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BACKGROUND: Gastric electrical stimulation (GES) is used for patients with drug-refractory gastroparesis (Gp) symptoms. Approximately two-thirds of patients with Gp symptoms are either overweight or obese. We aimed to assess symptoms and nutritional status pre-GES and post-GES placement in a large sample of drug-refractory Gp patients. METHODS: We conducted a chart review of 282 patients with drug-refractory Gp who received temporary followed by permanent GES at an academic medical center. Gastrointestinal symptoms were collected by a traditional standardized PRO (0-4, 0 being asymptomatic and 4 being worst symptoms), baseline nutritional status by BMI plus subjective global assessment (SGA score A, B, C, for mild, moderate, and severe nutritional deficits), ability to tolerate diet, enteral tube access, and parenteral therapy were assessed at baseline and after permanent GES placement. RESULTS: Comparing baseline with permanent, GES was found to significantly improve upper GI symptoms in all quartiles. Of the 282 patients with baseline body mass index (BMI) information, 112 (40%) patients were severely malnourished at baseline, of which 36 (32%) patients' nutritional status improved after GES. Among all patients, 76 (68%) patients' nutritional status remained unchanged. Many patients with high BMI were malnourished by SGA. CONCLUSION: We conclude that symptomatic patients of different BMIs showed improvement in their GI symptoms irrespective of baseline nutritional status. Severely malnourished patients were found to have an improvement in their nutritional status after GES therapy. We conclude that BMI, even if high, is not by itself a contraindication for GES therapy for symptomatic patients.
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Terapia por Estimulação Elétrica , Gastroenteropatias , Gastroparesia , Humanos , Avaliação Nutricional , Gastroparesia/diagnóstico , Gastroparesia/terapia , Gastroenteropatias/terapia , Estado Nutricional , Estimulação Elétrica , Resultado do Tratamento , Esvaziamento GástricoRESUMO
BACKGROUND: We aimed to evaluate and compare the performance of multiple myeloma (MM) selection algorithms for use in Veterans Affairs (VA) research. METHODS: Using the VA Corporate Data Warehouse (CDW), the VA Cancer Registry (VACR), and VA pharmacy data, we randomly selected 500 patients from 01/01/1999 to 06/01/2021 who had (1) either one MM diagnostic code OR were listed in the VACR as having MM AND (2) at least one MM treatment code. A team reviewed oncology notes for each veteran to annotate details regarding MM diagnosis and initial treatment within VA. We evaluated inter-annotator agreement and compared the performance of four published algorithms (two developed and validated external to VA data and two used in VA data). RESULTS: A total of 859 patients were reviewed to obtain 500 patients who were annotated as having MM and initiating MM treatment in VA. Agreement was high among annotators for all variables: MM diagnosis (98.3% agreement, Kappa = 0.93); initial treatment in VA (91.8% agreement; Kappa = 0.77); and initial treatment classification (87.6% agreement; Kappa = 0.86). VA Algorithms were more specific and had higher PPVs than non-VA algorithms for both MM diagnosis and initial treatment in VA. We developed the "VA Recommended Algorithm," which had the highest PPV among all algorithms in identifying patients diagnosed with MM (PPV = 0.98, 95% CI = 0.95-0.99) and in identifying patients who initiated their MM treatment in VA (PPV = 0.93, 95% CI = 0.90-0.96). CONCLUSION: Our VA Recommended Algorithm optimizes sensitivity and PPV for cohort selection and treatment classification.
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Mieloma Múltiplo , Veteranos , Humanos , Estados Unidos/epidemiologia , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/epidemiologia , United States Department of Veterans Affairs , Algoritmos , Atenção à SaúdeRESUMO
INTRODUCTION: Crohn's Disease (CD) results from chronic inflammation of the gastrointestinal (GI) tract involving TNF-α release. Gastrointestinal electrical stimulation (GES), a form of neuromodulation used to treat upper GI motility symptoms (UGI Sx), exerts an anti-inflammatory effect via TNF-α suppression. We hypothesized patients with CD symptoms in patients with gastroparesis (GP) may respond to GES. METHODS: We retrospectively examined 284 patients with symptomatic gastroparesis (Gp Sx), who underwent GES placement. Patients with Gp Sx were evaluated by validated GI Sx patient reported outcome. Scores were obtained at baseline, after temporary GES placement and after permanent GES placement. Eleven patients from this cohort with coexisting CD were analyzed for improvements in their CD symptomatology using the Harvey Bradshaw Index (HBI). HBI scores were compared from before GES to after two sequential applications of electrical stimulation (temporary then permanent). A 3-point decrease in HBI indicated a clinical response and an HBI <5 indicated clinical remission after GES. An unadjusted repeated measures model was used in the analysis with statistical significance set at p ≤ 0.05. RESULTS: Our cohort prevalence of CD was 3.9% (2 M & 9 F, mean age 49.8 yrs.). Within both the Gp + CD & Gp subgroups, UGI Sx substantially improved after temporary and permanent GES. Furthermore, 55% of the GP + CD subgroup demonstrated a clinical response by HBI, while one patient achieved clinical remission (p < 0.01). CD medications were reviewed before and after GES placement, and any interval changes are unlikely to explain the improved HBI scores. DISCUSSION: We conclude that both UGI and CD symptoms in GP + CD patients responded well to GES. The interaction of Gp and CD and the effects of neuromodulation on CD symptoms warrant additional investigation.
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Doença de Crohn , Terapia por Estimulação Elétrica , Gastroparesia , Doença de Crohn/complicações , Doença de Crohn/terapia , Feminino , Gastroparesia/etiologia , Gastroparesia/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND/AIMS: Patients with gastroparesis often have biliary/pancreatic and small bowel symptoms but the effects of gastric electrical stimulation on small bowel electrical activity of the mid-gut have not been studied. Animal model aim: Establish gastric and upper small bowel/biliary slow wave activity relationships with electrical stimulation. Human study aim: Demonstrate improvement in symptoms associated with proximal small bowel dysmotility in gastric stimulated patients. MATERIALS AND METHODS: Animal model: In vivo evoked responses of duodenal and Sphincter of Oddi measures recorded during gastric electrical stimulation in a nonsurvival swine model (N = 3). High-resolution electrical slow wave mapping of frequency, amplitude, and their ratio, for duodenal and Sphincter of Oddi electrical activity were recorded. Human study: Patients (N = 8) underwent temporary gastric stimulation with small bowel electrodes. Subjective and objective data was collected before and after temporary gastric stimulation. Symptom scores, gastric emptying times, and mucosal electrograms via low-resolution mapping were recorded. RESULTS: Animal gastric stimulation resulted in some changes in electrical activity parameters, especially with the highest energies delivered but the changes were not statistically significant. Human study revealed improvement in symptom and illness severity scores, and changes in small bowel mucosal slow wave activity. CONCLUSIONS: Gastric electrical stimulation in an animal model seems to show nonsignificant effects small bowel slow wave activity and myoelectric signaling, suggesting the existence of intrinsic neural connections. Human data shows more significance, with possible potential for therapeutic use of electrical stimulation in patients with gastroparesis and pancreato-biliary and small bowel symptoms of the mid-gut. This study was limited by the nonsurvival pig model, small sample size, and open label human study.
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Terapia por Estimulação Elétrica/métodos , Eletrodos Implantados , Motilidade Gastrointestinal/fisiologia , Gastroparesia/terapia , Enteropatias/terapia , Intestino Delgado/fisiologia , Pancreatite/terapia , Adulto , Animais , Modelos Animais de Doenças , Feminino , Gastroparesia/diagnóstico , Gastroparesia/fisiopatologia , Humanos , Enteropatias/diagnóstico , Enteropatias/fisiopatologia , Intestino Delgado/inervação , Masculino , Pessoa de Meia-Idade , Pancreatite/diagnóstico , Pancreatite/fisiopatologia , Projetos Piloto , Suínos , Resultado do TratamentoRESUMO
Perovskite solar cells (PSCs) compete with conventional solar cells regarding their low-temperature processing and suitable power conversion efficiency. In PSCs, the electron transport layer (ETL) plays a vital role in charge extraction and avoiding recombination; however, poor charge transport of ETL leads to high internal resistance and associated low fill factors. To successfully resolve this challenge, copper-doped zinc oxide nanofibers as an electron transport layer are prepared with various doping levels of 1, 2, and 3 wt% using the electrospinning sol-gel method. The 3 wt% doping of Cu revealed the optimum performance as an ETL, as it offers an electrically efficient transporting structure. SEM images revealed a randomly oriented distribution of nanofibers with different sizes having mesoporous uniformity. Optical properties of doped nanofibers examined using UV-visible analysis showed an extended light absorption due to heteroatom-doping. Adding Cu into the ZnO leads to enhanced charge mobility across the electron transport material. According to Hall measurements, dopant concentration favors the conductivity and other features essentially required for charge extraction and transport. The solar cell efficiency of ZnO doped with 0%, 1%, 2%, and 3% Cu is 4.94%, 5.97%, 6.89%, and 9.79%, respectively. The antibacterial and photocatalytic activities of the prepared doped and undoped ZnO are also investigated. The better light absorption of Cu-ZnO showed a pronounced improvement in the photocatalytic activity of textile electrodes loaded with doped ZnO. The dye degradation rate reaches 95% in 180 min under visible light. In addition, these textile electrodes showed strong antibacterial activity due to the production of reactive oxygen species under light absorption.
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BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disorder, and more than 80% of PD patients will develop oropharyngeal dysphagia. Despite its striated histology, proximity to airway, and potential negative impact of its dysfunction on bolus transport and airway safety, the contractile function of the striated esophagus in PD patients has not been systematically studied. METHODS: Using our repository of clinical manometry and the Milwaukee ManoBank, we analyzed high-resolution manometry (HRM) studies of 20 PD patients, mean age 69.1 (range 38-87 years); 30 non-PD patients with dysphagia, mean age 64.0 (44-86 years); and 32 healthy volunteers, mean age 65.3 (39-86 years). Patients with abnormal findings based on Chicago Classification 4.0 were identified. Repeat analysis was performed in 20% of the manometric tracings by a different investigator with inter-rater concordance between 0.91 and 0.99. KEY RESULTS: The striated esophageal contractile integral in PD patients was significantly lower than that in non-PD dysphagic patients and healthy controls (p = 0.03 and <0.01, respectively). This significant difference persisted after excluding patients with concurrent Chicago Classification motility disorders (p = 0.02 and 0.01, respectively). In both analyses, the distal esophageal contractile integral did not show any significant difference between groups (p = 0.58 and 0.93, respectively). CONCLUSIONS & INFERENCES: PD is associated with a significant decrease in striated esophagus contractility compared to non-PD and healthy controls. This finding may play a pathophysiologic role in development of dysphagia in this patient population.
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Transtornos de Deglutição , Esôfago , Manometria , Doença de Parkinson , Humanos , Idoso , Transtornos de Deglutição/fisiopatologia , Transtornos de Deglutição/etiologia , Transtornos de Deglutição/diagnóstico , Masculino , Doença de Parkinson/fisiopatologia , Doença de Parkinson/complicações , Feminino , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Adulto , Esôfago/fisiopatologia , Contração Muscular/fisiologia , Transtornos da Motilidade Esofágica/fisiopatologia , Transtornos da Motilidade Esofágica/diagnósticoRESUMO
[This corrects the article DOI: 10.1039/D4RA01544D.].
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The simultaneous occurrence of Waldenström macroglobulinemia and multiple myeloma in the same patient has been published as case reports. Patients with Waldenström macroglobulinemia often have a small clone of plasma cells. However, the concurrent occurrence of symptomatic myeloma with lytic bone lesions is rare. The diagnosis of this 'hybrid' entity is challenging, and there are no standard therapies. We present six patients from five centers (three in Israel and two in the United States). We describe these patients' unique clinical course and treatment approaches.
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Mieloma Múltiplo , Macroglobulinemia de Waldenstrom , Humanos , Mieloma Múltiplo/complicações , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/terapia , Macroglobulinemia de Waldenstrom/complicações , Macroglobulinemia de Waldenstrom/diagnóstico , Macroglobulinemia de Waldenstrom/terapia , Masculino , Idoso , Pessoa de Meia-Idade , Feminino , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Idoso de 80 Anos ou maisRESUMO
With the growing knowledge of multiple myeloma (MM) pathobiology and the introduction of novel therapies, risk stratification continues to evolve. Myeloid-derived suppressor cells and tumor-associated macrophages, derived from peripheral blood monocytes, support malignant plasma cell proliferation in the bone marrow. Because peripheral blood absolute monocyte count (AMC) is thought to reflect the bone marrow microenvironment, we sought to evaluate the prognostic significance of AMC in MM. We retrospectively analyzed 10 822 patients newly diagnosed with MM between 2000 and 2019 at Veteran's Administration hospitals. We obtained AMC closest to diagnosis and every 3 months thereafter up to 2.5 years. Patients were stratified into 4 groups: low, normal, elevated, and severely elevated AMC (<0.2, 0.2-<0.8, 0.8-<1.25, and ≥1.25 × 103/mm3, respectively). Abnormal AMC at diagnosis was observed in 25.3% of the patients and was associated with an inferior overall survival (OS). In patients with low, severely elevated, elevated, and normal AMC, respectively, median OS at diagnosis was 2.3, 2.7, 3.1, and 3.6 years (P < .001) and at 2.5 years was 2.0, 2.6, 3.4, and 3.9 years (P < .001). Patients with normal AMC at diagnosis who developed an abnormal AMC >1 year after diagnosis also had an inferior OS relative to patients who maintained a normal AMC. Abnormal AMC was also associated with inferior OS independent of validated prognostic markers, including the international staging system and lactate dehydrogenase. Our findings provide novel clues for future prospective studies on the functional role of monocytes in MM, which could be a readily available metric for risk stratification.
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Monócitos , Mieloma Múltiplo , Humanos , Monócitos/patologia , Prognóstico , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/patologia , Estudos Retrospectivos , Estudos Prospectivos , Biomarcadores , Microambiente TumoralRESUMO
Although randomized controlled trial data suggest that the more intensive triplet bortezomib-lenalidomide-dexamethasone (VRd) is superior to the less intensive doublet lenalidomide-dexamethasone (Rd) in patients newly diagnosed with multiple myeloma (MM), guidelines have historically recommended Rd over VRd for patients who are frail and may not tolerate a triplet. We identified 2573 patients (median age, 69.7 years) newly diagnosed with MM who were initiated on VRd (990) or Rd (1583) in the national US Veterans Affairs health care System from 2004 to 2020. We measured frailty using the Veterans Affairs Frailty Index. To reduce imbalance in confounding, we matched patients for MM stage and 1:1 based on a propensity score. Patients who were moderate-severely frail had a higher prevalence of stage III MM and myeloma-related frailty deficits than patients who were not frail. VRd vs Rd was associated with lower mortality (hazard ratio [HR], 0.81; 95% confidence interval [CI], 0.70-0.94) in the overall matched population. Patients who were moderate-severely frail demonstrated the strongest association (HR 0.74; 95% CI, 0.56-0.97), whereas the association weakened in those who were mildly frail (HR, 0.80; 95% CI, 0.61-1.05) and nonfrail (HR, 0.86; 95% CI, 0.67-1.10). VRd vs Rd was associated with a modestly higher incidence of hospitalizations in the overall population, but this association weakened in patients who were moderate-severely frail. Our findings confirm the benefit of VRd over Rd in US veterans and further suggest that this benefit is strongest in patients with the highest levels of frailty, arguing that more intensive treatment of myeloma may be more effective treatment of frailty itself.
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Fragilidade , Mieloma Múltiplo , Humanos , Idoso , Mieloma Múltiplo/terapia , Lenalidomida/uso terapêutico , Idoso Fragilizado , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bortezomib/uso terapêutico , Dexametasona/uso terapêuticoRESUMO
OBJECTIVE/BACKGROUND: In the era of novel agents, Bruton tyrosine kinase (BTK) inhibitors have changed the dynamics of treating chronic lymphocytic leukemia. However, small studies have shown conflicting results regarding the additive humoral dysfunction with their use. METHODS: We prospectively compared vaccine responses in patients on ibrutinib (n = 10) with matched controls (n = 16) and analyzed whether a protein-based (tetanus-diphtheria toxoid) or a carbohydrate (Pneumovax) moiety will result in an improved immunological response. RESULTS: An appropriate serological response in IgG titers for diphtheria was seen in 40% of patients on ibrutinib and 31% of patients in the control group. About 30% of patients on ibrutinib and 44% of patients in the control group had an adequate response to tetanus toxoid. None of the patients on ibrutinib mounted an adequate response to Pneumovax, while 31% of patients in the control arm responded appropriately. These differences in the results were considered insignificant as all p values were greater than the cut-off of 0.05. CONCLUSION: Our study did not show significant detrimental vaccine responses with ibrutinib and calls for larger multicenter studies to elucidate long-term effects, especially in patients with prior exposure to anti-CD20 monoclonal antibodies.
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Leucemia Linfocítica Crônica de Células B , Proteínas Tirosina Quinases , Humanos , Tirosina Quinase da Agamaglobulinemia , Adenina , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Inibidores de Proteínas QuinasesRESUMO
High-dose melphalan and autologous stem cell transplantation (HDM/SCT) induces deep hematologic responses (HR) in patients with newly diagnosed systemic immunoglobulin light-chain (AL) amyloidosis. Modifying melphalan conditioning dose (mHDM <140 mg/m2) is considered in older patients because of concerns regarding tolerability. Age does not predict frailty, and dose modification could compromise responses in an era where effective non-transplant regimens are available. We analyzed 43 patients ≥ 65 years with AL amyloidosis who underwent SCT at Boston University Amyloidosis Center between 2011 and 2020. Median age was 66 years (range 65-68) versus 69 years (range 65-76) in the HDM and mHDM groups, respectively. HR of ≥ very good partial response at 12 months was 66.7% versus 42.3% for patients treated with HDM versus mHDM. Median progression-free survival (PFS) from day 0 of SCT was not reached versus 12.0 months (P =.13); grade ≥ 3 non-hematologic transplant-related toxicities occurred in 87.5% versus 76.9%; and transplant-related mortality was 0% versus 2.3% in the HDM versus mHDM group, respectively. In carefully selected older patients with AL amyloidosis, HDM is well tolerated. Use of mHDM results in reduced HR and PFS; an important consideration with the advent of highly effective non-transplant therapies.
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Amiloidose , Transplante de Células-Tronco Hematopoéticas , Amiloidose de Cadeia Leve de Imunoglobulina , Humanos , Idoso , Melfalan/efeitos adversos , Amiloidose de Cadeia Leve de Imunoglobulina/terapia , Transplante de Células-Tronco Hematopoéticas/métodos , Transplante Autólogo/métodos , Amiloidose/terapiaRESUMO
INTRODUCTION: Gastric electrical stimulation (GES) has been recommended for drug refractory patients with gastroparesis, but no clear baseline predictors of symptom response exist. We hypothesized that long-term predictors to GES for foregut and hindgut symptoms exist, particularly when using augmented energies. PATIENTS: We evaluated 307 patients at baseline, 1 week post temporary GES, and one year after permanent GES. Baseline measures included upper and lower symptoms by patient-reported outcomes (PRO), solid and liquid gastric emptying (GET), cutaneous, mucosal, and serosal electrophysiology (EGG, m/s EG), BMI, and response to temporary stimulation. METHODS: Foregut and hindgut PRO symptoms were analyzed for 12-month patient outcomes. All patients utilized a standardized energy algorithm with the majority of patients receiving medium energy at 12 months. Patients were categorized based on change in average GI symptom scores at the time of permanent GES compared to baseline using a 10% decrease over time as the cutoff between improvers versus non-improvers. RESULTS: By permanent GES implant, average foregut and hindgut GI symptom scores reduced 42% in improved patients (n = 199) and increased 27% in non-improved patients (n = 108). Low BMI, baseline infrequent urination score, mucosal EG ratio, and proximal mucosal EG low-resolution amplitude remained significant factors for improvement status. CONCLUSIONS: GES, for patients responding positively, improved both upper/foregut and lower/hindgut symptoms with most patients utilizing higher than nominal energies. Low baseline BMI and the presence of infrequent urination along with baseline gastric electrophysiology may help identify those patients with the best response to GES/bio-electric neuromodulation.
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Terapia por Estimulação Elétrica , Gastroparesia , Estimulação Elétrica , Esvaziamento Gástrico/fisiologia , Gastroparesia/terapia , Humanos , Resultado do TratamentoRESUMO
Multiple myeloma (MM) is a heterogeneous disease featured by clonal plasma cell proliferation and genomic instability. The advent of next-generation sequencing allowed unraveling the complex genomic landscape of the disease. Several recurrent genomic aberrations including immunoglobulin genes translocations, copy number abnormalities, complex chromosomal events, transcriptomic and epigenomic deregulation, and mutations define various molecular subgroups with distinct outcomes. In this review, we describe the recurrent genomic events identified in MM impacting patients' outcome and survival. These genomic aberrations constitute new markers that could be incorporated into a prognostication model to eventually guide therapy at every stage of the disease.
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Outcomes for patients with systemic light-chain (AL) amyloidosis have improved over the last two decades with timely diagnosis, use of novel chemotherapeutic agents, risk stratification and better patient selection criteria before hematopoietic autologous stem cell transplant (ASCT). However, majority of patients have advanced stage disease at initial presentation and at relapse rendering them ineligible for intensive cytotoxic chemotherapy or ASCT. Daratumumab (Dara) with or without standard chemotherapy appears to be an excellent treatment option for newly diagnosed and relapsed refractory AL amyloidosis. This is largely due to its tolerable safety and remarkable efficacy as seen in multiple retrospective, small phase II studies as well as a phase III randomized controlled trial. Here we review published clinical trials and retrospective data of Dara in AL amyloidosis that explore its role as a valuable addition to the treatment armamentarium for this challenging disease.
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Amiloidose de Cadeia Leve de Imunoglobulina , Anticorpos Monoclonais , Humanos , Amiloidose de Cadeia Leve de Imunoglobulina/tratamento farmacológico , Recidiva Local de Neoplasia , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Gastric emptying tests (GET) are the gold standard for diagnosing gastroparesis, but many patients do not have delayed emptying. We aimed to examine the combination of autonomic nervous system testing (ANS) and the enteric measure (ENS) of electrogastrography (EGG) to predict disordered GET. Seventy-six patients (47 F, 29 M mean age 40 years) with diabetes mellitus underwent evaluation for end-organ failure including gastroparesis. ANS testing assessed autonomic function by finger capillary pulse to positional changes (PAR), vasoconstriction to cold (VC), and EKG R-R interval change (RRI) with deep breathing; the ENS measures of cutaneous EGG assessed gastric myoelectrical activity. Solid (S) GET subgroups were based on 50% emptying (TS50). Via linear regression analysis: VC, PAR, and EGG had a significant inverse correlation with GET TS50 and decreased in response to a delay in gastric emptying (p < 0.05). Via ordinal logistic regression RRI and EGG-predicted gastric emptying (p < 0.01). Patients with a higher RRI and EGG value were 0.93 and 0.14 times more likely to be diagnosed with rapid gastric emptying. The areas under the curve for receiver operator characteristics (AUROC) for all measures were 0.72 in comparison to 0.59 with EGG. Based on the results, four components (RRI, VC, PAR, and EGG) quantitatively describe gastric emptying in patients with signs of diabetic gastropathy better than EGG alone.
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Diabetes Mellitus , Neuropatias Diabéticas , Gastroparesia , Adulto , Sistema Nervoso Autônomo , Esvaziamento Gástrico , Gastroparesia/diagnóstico , HumanosRESUMO
A hallmark feature of tumorigenesis is uncontrolled cell division. Autophagy is regulated by more than 30 genes and it is one of several mechanisms by which cells maintain homeostasis. Autophagy promotes cancer progression and drug resistance. Several genes play important roles in autophagy-induced tumorigenesis and drug resistance including Beclin-1, MIF, HMGB1, p53, PTEN, p62, RAC3, SRC3, NF-2, MEG3, LAPTM4B, mTOR, BRAF and c-MYC. These genes alter cell growth, cellular microenvironment and cell division. Mechanisms involved in tumorigenesis and drug resistance include microdeletions, genetic mutations, loss of heterozygosity, hypermethylation, microsatellite instability and translational modifications at a molecular level. Disrupted or altered autophagy has been reported in hematological malignancies like lymphoma, leukemia and myeloma as well as multiple solid organ tumors like colorectal, hepatocellular, gall bladder, pancreatic, gastric and cholangiocarcinoma among many other malignancies. In addition, defects in autophagy also play a role in drug resistance in cancers like osteosarcoma, ovarian and lung carcinomas following treatment with drugs such as doxorubicin, paclitaxel, cisplatin, gemcitabine and etoposide. Therapeutic approaches that modulate autophagy are a novel future direction for cancer drug development that may help to prevent issues with disease progression and overcome drug resistance.
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Antineoplásicos/farmacologia , Autofagia , Biomarcadores Tumorais/metabolismo , Carcinogênese/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Carcinogênese/metabolismo , Carcinogênese/patologia , Humanos , Neoplasias/metabolismoRESUMO
BACKGROUND: Cajal cells have a fundamental role in generating slow waves that regulate gastric motility. Gastric electrical stimulation (GES) is Food and Drug Administration (FDA)-approved for symptomatic treatment of drug refractory gastroparesis. We hypothesized that using two leads will vary from a single lead by providing greater insight of gastric electrical wave propagation, through differences in measured frequency, amplitude, and frequency over amplitude ratio. We also hypothesized that a significant reduction in symptomatic vomiting score is highly predictive in a single lead temporary gastric electrical stimulation. METHODS: A total of 111 patients with drug-refractory gastroparesis were enrolled. Forty-two patients had single lead, while 69 patients had two leads. All recordings measured mean frequency and amplitude in each lead. Patients documented symptoms using standardized symptom scores at baseline and day 5 post-procedure. RESULTS: Single lead patients with initial low mucosal frequency showed an increase from 3.10 to 4.93 (P = 0.0155), while the high frequency group decreased from 5.89 to 5.12 (P = 0.135). Vomiting score decreased significantly among both groups with GES (P = 0.0001). For two leads, the mucosal frequency decreased at the proximal electrode (P = 0.402), and increased at the distal electrode (P = 0.514), neither statistically significant (P = 0.143). Mucosal electrogram amplitude values changed for both proximal, mean decrease of 0.34 mV (P = 0.241), and distal, mean increase of 0.05 mV (P = 0.65) with a mean difference 0.34 mV (P = 0.238). However, mucosal electrogram frequency and amplitudes on day 5 were highly dependent on the baseline values (P < 0.001). CONCLUSIONS: Compared to the use of single point electrodes, the use of two low-resolution electrodes allows recording gastric electrical wave propagation with greater detail. Low resolution recording appears to be superior to single point recordings, while awaiting practical high-resolution recordings.
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Introduction: Catheter-associated urinary tract infection (CAUTI) is one of the most common nosocomial infections in hospitals, accounting for 36% of all health care-associated infections. Areas covered: We aimed to address the potential impact of antimicrobial coating of catheter materials for the prevention of CAUTI and to analyze the progress made in this field. We conducted literature searches in the PubMed, Embase, and Cochrane Library databases, and found 578 articles. Data from 60 articles in either the preclinical or clinical stage were analyzed in this expert review. Expert opinion: The literature review revealed many promising methods for preventing CAUTI. Recent studies have suggested the combination of silver-based products and antibiotics, owing to their synergistic effect, to help address the problem of antibiotic resistance. Other coating materials that have been tested include nitric oxide, chlorhexidine, antimicrobial peptides, enzymes, and bacteriophages. Because of heterogeneity among studies, it is difficult to reliably comment on the clinical efficacy of different coating materials. Future research should focus on double-blind randomized clinical trials for evaluating the role of these potential coating agents.
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Anti-Infecciosos/farmacologia , Infecções Relacionadas a Cateter/prevenção & controle , Materiais Revestidos Biocompatíveis/farmacologia , Cateteres Urinários/microbiologia , Infecções Urinárias/prevenção & controle , Animais , Infecções Relacionadas a Cateter/microbiologia , Humanos , Prata/farmacologiaRESUMO
INTRODUCTION: Pomalidomide (Pom) has demonstrated synergistic antiproliferative activity in combination regimens as a result of its distinct anticancer, antiangiogenic, and immunomodulatory effects. This review aimed to compare outcome measures of different Pom regimens for relapsed/refractory multiple myeloma. METHODS: A comprehensive literature search identified a total of 1374 studies. Thirty-five studies assessing 4623 subjects met the inclusion criteria: phase 2/3 trial, ≥ 2 prior lines of therapy, and clearly documented efficacy outcomes like overall response rate (ORR), overall survival, and progression-free survival. Statistical analyses for meta-analysis was performed by CMA version 3 and Cochrane Q statistics (P < .05 considered significant, I2 index for heterogeneity). A random effects model was used if there was significant heterogeneity (P ≥ .05 over I2 ≥ 50%). RESULTS: Pooled analysis showed ORR 47.1% across all Pom-based (2- and 3-drug) regimens. Stratified analysis for efficacy outcomes (pooled ORR [%] and mean progression-free survival [months]) are reported. With doublet regimen, Pom with low-dose dexamethasone (LoDex) was the most common regimen (35.7%, 6.1 months), and overall survival was 14.37 months. With triplet regimens, pooled ORR was 61.9% (I2 = 87.3%). These included bortezomib + Pom + LoDex (83.5%, 15.7 months), carfilzomib-Pom + LoDex (77.1%, 15.3 months), Pom + LoDex-bendamustine (74.2%), Pom-dexamethasone-daratumumab (64.5%), Pom + LoDex-cyclophosphamide (59.4%, 9.5 months), and Pom + LoDex-doxorubicin (32%). Leading adverse events were myelosuppression, with mean incidences of grade 3 or higher neutropenia, anemia, and thrombocytopenia of 47.6%, 26.5%, and 20.8%, respectively. Mean incidence of grade 3 or higher nonhematologic adverse events were infections 29.1%, pneumonia 13.8%, and fatigue 10%. CONCLUSION: Three-drug Pom regimens yielded double the response rates compared to Pom + LoDex (pooled ORR, 61.9% vs. 35.7%), with bortezomib + Pom + LoDex and carfilzomib-Pom + LoDex demonstrating better outcomes than other regimens.