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1.
J Am Geriatr Soc ; 2024 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-38725422

RESUMO

BACKGROUND: Potentially inappropriate medications (PIMs) are associated with worse health outcomes among older adults. Our objective was to examine the association between PIM prescription and health-related quality of life (HRQoL) among older adults in the United States using nationally representative data. METHODS: This was a retrospective study utilizing 2011-2015 Medical Expenditure Panel Survey (MEPS) data. Community dwelling US adults aged 65 years or older were included. A qualified definition operationalized from the 2019 American Geriatrics Society Beers Criteria® was used to define exposure to PIMs during the study period. The Physical Component Summary (PCS) and Mental Component Summary (MCS) of the Medical Outcomes Study 12-Item Short Form Health Survey (SF-12) were used to measure HRQoL. Survey-weighted linear regression models were constructed to investigate the association between PIM exposure and participants' PCS and MCS scores. Analyses were stratified across three age cohorts (65-74, 75-85, and ≥85 years). RESULTS: Unadjusted analysis showed poorer scores in the PIM exposed group for both PCS and MCS (all p < 0.001). PIM exposure was associated with poorer PCS scores across all age groups with those aged 65-74 years (adjusted regression coefficient = -1.60 [95% CI = -2.27, -0.93; p < 0.001]), those 75-84 years (adjusted regression coefficient: -1.49 [95% CI = -2.45, -0.53; p = 0.003]), and those 85 years and older (adjusted regression coefficient = -1.65 [95% CI = -3.03, -0.27; p = 0.02]). PIM exposure was also associated with poorer MCS scores in participants aged 65-74 years (adjusted regression coefficient = -0.69 [95% CI = -1.16, -0.22; p = 0.004]) and 85 years and older (adjusted regression coefficient = -2.01 [95% CI = -3.25, -0.78; p = 0.002]). CONCLUSIONS: Our results suggest that patients' exposure to PIMs is associated with poorer HRQoL. Further work is needed to assess whether interventions to deprescribe PIMs may help to improve patients' HRQoL.

2.
Nat Commun ; 15(1): 3741, 2024 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-38702301

RESUMO

Targeted therapy is effective in many tumor types including lung cancer, the leading cause of cancer mortality. Paradigm defining examples are targeted therapies directed against non-small cell lung cancer (NSCLC) subtypes with oncogenic alterations in EGFR, ALK and KRAS. The success of targeted therapy is limited by drug-tolerant persister cells (DTPs) which withstand and adapt to treatment and comprise the residual disease state that is typical during treatment with clinical targeted therapies. Here, we integrate studies in patient-derived and immunocompetent lung cancer models and clinical specimens obtained from patients on targeted therapy to uncover a focal adhesion kinase (FAK)-YAP signaling axis that promotes residual disease during oncogenic EGFR-, ALK-, and KRAS-targeted therapies. FAK-YAP signaling inhibition combined with the primary targeted therapy suppressed residual drug-tolerant cells and enhanced tumor responses. This study unveils a FAK-YAP signaling module that promotes residual disease in lung cancer and mechanism-based therapeutic strategies to improve tumor response.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Resistencia a Medicamentos Antineoplásicos , Neoplasias Pulmonares , Transdução de Sinais , Fatores de Transcrição , Proteínas de Sinalização YAP , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Proteínas de Sinalização YAP/metabolismo , Linhagem Celular Tumoral , Animais , Resistencia a Medicamentos Antineoplásicos/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Neoplasia Residual , Camundongos , Quinase 1 de Adesão Focal/metabolismo , Quinase 1 de Adesão Focal/genética , Receptores ErbB/metabolismo , Receptores ErbB/genética , Quinase do Linfoma Anaplásico/metabolismo , Quinase do Linfoma Anaplásico/genética , Quinase do Linfoma Anaplásico/antagonistas & inibidores , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Circ Cardiovasc Imaging ; 17(4): e016415, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38563143

RESUMO

BACKGROUND: In heart transplant recipients, right ventricular (RV) dysfunction may occur for a variety of reasons. Whether RV dysfunction in the stable phase after heart transplantation is associated with long-term adverse outcomes is unknown. We aimed to determine the long-term prognostic significance of RV dysfunction identified on cardiovascular magnetic resonance imaging (CMR) at least 1 year after heart transplantation. METHODS: In consecutive heart transplant recipients who underwent CMR for surveillance, we assessed 2 CMR measures of RV function: RV ejection fraction and RV global longitudinal strain (RVGLS). We investigated associations between RV dysfunction and a composite end point of death or major adverse cardiac events, including retransplantation, nonfatal myocardial infarction, coronary revascularization, and heart failure hospitalization. RESULTS: A total of 257 heart transplant recipients (median age, 59 years; 75% men) who had CMR at a median of 4.3 years after heart transplantation were included. Over a median follow-up of 4.4 years after the CMR, 108 recipients experienced death or major adverse cardiac events. In a multivariable Cox regression analysis adjusted for age, time since transplantation, indication for transplantation, cardiac allograft vasculopathy, history of rejection, and CMR covariates, RV ejection fraction was not associated with the composite end point, but RVGLS was independently associated with the composite end point with a hazard ratio of 1.08 per 1% worsening in RVGLS ([95% CI, 1.00-1.17]; P=0.046). RVGLS provided incremental prognostic value over other variables in multivariable analyses. The association was replicated in subgroups of recipients with normal RV ejection fraction and recipients with late gadolinium enhancement imaging. A similar association was seen with a composite end point of cardiovascular death or major adverse cardiac events. CONCLUSIONS: CMR feature tracking-derived RVGLS assessed at least 1 year after heart transplantation was independently associated with the long-term risk of death or major adverse cardiac events. Future studies should investigate its role in guiding clinical decision-making in heart transplant recipients.


Assuntos
Transplante de Coração , Infarto do Miocárdio , Masculino , Humanos , Pessoa de Meia-Idade , Feminino , Imagem Cinética por Ressonância Magnética , Função Ventricular Direita , Meios de Contraste , Fatores de Risco , Valor Preditivo dos Testes , Gadolínio , Imageamento por Ressonância Magnética , Volume Sistólico , Transplante de Coração/efeitos adversos , Prognóstico , Função Ventricular Esquerda
4.
Nat Cancer ; 2024 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-38637658

RESUMO

Tailoring optimal treatment for individual cancer patients remains a significant challenge. To address this issue, we developed PERCEPTION (PERsonalized Single-Cell Expression-Based Planning for Treatments In ONcology), a precision oncology computational pipeline. Our approach uses publicly available matched bulk and single-cell (sc) expression profiles from large-scale cell-line drug screens. These profiles help build treatment response models based on patients' sc-tumor transcriptomics. PERCEPTION demonstrates success in predicting responses to targeted therapies in cultured and patient-tumor-derived primary cells, as well as in two clinical trials for multiple myeloma and breast cancer. It also captures the resistance development in patients with lung cancer treated with tyrosine kinase inhibitors. PERCEPTION outperforms published state-of-the-art sc-based and bulk-based predictors in all clinical cohorts. PERCEPTION is accessible at https://github.com/ruppinlab/PERCEPTION . Our work, showcasing patient stratification using sc-expression profiles of their tumors, will encourage the adoption of sc-omics profiling in clinical settings, enhancing precision oncology tools based on sc-omics.

5.
PLoS One ; 19(4): e0300348, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38687705

RESUMO

The sarcomere is the fundamental contractile unit in skeletal muscle, and the regularity of its structure is critical for function. Emerging data demonstrates that nanoscale changes to the regularity of sarcomere structure can affect the overall function of the protein dense ~2µm sarcomere. Further, sarcomere structure is implicated in many clinical conditions of muscle weakness. However, our understanding of how sarcomere structure changes in disease, especially at the nanoscale, has been limited in part due to the inability to robustly detect and measure at sub-sarcomere resolution. We optimized several methodological steps and developed a robust pipeline to analyze sarcomere structure using structured illumination super-resolution microscopy in conjunction with commercially-available and fluorescently-conjugated Variable Heavy-Chain only fragment secondary antibodies (nanobodies), and achieved a significant increase in resolution of z-disc width (353nm vs. 62nm) compared to confocal microscopy. The combination of these methods provides a unique approach to probe sarcomere protein localization at the nanoscale and may prove advantageous for analysis of other cellular structures.


Assuntos
Sarcômeros , Anticorpos de Domínio Único , Sarcômeros/metabolismo , Sarcômeros/ultraestrutura , Anticorpos de Domínio Único/química , Animais , Microscopia de Fluorescência/métodos , Camundongos , Microscopia Confocal/métodos
6.
Neurol Neuroimmunol Neuroinflamm ; 11(4): e200243, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38630950

RESUMO

Acute disseminated encephalomyelitis (ADEM) is one characteristic manifestation of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). A previously healthy man presented with retro-orbital headache and urinary retention 14 days after Tdap vaccination. Brain and spine MRI suggested a CNS demyelinating process. Despite treatment with IV steroids, he deteriorated, manifesting hemiparesis and later impaired consciousness, requiring intubation. A repeat brain MRI demonstrated new bilateral supratentorial lesions associated with venous sinus thrombosis, hemorrhage, and midline shift. Anti-MOG antibody was present at a high titer. CSF IL-6 protein was >2,000 times above the upper limits of normal. He improved after plasma exchange, then began monthly treatment alone with anti-IL-6 receptor antibody, tocilizumab, and has remained stable. This case highlights how adult-onset MOGAD, like childhood ADEM, can rapidly become life-threatening. The markedly elevated CSF IL-6 observed here supports consideration for evaluating CSF cytokines more broadly in patients with acute MOGAD.


Assuntos
Encefalomielite Aguda Disseminada , Masculino , Adulto , Humanos , Criança , Interleucina-6/metabolismo , Glicoproteína Mielina-Oligodendrócito , Encéfalo/patologia , Citocinas/metabolismo
8.
Urogynecology (Phila) ; 30(3): 381-387, 2024 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-38484257

RESUMO

IMPORTANCE: The associated effect of duration of the second stage of labor (SSL) on pelvic floor symptoms development is not well studied. OBJECTIVE: This study aimed to examine the association between duration of SSL and pelvic floor symptoms at 6 months postpartum among primiparous women. STUDY DESIGN: A planned secondary analysis of a multicenter randomized trial evaluating the impact of immediate versus delayed pushing on vaginal delivery rates, maternal morbidity, and neonatal outcomes was conducted between 2014 and 2018. For pelvic floor arm participants, demographic, pelvic examination, and validated questionnaire data were collected postpartum. Primary outcome was change in Pelvic Floor Distress Inventory 20 (PFDI-20) score from immediate to 6 months postpartum. Secondary outcomes included changes in the Pelvic Floor Impact Questionnaire, Fecal Incontinence Severity Index, Modified Manchester Health Questionnaire scores, and Pelvic Organ Prolapse Quantification measurements at 6 months postpartum. Participants were analyzed by SSL duration ≤60 minutes or >60 minutes. RESULTS: Of the 2,414 trial participants, 767 (32%) completed pelvic floor assessments at 6 months. Pelvic Floor Distress Inventory 20 scores significantly improved at 6 months in the ≤60 minutes SSL group compared with >60 minutes SSL (-14.3 ± 48.0 and -3.2 ± 45.3, respectively; P = 0.04). Changes from immediate postpartum in total and subscale scores for other questionnaires at 6 months did not differ between groups. Prolapse stage did not differ between groups. Perineal body was significantly shorter in the >60 minutes SSL group (3.7 ± 0.7, 3.5 ± 0.8; P = 0.03). CONCLUSIONS: Women with SSL >60 minutes experience less improvement in PFDI-20 scores at 6 months. Greater tissue and innervation trauma in those with SSL >60 minutes may explain persistently less improvement in PFDI-20 scores.


Assuntos
Incontinência Fecal , Prolapso de Órgão Pélvico , Gravidez , Recém-Nascido , Feminino , Humanos , Diafragma da Pelve , Segunda Fase do Trabalho de Parto , Incontinência Fecal/epidemiologia , Período Pós-Parto
9.
Curr Probl Cancer ; 49: 101065, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38341356

RESUMO

The mitogen-activated protein kinase (MAPK or MEK) pathway modulates tumor cell survival and proliferation in non-small cell lung cancer (NSCLC). Unlike RAS or EGFR, activating mutations in MEK are exceedingly rare in NSCLC. Instead, enhanced activation of the MEK pathway is often linked to increased signaling by upstream oncogenic driver mutations. Thus far, MEK inhibitor monotherapy has shown little promise. However, treatment strategies involving MEK inhibition in combination with other targeted therapies in other oncogene-driven NSCLC has proven to be encouraging. For example, MEK inhibition - when combined with BRAF inhibition, - has shown strong anti-tumor activity in BRAF V600 mutated NSCLC. In this review, recent data on MEK inhibitor strategies in NSCLC are summarized. Furthermore, ongoing early phase trials investigating MEK inhibitor combination therapy with immunotherapy, chemotherapy and other oncogene drivers are highlighted. These and other studies could help inform future rational combination strategies of MEK-ERK inhibition in oncogene-driven NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Inibidores de Proteínas Quinases , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Terapia de Alvo Molecular/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Mutação
10.
Aging Cell ; : e14094, 2024 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-38332629

RESUMO

Oxidative stress is considered a contributor to declining muscle function and mobility during aging; however, the underlying molecular mechanisms remain poorly described. We hypothesized that greater levels of cysteine (Cys) oxidation on muscle proteins are associated with decreased measures of mobility. Herein, we applied a novel redox proteomics approach to measure reversible protein Cys oxidation in vastus lateralis muscle biopsies collected from 56 subjects in the Study of Muscle, Mobility and Aging (SOMMA), a community-based cohort study of individuals aged 70 years and older. We tested whether levels of Cys oxidation on key muscle proteins involved in muscle structure and contraction were associated with muscle function (leg power and strength), walking speed, and fitness (VO2 peak on cardiopulmonary exercise testing) using linear regression models adjusted for age, sex, and body weight. Higher oxidation levels of select nebulin Cys sites were associated with lower VO2 peak, while greater oxidation of myomesin-1, myomesin-2, and nebulin Cys sites was associated with slower walking speed. Higher oxidation of Cys sites in key proteins such as myomesin-2, alpha-actinin-2, and skeletal muscle alpha-actin were associated with lower leg power and strength. We also observed an unexpected correlation (R = 0.48) between a higher oxidation level of eight Cys sites in alpha-actinin-3 and stronger leg power. Despite this observation, the results generally support the hypothesis that Cys oxidation of muscle proteins impairs muscle power and strength, walking speed, and cardiopulmonary fitness with aging.

11.
J Neuroophthalmol ; 2024 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-38324479

RESUMO

ABSTRACT: A 19-year-old man presented with 3 years of gradually progressive, painless vision loss in both eyes. The ophthalmic examination showed bilateral diminished visual acuity, dyschromatopsia, and temporal optic nerve pallor. The neurological examination was consistent with a mild myelopathy with decreased pin-prick sensation starting at T6-T7 and descending through the lower extremities. Hyperreflexia was also present in the lower more than upper extremities. Infectious, inflammatory, and nutritional serum workup and cerebrospinal fluid analysis were both unrevealing. MRI of the brain and spinal cord showed abnormal T2 hyperintensity of the fornix, corpus callosum, optic nerves, and lateral columns of the cervical and thoracic spine, with diffusion restriction in the inferior-posterior corpus callosum and fornix. Biotinidase serum enzyme activity was tested and showed a decreased level of activity. Biotinidase gene testing showed a homozygous pathogenic variant, c.424C>A (p.P142T), confirming the diagnosis of biotinidase deficiency and prompting oral biotin supplementation. Three months after starting treatment, the patient's visual acuity, color vision, visual fields, and MRI spine abnormalities all improved significantly. Biotinidase deficiency is an important diagnostic consideration in patients with unexplained optic neuropathy and/or myelopathy.

12.
Cureus ; 16(1): e51522, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38304669

RESUMO

Spinal cord ischemia (SCI) is an uncommon but serious complication of thoracic endovascular aortic repair (TEVAR). SCI after TEVAR is thought to result from decreased segmental blood supply to an important network of collateral blood flow in the spinal cord. Little is known about the prevalence and optimal treatment of SCI that occurs beyond the periprocedural period. We report a case of delayed SCI in a 67-year-old patient who underwent TEVAR. The patient presented almost two years after TEVAR with acute paraplegia preceded by pre-syncope. The delayed SCI was likely triggered by pre-syncope, a thrombosed endoleak shown on imaging, and the patient's vascular risk factors. Treatments included cerebrospinal fluid (CSF) drainage, mean arterial pressure (MAP) augmentation, and a naloxone infusion, which resulted in moderate recovery in lower extremity motor function. This case highlights the tenuous nature of spinal cord perfusion after TEVAR and that prompt recognition and early treatment of SCI are critical in preventing the progression from ischemia to infarction.

13.
Mil Med ; 2024 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-38243767

RESUMO

INTRODUCTION: Military trainees are at increased risk for infectious disease outbreaks because of the unique circumstances of the training environment (e.g., close proximity areas and physiologic/psychologic stress). Standard medical countermeasures in military training settings include routine immunization (e.g., influenza and adenovirus) as well as chemoprophylaxis [e.g., benzathine penicillin G (Bicillin) for the prevention of group A streptococcal disease] for pathogens associated with outbreaks in these settings. In a population of U.S. Army Infantry trainees, we evaluated changes in the oral microbiome during a 14-week military training cycle. MATERIALS AND METHODS: Trainees were enrolled in an observational cohort study in 2015-2016. In 2015, Bicillin was administered to trainees to ameliorate the risk of group A Streptococcus outbreaks, whereas in 2016, trainees did not receive a Bicillin inoculation. Oropharyngeal swabs were collected from participants at days 0, 7, 14, 28, 56, and 90 of training. Swabs were collected, flash frozen, and stored. DNA was extracted from swabs, and amplicon sequencing of the 16s rRNA gene was performed. Microbiome dynamics were evaluated using the QIIME 2 workflow along with DADA2, SINA with SILVA, and an additional processing in R. RESULTS: We observed that microbiome samples from the baseline (day 0) visit were distinct from one another, whereas samples collected on day 14 exhibited significant microbiome convergence. Day 14 convergence was coincident with an increase in DNA sequences associated with Streptococcus, though there was not a significant difference between Streptococcus abundance over time between 2015 and 2016 (P = .07), suggesting that Bicillin prophylaxis did not significantly impact overall Streptococcus abundance. CONCLUSIONS: The temporary convergence of microbiomes is coincident with a rise in communicable infections in this population. The dynamic response of microbiomes during initial military training supports similar observations in the literature of transient convergence of the human microbiome under cohabitation in the time frame including in this experiment. This population and the associated longitudinal studies allow for controlled studies of human microbiome under diverse conditions.

14.
Clin Neuroradiol ; 2024 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-38172261

RESUMO

PURPOSE: To determine a potential threshold optic nerve diameter (OND) that could reliably differentiate healthy nerves from those affected by optic atrophy (OA) and to determine correlations of OND in OA with retinal nerve fiber layer (RNFL) thickness, visual acuity (VA), and visual field mean deviation (VFMD). METHODS: This was a retrospective case control study. Magnetic resonance (MR) images were reviewed from individuals with OA aged 18 years or older with vision loss for more than 6 months and an OA diagnosis established by a neuro-ophthalmologist. Individuals without OA who underwent MR imaging of the orbit for other purposes were also collected. OND was measured on coronal T2-weighted images in the midorbital section, 1cm posterior to the optic disc. Measurements of mean RNFL thickness, VA and VFMD were also collected. RESULTS: In this study 47 OA subjects (63% women, 78 eyes) and 75 normal subjects (42.7% women, 127 eyes) were assessed. Healthy ONDs (mean 2.73 ± 0.24 mm) were significantly greater than OA nerve diameters (mean 1.94 ± 0.32 mm; P < 0.001). A threshold OND of ≤2.3 mm had a sensitivity of 0.92 and a specificity of 0.93 in predicting OA. Mean RNFL (r = 0.05, p = 0.68), VA (r = 0.17, p = 0.14), and VFMD (r = 0.18, p = 0.16) were not significantly associated with OND. CONCLUSION: ONDs are significantly reduced in patients with OA compared with healthy nerves. A threshold OND of ≤2.3 mm is highly sensitive and specific for a diagnosis of OA. OND was not significantly correlated with RNFL thickness, VA, or VFMD.

15.
BMC Musculoskelet Disord ; 25(1): 46, 2024 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-38200469

RESUMO

BACKGROUND: Patients who undergo lumbar discectomy may experience ongoing lumbosacral radiculopathy (LSR) and seek spinal manipulative therapy (SMT) to manage these symptoms. We hypothesized that adults receiving SMT for LSR at least one year following lumbar discectomy would be less likely to undergo lumbar spine reoperation compared to matched controls not receiving SMT, over two years' follow-up. METHODS: We searched a United States network of health records (TriNetX, Inc.) for adults aged ≥ 18 years with LSR and lumbar discectomy ≥ 1 year previous, without lumbar fusion or instrumentation, from 2003 to 2023. We divided patients into two cohorts: (1) chiropractic SMT, and (2) usual care without chiropractic SMT. We used propensity matching to adjust for confounding variables associated with lumbar spine reoperation (e.g., age, body mass index, nicotine dependence), calculated risk ratios (RR), with 95% confidence intervals (CIs), and explored cumulative incidence of reoperation and the number of SMT follow-up visits. RESULTS: Following propensity matching there were 378 patients per cohort (mean age 61 years). Lumbar spine reoperation was less frequent in the SMT cohort compared to the usual care cohort (SMT: 7%; usual care: 13%), yielding an RR (95% CIs) of 0.55 (0.35-0.85; P = 0.0062). In the SMT cohort, 72% of patients had ≥ 1 follow-up SMT visit (median = 6). CONCLUSIONS: This study found that adults experiencing LSR at least one year after lumbar discectomy who received SMT were less likely to undergo lumbar spine reoperation compared to matched controls not receiving SMT. While these findings hold promise for clinical implications, they should be corroborated by a prospective study including measures of pain, disability, and safety to confirm their relevance. We cannot exclude the possibility that our results stem from a generalized effect of engaging with a non-surgical clinician, a factor that may extend to related contexts such as physical therapy or acupuncture. REGISTRATION: Open Science Framework ( https://osf.io/vgrwz ).


Assuntos
Manipulação da Coluna , Adulto , Humanos , Pessoa de Meia-Idade , Reoperação , Estudos Prospectivos , Estudos Retrospectivos , Discotomia/efeitos adversos
16.
Cancer Med ; 2024 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-38186321

RESUMO

BACKGROUND: Immunotherapies have changed the landscape of late-stage melanoma; however, data evaluating timely access to immunotherapy are lacking. METHODS: A retrospective cohort study utilizing the National Cancer Database was conducted. Stage III and IV melanoma cases diagnosed between 2011 and 2018 that received systemic treatment with either immunotherapy or chemotherapy were included. Chemotherapy included BRAF/MEK inhibitors. Multivariable logistic regression models were utilized to evaluate factors associated with the likelihood of receiving immunotherapy as primary systemic treatment relative to chemotherapy; additionally, Cox proportional hazards models were utilized to incorporate time from diagnosis to primary systemic therapy into the analysis. RESULTS: The study population was comprised of 14,446 cases. The cohort included 12,053 (83.4%) immunotherapy and 2393 (16.6%) chemotherapy cases. In multivariable logistic regression analysis, factors significantly associated with immunotherapy receipt included population density, circle distance, year of diagnosis, Breslow thickness, and cancer stage. Immunotherapy timing was evaluated using multivariable Cox regression analysis. Minorities were less likely to receive timely immunotherapy than non-Hispanic Whites (HR 0.83, CI 0.74-0.93, p = 0.001). Patients at circle distances of 10-49 miles (HR 0.94, CI 0.89-0.99, p = 0.02) and ≥50 miles (HR 0.83, CI 0.77-0.90, p < 0.001) were less likely to receive timely immunotherapy. CONCLUSION: Patients traveling ≥10 miles and minorities have a decreased likelihood of receiving timely immunotherapy administration for primary systemic treatment. Future research is needed to identify what barriers and approaches can be leveraged to address these inequities.

18.
Nat Genet ; 56(1): 60-73, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38049664

RESUMO

In this study, the impact of the apolipoprotein B mRNA-editing catalytic subunit-like (APOBEC) enzyme APOBEC3B (A3B) on epidermal growth factor receptor (EGFR)-driven lung cancer was assessed. A3B expression in EGFR mutant (EGFRmut) non-small-cell lung cancer (NSCLC) mouse models constrained tumorigenesis, while A3B expression in tumors treated with EGFR-targeted cancer therapy was associated with treatment resistance. Analyses of human NSCLC models treated with EGFR-targeted therapy showed upregulation of A3B and revealed therapy-induced activation of nuclear factor kappa B (NF-κB) as an inducer of A3B expression. Significantly reduced viability was observed with A3B deficiency, and A3B was required for the enrichment of APOBEC mutation signatures, in targeted therapy-treated human NSCLC preclinical models. Upregulation of A3B was confirmed in patients with NSCLC treated with EGFR-targeted therapy. This study uncovers the multifaceted roles of A3B in NSCLC and identifies A3B as a potential target for more durable responses to targeted cancer therapy.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Animais , Camundongos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação , Regulação para Cima/genética , Receptores ErbB/genética , Receptores ErbB/metabolismo , Citidina Desaminase/genética , Antígenos de Histocompatibilidade Menor/genética , Antígenos de Histocompatibilidade Menor/metabolismo
20.
Eye (Lond) ; 38(2): 274-278, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-37491440

RESUMO

OBJECTIVE: To describe the clinical characteristics, outcomes, and management of a large cohort of patients with concomitant malignant arterial hypertension and intracranial hypertension. METHODS: Design: Retrospective case series. SUBJECTS: Patients aged ≥ 18 years with bilateral optic disc oedema (ODE), malignant arterial hypertension and intracranial hypertension at five academic institutions. Patient demographics, clinical characteristics, diagnostic studies, and management were collected. RESULTS: Nineteen patients (58% female, 63% Black) were included. Median age was 35 years; body mass index (BMI) was 30 kg/m2. Fourteen (74%) patients had pre-existing hypertension. The most common presenting symptom was blurred vision (89%). Median blood pressure (BP) was 220 mmHg systolic (IQR 199-231.5 mmHg) and 130 mmHg diastolic (IQR 116-136 mmHg) mmHg), and median lumbar puncture opening pressure was 36.5 cmH2O. All patients received treatment for arterial hypertension. Seventeen (89%) patients received medical treatment for raised intracranial pressure, while six (30%) patients underwent a surgical intervention. There was significant improvement in ODE, peripapillary retinal nerve fibre layer thickness, and visual field in the worst eye (p < 0.05). Considering the worst eye, 9 (47%) presented with acuity ≥ 20/25, while 5 (26%) presented with ≤ 20/200. Overall, 7 patients maintained ≥ 20/25 acuity or better, 6 demonstrated improvement, and 5 demonstrated worsening. CONCLUSIONS: Papilloedema and malignant arterial hypertension can occur simultaneously with potentially greater risk for severe visual loss. Clinicians should consider a workup for papilloedema among patients with significantly elevated blood pressure and bilateral optic disc oedema.


Assuntos
Hipertensão Maligna , Hipertensão , Hipertensão Intracraniana , Papiledema , Pseudotumor Cerebral , Humanos , Feminino , Adulto , Masculino , Papiledema/diagnóstico , Papiledema/etiologia , Estudos Retrospectivos , Hipertensão Intracraniana/complicações , Hipertensão Intracraniana/diagnóstico , Hipertensão/complicações , Hipertensão Maligna/complicações , Hipertensão Maligna/diagnóstico , Transtornos da Visão/diagnóstico , Transtornos da Visão/etiologia , Pseudotumor Cerebral/complicações , Pressão Intracraniana/fisiologia
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