes. The most frequent gaps in service provision identified by HODs were acute geriatrics, surgical liaison, a designated dementia/delirium behavioural management unit, geriatricians in Emergency, outreach/inreach to residential care and shared care with some medical specialities. Increasing staff numbers and government policy change were the most frequently identified ways to address these gaps. CONCLUSIONS: Geriatric medicine service provision is variable across Australia and New Zealand, with key gaps identified. These findings will inform future directions in implementation of geriatric medicine models of care and discussions with various levels of government about the ongoing development of geriatric medicine services.

10.
Artículo en Inglés | MEDLINE | ID: mdl-38685206

RESUMEN

INTRODUCTION: Early operative intervention in orthopaedic injuries is associated with decreased morbidity and mortality. Relevant process measures (e.g. femoral shaft fixation <24 hours) are used in trauma quality improvement programs to evaluate performance. Currently, there is no mechanism to account for patients who are unable to undergo surgical intervention (i.e. physiologically unstable). We characterized the factors associated with patients who did not meet these orthopaedic process measures. METHODS: A retrospective cohort study of patients from 35 ACS-COT verified Level 1 and Level 2 trauma centers was performed utilizing quality collaborative data (2017-2022). Inclusion criteria were adult patients (≥18 years), ISS ≥5, and a closed femoral shaft or open tibial shaft fracture classified via the Abbreviated Injury Scale version 2005 (AIS2005). Relevant factors (e.g. physiologic) associated with a procedural delay >24 hours were identified through a multivariable logistic regression and the effect of delay on inpatient outcomes was assessed. A sub-analysis characterized the rate of delay in "healthy patients". RESULTS: We identified 5,199 patients with a femoral shaft fracture and 87.5% had a fixation procedure, of which 31.8% had a delay, and 47.1% of those delayed were "healthy." There were 1,291 patients with an open tibial shaft fracture, 92.2% had fixation, 50.5% had an irrigation and debridement and 11.2% and 18.7% were delayed, respectively. High ISS, older age and multiple medical comorbidities were associated with a delay in femur fixation, and those delayed had a higher incidence of complications. CONCLUSIONS: There is a substantial incidence of surgical delays in some orthopaedic trauma process measures that are predicted by certain patient characteristics, and this is associated with an increased rate of complications. Understanding these factors associated with a surgical delay, and effectively accounting for them, is key if these process measures are to be used appropriately in quality improvement programs. LEVEL OF EVIDENCE: Level III; Therapeutic/Care Management.

11.
Small ; : e2400646, 2024 Apr 30.
Artículo en Inglés | MEDLINE | ID: mdl-38686673

RESUMEN

The elastic interaction between kinks (and antikinks) within domain walls plays a pivotal role in shaping the domain structure, and their dynamics. In bulk materials, kinks interact as elastic monopoles, dependent on the distance between walls (d-1) and typically characterized by a rigid and straight domain configuration. In this work the evolution of the domain structure is investigated, as the sample size decreases, by the means of in situ heating microscopy techniques on free-standing samples. As the sample size decreases, a significant transformation is observed: domain walls exhibit pronounced curvature, accompanied by an increase in both domain wall and junction density. This transformation is attributed to the pronounced influence of kinks, inducing sample warping, where "dipole-dipole" interactions are dominant (d-2). Moreover, a critical thickness range that delineates a crossover between the monopolar and dipolar regimens is experimentally identified and corroborated by atomic simulations. These findings are relevant for in situ TEM studies and for the development of novel devices based on free-standing ferroic thin films and nanomaterials.

12.
Lancet Glob Health ; 12(5): e859-e867, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38614633

RESUMEN

BACKGROUND: People who inject drugs are at increased risk of both HIV and hepatitis C virus (HCV) infections but face barriers to testing and engagement in care. Assisted partner services are effective in locating people with HIV but are understudied among people who inject drugs. We assessed whether assisted partner services could be used to find, test for HIV and HCV infections, and link to care the partners of people who inject drugs in Kenya. METHODS: In this prospective study at eight sites offering harm-reduction services in Kenya, we enrolled people aged 18 years or older who inject drugs and were living with HIV (index participants) between Feb 27, 2018, and Nov 1, 2021. Index participants provided information about their sexual and injecting partners (ie, anyone with whom they had had sexual intercourse or injected drugs in the previous 3 years), and then community-embedded peer educators located partners and referred them for enrolment in the study (partner participants). All participants underwent testing for HCV infection, and partner participants also underwent HIV testing. Index and partner participants with HIV but who were not on antiretroviral therapy (ART) were linked with treatment services, and those positive for HCV were linked to treatment with direct-acting antivirals. We calculated the number of index participants whom we needed to interview to identify partner participants with HIV and HCV infection. FINDINGS: We enrolled 989 people living with HIV who inject drugs, who mentioned 4705 sexual or injecting partners. Of these 4705 partners, we enrolled 4597 participants, corresponding to 3323 unique individuals. 597 (18%) partner participants had HIV, of whom 506 (85%) already knew their status. 358 (71%) of those who knew they were HIV positive were virally suppressed. 393 (12%) partner participants were HCV antibody positive, 213 (54%) of whom had viraemia and 104 (26%) of whom knew their antibody status. 1·66 (95% CI 1·53-1·80) index participants had to be interviewed to identify a partner with HIV, and 4·24 (3·75-4·85) had to be interviewed to find a partner living with HIV who was unaware of their HIV status, not on ART, or not virally suppressed. To find a partner seropositive for HCV who did not know their antibody status, 3·47 (3·11-3·91) index participants needed to be interviewed. Among the 331 index and partner participants living with HIV who were not on ART at enrolment, 238 (72%) were taking ART at 6-month follow-up. No adverse events were attributed to study procedures. INTERPRETATION: Use of assisted partner services among people with HIV who inject drugs was safe and identified partners with HIV and HCV infections. Assisted partner services was associated with increased uptake of ART for both index participants and partners. FUNDING: US National Institutes of Health.


Asunto(s)
Consumidores de Drogas , Hepatitis C Crónica , Hepatitis C , Estados Unidos , Humanos , Hepacivirus , Estudios Prospectivos , Kenia/epidemiología , Antivirales , Hepatitis C/epidemiología
14.
Health Aff (Millwood) ; 43(3): 363-371, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38437607

RESUMEN

Primary care physicians are often the first to screen and identify patients with access-sensitive surgical conditions that should be treated electively. These conditions require surgery that is preferably planned (elective), but, when access is limited, treatment may be delayed and worsening symptoms lead to emergency surgery (for example, colectomy for cancer, abdominal aortic aneurysm repair, and incisional hernia repair). We evaluated the rates of elective versus emergency surgery for patients with three access-sensitive surgical conditions living in primary care Health Professional Shortage Areas during 2015-19. Medicare beneficiaries in more severe primary care shortage areas had higher rates of emergency surgery compared with rates in the least severe shortage areas (37.8 percent versus 29.9 percent). They were also more likely to have serious complications (14.9 percent versus 11.7 percent) and readmissions (15.7 percent versus 13.5 percent). When we accounted for areas with a shortage of surgeons, the findings were similar. Taken together, these findings suggest that residents of areas with greater primary care workforce shortages may also face challenges in accessing elective surgical care. As policy makers consider investing in Health Professional Shortage Areas, our findings underscore the importance of primary care access to a broader range of services.


Asunto(s)
Readmisión del Paciente , Cirujanos , Estados Unidos , Humanos , Anciano , Medicare , Procedimientos Quirúrgicos Electivos , Atención Primaria de Salud
15.
J Ambul Care Manage ; 47(2): 51-63, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38441558

RESUMEN

Learning collaboratives are seldom used outside of health care quality improvement. We describe a condensed, 10-week learning collaborative ("Telemedicine Hack") that facilitated telemedicine implementation for outpatient clinicians early in the COVID-19 pandemic. Live attendance averaged 1688 participants per session. Of 1005 baseline survey respondents, 57% were clinicians with one-third identifying as from a racial/ethnic minoritized group. Practice characteristics included primary care (71%), rural settings (51%), and community health centers (28%). Of three surveys, a high of 438 (81%) of 540 clinicians had billed ≥1 video-based telemedicine visit. Our learning collaborative "sprint" is a promising model for scaling knowledge during emergencies and addressing health inequities.


Asunto(s)
COVID-19 , Telemedicina , Humanos , Pandemias , Pacientes Ambulatorios , COVID-19/epidemiología , Centros Comunitarios de Salud
16.
Open Forum Infect Dis ; 11(3): ofae080, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38449917

RESUMEN

The current landscape of clinician burnout is prompting the need for our health care system to revise its approach toward complex conditions such as long coronavirus disease (COVID), myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and other postinfectious fatiguing illnesses (PIFIs). We discuss our efforts here at Family Health Center of San Diego (FHCSD) to help share insight and glean perspective from clinicians who have participated in our Centers for Disease Control and Prevention (CDC)-funded 3-year continuing professional development initiative. The Long COVID and Fatiguing Illness Recovery Program uses multidisciplinary team-based case consultation and peer-to-peer sharing of emerging best and promising practices (ie, teleECHO [Extension for Community Healthcare Outcomes]) to support the management of complex cases associated with long COVID, ME/CFS, and other PIFIs. We believe that this perspective captures a key moment in the trajectory of postpandemic clinician burnout and prompts further reflection and action from the health care system to improve clinician- and patient-level outcomes related to the care of patients with postinfectious fatiguing illnesses.

17.
J Trauma Acute Care Surg ; 96(6): 986-991, 2024 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-38439149

RESUMEN

ABSTRACT: Acute care surgery (ACS) patients are frequently faced with significant long-term recovery and financial implications that extend far beyond their hospitalization. While major injury and emergency general surgery (EGS) emergencies are often viewed solely as acute moments of crisis, the impact on patients can be lifelong. Financial outcomes after major injury or emergency surgery have only begun to be understood. The Healthcare Economics Committee from the American Association for the Surgery of Trauma previously published a conceptual overview of financial toxicity in ACS, highlighting the association between financial outcomes and long-term physical recovery. The aims of second-phase financial toxicity review by the Healthcare Economics Committee of the American Association for the Surgery of Trauma are to (1) understand the unique impact of financial toxicity on ACS patients; (2) delineate the current limitations surrounding measurement domains of financial toxicity in ACS; (3) explore the "when, what and how" of optimally capturing financial outcomes in ACS; and (4) delineate next steps for integration of these financial metrics in our long-term patient outcomes. As acute care surgeons, our patients' recovery is often contingent on equal parts physical, emotional, and financial recovery. The ACS community has an opportunity to impact long-term patient outcomes and well-being far beyond clinical recovery.


Asunto(s)
Heridas y Lesiones , Humanos , Estados Unidos , Heridas y Lesiones/cirugía , Heridas y Lesiones/economía , Procedimientos Quirúrgicos Operativos/economía , Cuidados Críticos/economía , Cirugía de Cuidados Intensivos
18.
Sci Adv ; 10(8): eadl1258, 2024 Feb 23.
Artículo en Inglés | MEDLINE | ID: mdl-38381834

RESUMEN

Adrenal Cushing's syndrome is a disease of cortisol hypersecretion often caused by mutations in protein kinase A catalytic subunit (PKAc). Using a personalized medicine screening platform, we discovered a Cushing's driver mutation, PKAc-W196G, in ~20% of patient samples analyzed. Proximity proteomics and photokinetic imaging reveal that PKAcW196G is unexpectedly distinct from other described Cushing's variants, exhibiting retained association with type I regulatory subunits (RI) and their corresponding A kinase anchoring proteins (AKAPs). Molecular dynamics simulations predict that substitution of tryptophan-196 with glycine creates a 653-cubic angstrom cleft between the catalytic core of PKAcW196G and type II regulatory subunits (RII), but only a 395-cubic angstrom cleft with RI. Endocrine measurements show that overexpression of RIα or redistribution of PKAcW196G via AKAP recruitment counteracts stress hormone overproduction. We conclude that a W196G mutation in the kinase catalytic core skews R subunit selectivity and biases AKAP association to drive Cushing's syndrome.


Asunto(s)
Síndrome de Cushing , Humanos , Síndrome de Cushing/genética , Proteínas de Anclaje a la Quinasa A/genética , Proteínas de Anclaje a la Quinasa A/metabolismo , Transducción de Señal , Dominio Catalítico , Sesgo
19.
Trends Biochem Sci ; 49(4): 305-317, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38310024

RESUMEN

Louis Pasteur once famously said 'in the fields of observation chance favors only the prepared mind'. Much of chance is being in the right place at the right time. This is particularly true in the crowded molecular environment of the cell where being in the right place is often more important than timing. Although Brownian motion argues that enzymes will eventually bump into substrates, this probability is greatly enhanced if both molecules reside in the same subcellular compartment. However, activation of cell signaling enzymes often requires the transmission of chemical signals from extracellular stimuli to intracellular sites of action. This review highlights new developments in our understanding of cAMP generation and the 3D utilization of this second messenger inside cells.


Asunto(s)
AMP Cíclico , Transducción de Señal , Transducción de Señal/fisiología
20.
JAMA Surg ; 159(4): 420-427, 2024 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-38324286

RESUMEN

Importance: Access-sensitive surgical conditions, such as abdominal aortic aneurysm, ventral hernia, and colon cancer, are ideally treated with elective surgery, but when left untreated have a natural history requiring an unplanned operation. Patients' health insurance status may be a barrier to receiving timely elective care, which may be associated with higher rates of unplanned surgery and worse outcomes. Objective: To evaluate the association between patients' insurance status and rates of unplanned surgery for these 3 access-sensitive surgical conditions and postoperative outcomes. Design, Setting, and Participants: This cross-sectional cohort study examined a geographically broad patient sample from the Healthcare Cost and Utilization Project State Inpatient Databases, including data from 8 states (Arizona, Colorado, Florida, Kentucky, Maryland, North Carolina, Washington, and Wisconsin). Participants were younger than 65 years who underwent abdominal aortic aneurysm repair, ventral hernia repair, or colectomy for colon cancer between 2016 and 2020. Patients were stratified into groups by insurance status. Data were analyzed from June 1 to July 1, 2023. Exposure: Health insurance status (private insurance, Medicaid, or no insurance). Main Outcomes and Measures: The primary outcome was the rate of unplanned surgery for these 3 access-sensitive conditions. Secondary outcomes were rates of postoperative outcomes including inpatient mortality, any hospital complications, serious complications (a complication with a hospital length of stay longer than the 75th percentile for that procedure), and hospital length of stay. Results: The study included 146 609 patients (mean [SD] age, 50.9 [10.3] years; 73 871 females [50.4%]). A total of 89 018 patients (60.7%) underwent elective surgery while 57 591 (39.3%) underwent unplanned surgery. Unplanned surgery rates varied significantly across insurance types (33.14% for patients with private insurance, 51.46% for those with Medicaid, and 72.60% for those without insurance; P < .001). Compared with patients with private insurance, patients without insurance had higher rates of inpatient mortality (1.29% [95% CI, 1.04%-1.54%] vs 0.61% [0.57%-0.66%]; P < .001), higher rates of any complications (19.19% [95% CI, 18.33%-20.05%] vs 12.27% [95% CI, 12.07%-12.47%]; P < .001), and longer hospital stays (7.27 [95% CI, 7.09-7.44] days vs 5.56 [95% CI, 5.53-5.60] days, P < .001). Conclusions and Relevance: Findings of this cohort study suggest that uninsured patients more often undergo unplanned surgery for conditions that can be treated electively, with worse outcomes and longer hospital stays compared with their counterparts with private health insurance. As efforts are made to improve insurance coverage, tracking elective vs unplanned surgery rates for access-sensitive surgical conditions may be a useful measure to assess progress.


Asunto(s)
Aneurisma de la Aorta Abdominal , Neoplasias del Colon , Hernia Ventral , Femenino , Estados Unidos , Humanos , Persona de Mediana Edad , Estudios de Cohortes , Estudios Transversales , Seguro de Salud , Aneurisma de la Aorta Abdominal/cirugía
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