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Background: Spina bifida is a type of neural tube defect (NTD); NTDs are developmental malformations of the spinal cord that result from failure of neural tube closure during embryogenesis and are likely caused by interactions between genetic and environmental factors. Arsenic induces NTDs in animal models, and studies demonstrate that mice with genetic defects related to folate metabolism are more susceptible to arsenic's effects. We sought to determine whether 25 single-nucleotide polymorphisms (SNPs) in genes involved in folate and arsenic metabolism modified the associations between maternal arsenic exposure and risk of spina bifida (a common NTD) among a hospital-based case-control study population in Bangladesh., Methods: We used data from 262 mothers and 220 infants who participated in a case‒control study at the National Institutes of Neurosciences & Hospital and Dhaka Shishu Hospital in Dhaka, Bangladesh. Neurosurgeons assessed infants using physical examinations, review of imaging, and we collected histories using questionnaires. We assessed arsenic from mothers' toenails using inductively coupled plasma mass spectrometry (ICP-MS), and we genotyped participants using the Illumina Global Screening Array v1.0. We chose candidate genes and SNPs through a review of the literature. We assessed SNP-environment interactions using interaction terms and stratified models, and we assessed gene-environment interactions using interaction sequence/SNP-set kernel association tests (iSKAT)., Results: The median toenail arsenic concentration was 0.42 μg/g (interquartile range [IQR]: 0.27-0.86) among mothers of cases and 0.47 μg/g (IQR: 0.30-0.97) among mothers of controls. We found an two SNPs in the infants' AS3MT gene (rs11191454 and rs7085104) and one SNP in mothers' DNMT1 gene (rs2228611) were associated with increased odds of spina bifida in the setting of high arsenic exposure (rs11191454, OR 3.01, 95% CI: 1.28-7.09; rs7085104, OR 2.33, 95% CI: 1.20-4.and rs2228611, OR 2.11, 95% CI: 1.11-4.01), along with significant SNP-arsenic interactions. iSKAT analyses revealed significant interactions between mothers' toenail concentrations and infants' AS3MT and MTR genes (p = 0.02), and mothers' CBS gene (p = 0.05)., Conclusions: Our results support the hypothesis that arsenic increases spina bifida risk via interactions with folate and arsenic metabolic pathways and suggests that individuals in the population who have certain genetic polymorphisms in genes involved with arsenic and folate metabolism may be more susceptible than others to the arsenic teratogenicity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: Reports on the management and survival of children with myelomeningocele defects in Bangladesh are limited. This study describes the characteristics and outcomes of these children, focusing on the timing of surgical repair and factors affecting survival., Methods: We enrolled patients with myelomeningoceles in a case-control study on arsenic exposure and spina bifida in Bangladesh. Cases were subsequently followed at regular intervals to assess survival. Demographic, clinical, and surgical characteristics were reviewed. Univariate tests identified factors affecting survival., Results: Between 2016 and 2022, we enrolled 272 patients with myelomeningocele. Postnatal surgical repair was performed in 63% of cases. However, surgery within 5 days after birth was infrequent (<10%) due to delayed presentation, and there was a high rate (29%) of preoperative deaths. Surgical repair significantly improved patient survival (P < 0.0001). Older age at time of surgery was also associated with improved survival rates, which most likely represents that those who survived to older ages prior to surgery accommodated better with their lesions. Patients who presented with ruptured lesions had lower survival rates., Conclusions: Timely neurosurgical repair of myelomeningoceles in Bangladesh is hindered by late patient presentation, resulting in a high preoperative patient death rate. Neurosurgical intervention remains a significant predictor of survival. Increased access to neurosurgical care and education of families and non-neurosurgical providers on the need for timely surgical intervention are important for improving the survival of infants with myelomeningoceles., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Competing Interests: Declaration of competing interest The authors have declared no conflicts of interest.

Context: Given a shortage of specialty palliative care clinicians and geographic variation in availability, telemedicine has been proposed as one way to improve access to palliative care services for patients with cancer. However, the enduring digital divide raises questions about whether unequal access will exacerbate healthcare disparities., Objectives: To examine factors associated with utilization of telemedicine as compared to in-person visits by patients with cancer in the ambulatory palliative care setting., Methods: We collected data on patients seen in Supportive Oncology clinic by palliative care clinicians with an in-person or telemedicine visit from March 1 to December 30, 2020. A logistic regression with generalized estimating equation was fit to assess the association between visit type and patient characteristics., Results: A total of 491 patients and 1783 visits were identified, including 1061 (60%) in-person visits and 722 (40%) telemedicine visits. Female patients were significantly more likely to utilize telemedicine than male patients (OR 1.46; 95% CI 1.11-1.90). Spanish-speaking patients (OR 0.32, 95% CI 0.17-0.61), those without insurance (OR 0.28, 95% CI 0.15-0.52), and those without an activated patient portal (Inactivated: OR 0.46, 95% CI 0.26-0.82; Pending Activation: OR 0.29, 95% CI 0.18-0.48) were less likely to utilize telemedicine., Conclusion: Our study reveals disparities in telemedicine utilization in the ambulatory palliative care setting for patients with cancer who are male, Spanish-speaking, uninsured, or do not have an activated patient portal. In the wake of the COVID-19 pandemic, we can better meet the palliative care needs of patients with cancer through telemedicine only if equity is kept at the forefront of our discussions., (Copyright © 2021 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Background: While radiation therapy (RT) improves function, and quality of life for patients with advanced cancers, patients frequently experience a period of acute toxicity during which functional abilities may decline. Little is understood about changes in functional outcomes after RT in older adults. This study aims to examine changes in daily function at 1 and 6 months following RT., Methods: We reviewed the charts of 117 patients who underwent palliative RT on a prospective registry. Activities of daily living (ADL) and instrumental activities of daily living (IADL) scores ranging from 0 to 6 and 0-8, respectively, were collected at baseline, one-month, and six months post-RT. Patients were classified as low deficit for ADL/IADL if they had 0-1 deficits and high deficit if they had 2+ deficits., Results: One-hundred seventy RT courses were identified; 99 were evaluable at each time point. The median age was 67 years. At baseline, 29.5 and 29.9% of patients were classified as high-deficit for ADL and IADL functioning, respectively. At one-month, the majority of patients who were low-deficit at baseline remained so for both measures while approximately one quarter of high-deficit patients showed improvement. Most patients identified as low-deficit at one-month remained so at six-months, while no high-deficit patients improved from one- to six-months. Factors associated with high ADL and IADL deficits included: time (six months), increasing age, and Hispanic/other race. Compared to those with ECOG score of 3, patients with lower scores (0-2) had lower odds of high deficit., Conclusion: ADL and IADL tools may be useful in describing changes in daily function after palliative RT and in identifying groups of patients who may benefit from additional supportive geriatric care interventions., Competing Interests: Declaration of Competing Interest The authors wish to declare no conflicts of interest., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Purpose: Multiple Myeloma (MM), the second leading blood malignancy, has complex and costly disease management. We studied patterns of treatment disparities and unplanned interruptions among the MM patients after the Affordable Care Act to assess their prevalence and effect on survival., Materials and Methods: This retrospective study of 1002 MM patients at a tertiary referral center used standard guidelines as a reference to identify underuse of effective treatments. We used multivariate logistic regression and Cox proportionate hazard to study the prognostic effect on survival., Results: Median age in the cohort was 63.0 [IQR: 14] years. Non-Hispanic White (NHW) patients were older (p = 0.007) and more likely to present with stage I disease (p = 0.02). Underuse of maintenance therapy (aOR = 1.98; 95 % CI 1.12-3.48) and interruptions in treatment were associated with race/ethnicity and insurance (aOR = 4.14; 95 % CI: 1.78-9.74). Only underuse of induction therapy was associated with overall patient survival., Conclusion: Age, race, ethnicity and primary insurance contribute to the underuse of treatment and in unplanned interruptions in MM treatment. Addressing underuse causes in such patients is warranted., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Purpose: Discharges against medical advice (DAMA) are associated with adverse patient outcomes among those with epilepsy. Our goal was to examine trends and factors associated with DAMA among those living with epilepsy., Methods: A retrospective cross-sectional study was performed using the 2003-2014 National Inpatient Sample database. ICD-9-CM diagnosis codes were used to identify admissions of patients with epilepsy. Following outcomes were examined among epilepsy patients: proportion and predictors of DAMA, 12-year DAMA trends and causes of admissions., Results: In 2014, of the 187,850 admissions in patients with epilepsy, 3783 (2.01 %) were DAMA. Male sex, Black race, younger age, lower household income, Medicaid/self-pay/other as primary payer, lower Elixhauser comorbidities index, weekend admission, non-elective admission, hospital in northeast region, and urban nonteaching hospital were all associated with DAMA. There was a significant increase in the proportion of DAMA in people with epilepsy from 2003 to 2014 (1.13 %-2.01 %, p < 0.0001). The top reasons of admissions for epilepsy patients who were DAMA were: epilepsy/convulsion (21.02 %), alcohol- (8.86 %) and substance-related disorders (3.75 %), and diabetes mellitus with complications (3.33 %)., Conclusions: Our findings provide opportunities to understand DAMA among those living with epilepsy, which is more prevalent in socially-disadvantaged populations. This study highlight the need to develop electronic medical records-based prediction tools that could be used at the point-of-care to enable the early identification of people at risk for DAMA, since it is often likely preventable. Future mixed methods studies are recommended to identify facilitators of DAMA and strategies for prevention., (Copyright © 2020 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Introduction: Whole brain radiation therapy (WBRT) is widely used to treat patients with brain metastases. However, there is debate regarding its utility in patients with poor prognoses. In this study, we sought to characterize the use of WBRT in the United States, especially in adults aged 55 and above., Material and Methods: Patients with brain metastases were identified using the National Cancer Database between 2010 and 2013. The receipt and completion of WBRT with various patient factors were correlated using multivariable logistic regression., Results: 28,422 patients with brain metastases were identified, 23,362 of whom were aged 55 or above. 14,845 patients received WBRT and 12,310 patients completed treatment. Among adults aged 55 and above, 11,945 patients received WBRT, and 9812 patients completed treatment. Patients aged 60 and above were less likely to receive WBRT, while those aged 65 and above were less likely to complete WBRT., Discussion: These results suggest that WBRT may be over-utilized in the United States, especially among older adults. Better interventions to improve pre-WBRT decision-making in this population are needed to select patients who might derive benefit., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2020. Published by Elsevier Ltd.)

Background and Aims: While substance use can lead to incarceration, the disruptive effects of incarceration may lead to, or increase psychosocial vulnerability and substance use. Using causal inference methods, we measured longitudinal associations between incarceration and post-release substance use among Black men who have sex with men (BMSM), populations facing disproportionate risk of incarceration and substance use., Methods: Using data from the HIV Prevention Trials Network (HPTN 061) study (N = 1553) we estimated associations between past 6-month incarceration and binge drinking, marijuana use, and stimulant use post release (at 12-month follow-up visit). Adjusted models used inverse probability weighting (IPW) to control for baseline (pre-incarceration) substance use and additional risk factors., Results: There were 1133 participants present at the twelve-month follow-up visit. Participants were predominately non-Hispanic Blacks and unemployed. At baseline, 60.1 % reported a lifetime history of incarceration, 22.9 % were HIV positive and 13.7 % had a history of an STI infection. A total of 43 % reported a history of depression. In adjusted analyses with IPW, recent incarceration was associated with crack-cocaine (adjusted odds ratio (AOR): 1.53, 95 % confidence interval (CI): 1.03, 2.23) and methamphetamine use (AOR: 1.52, 95 % CI: 0.94-2.45). Controlling for pre-incarceration binge drinking, incarceration was associated with post-release binge drinking (AOR: 1.47, 95 % CI: 1.05, 2.04); in fully adjusted models the AOR was 1.14 (95 % CI: 0.81, 1.62). Incarceration was not associated with marijuana use., Conclusion: Findings underscore the need to provide substance use treatment in custody and post-release, and to consider alternatives to incarceration for substance using populations., Competing Interests: Declaration of Competing Interest No conflict of interest declared., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Purpose: Achieving a pathologic complete response (pCR) with neoadjuvant chemotherapy (NAC) for muscle-invasive bladder cancer (MIBC) is associated with a favorable prognosis. Patients with pathologic residual disease (pRD) generally have poor outcomes. However, prognosis after radical cystectomy (RC) improves with ongoing survivorship. Our objective was to determine whether the difference in prognosis of patients with pCR and pRD changes over time., Materials and Methods: We queried the National Cancer Database for patients who received NAC and RC for localized MIBC (cT2-T4aN0M0) between 1998 and 2012. pCR was defined as ≤Tis disease. Kaplan-Meier analysis was used to estimate conditional survival to 5 years given survival to 1, 2, 3, and 4 years post-RC. Cox proportional hazard modeling was used to estimate the effect of pRD vs. pCR on overall survival., Results: The cohort comprised 1,553 patients (pCR: 314 and pRD: 1,239). With median follow-up 2.65 years (range 0.01-9.97), median survival was 2.5 years (95% confidence interval 2.2-2.9) and not reached for pRD and pCR, respectively. All patients had improved conditional survival with each additional year of survivorship. Patients with pCR had improved overall survival relative to those with pRD. The effect of pRD vs. pCR on conditional survival did not differ over time (P = 0.7)., Conclusions: MIBC patients with pCR after NAC have improved conditional survival relative to those with pRD post-RC. This survival advantage does not significantly change over time. These findings may inform patient counseling, surveillance intensity, and novel adjuvant approaches for patients with pRD., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Studies on the effectiveness of multimodal analgesia, particularly in patients at higher perioperative risk from obstructive sleep apnoea (OSA), are lacking. We aimed to assess the impact of multimodal analgesia on opioid use and complications in this high-risk cohort., Methods: We conducted a population-based retrospective cohort study of OSA patients undergoing elective lower extremity joint arthroplasty (2006-16, Premier Healthcare database). Multimodal analgesia was defined as opioid use with the addition of one, two, or more non-opioid analgesic modes including, nonsteroidal anti-inflammatory drugs (NSAIDs), cyclooxygenase-2 inhibitors, paracetamol/acetaminophen, peripheral nerve blocks, steroids, gabapentin/pregabalin, or ketamine. Multilevel multivariable regression models measured associations between multimodal analgesia and opioid prescription (primary outcome; oral morphine equivalents). Secondary outcomes included opioid- and OSA-related complications, and resource utilisation. Odds ratios (OR) or % change and 95% confidence intervals (CI) are reported., Results: Among 181 182 OSA patients included, 88.5% (n = 160 299) received multimodal analgesia with increasing utilisation trends. Multivariable models showed stepwise beneficial postoperative outcome effects with increasing additional analgesic modes compared with opioid-only analgesia. In patients who received more than two additional analgesia modes (n = 64 174), opioid dose prescription decreased by 14.9% (CI -17.0%; -12.7%), while odds were significantly decreased for gastrointestinal complications (OR 0.65, CI 0.53; 0.78), mechanical ventilation (OR 0.23, CI 0.16; 0.32), and critical care admission (OR 0.60, CI 0.48; 0.75), all P<0.0001., Conclusions: In a population at high risk for perioperative complications from OSA, multimodal analgesia was associated with a stepwise reduction in opioid use and complications, including critical respiratory failure., (Copyright © 2018 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Background: Intravenous acetaminophen (IV APAP) is an option in multimodal postoperative analgesia. Prior trials focus on hip and knee arthroplasties, whereas large-scale data on utilization and effectiveness in shoulder arthroplasties are lacking., Methods: Data on 67,494 (452 hospitals) partial/total shoulder arthroplasties were extracted from the Premier claims database (2011-2016). Patients were categorized by receipt and dosage of IV APAP. Multilevel models measured associations between IV APAP and opioid utilization (in oral morphine equivalents), length/cost of stay and opioid-related complications. Effect estimates (adjusted % change) with 95% confidence intervals (CIs) are reported., Results: IV APAP was used in 17.7% (n = 11,949) of patients with an increasing utilization trend. Most patients received only one dose on the day of surgery (69.5%; n = 8308). When adjusting for relevant covariates, IV APAP was not associated with meaningful effects on outcomes. Specifically, its use (versus no use) was not associated with decreased (but rather somewhat increased) opioid utilization: + 5.4% (CI 3.6-7.1%; P < 0.05)., Conclusion: In this first large-scale study that assesses IV APAP in shoulder arthroplasties, IV APAP use was not associated with decreased opioid utilization or the length/cost of stay. These results do not support routine use of IV APAP in this cohort, especially given its high cost., The Translational Potential for This Article: Multimodal pain control to assist in reducing the opioid pain medications are seen as a route to improved postoperative patient outcomes, better pain control and expedited hospital discharge. Acetaminophen plays a significant role in these protocols in many institutions, but it is not established if this expensive IV formulation is superior to the oral formulation. This study evaluates the use and effectiveness of IV acetaminophen following shoulder arthroplasty at a large number of institutions.

Among a cohort of children located in rural areas of Bangladesh affected by high levels of exposure to environmental metals, we investigated the associations between anthropometric measures, growth trajectory, and neurodevelopment at age 20-40months. Our study population included mothers and their children who participated in a longitudinal birth cohort study that took in place in the Pabna and Sirajdikhan areas of Bangladesh. Anthropometric measures including weight, length, and head circumference were measured at birth, age 12months, and age 20-40months. Neurodevelopment was assessed using Bayley Scales of Infant and Toddler Development Third Edition (BSID-III) multi-scale at age 20-40months. A total of 777 mother-child pairs were included. Higher anthropometric measures at 20-40months were associated with higher cognitive, language, and motor scores on BSID-III. For example, a 1-kg increment in birthweight was associated with an increase of 2.11 for cognitive score (p<0.0001), 1.63 for language score (p=0.006), and 0.89 for motor scores (p=0.03). Greater positive changes in growth parameters, or growth trajectory, between birth and 20-40months were also associated with higher BSID-III scores. These associations remained significant after adjusting for potential confounders and prenatal exposure to environmental metals. These findings suggest that even when taking into account high environmental metal exposures, prenatal and early childhood growth have strong associations with neurodevelopmental test scores in early childhood., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Study Objective: The objective was to analyze the impact of a peripheral nerve block in addition to general anesthesia on hospital admission after surgical rotator cuff repair., Design: This was a population-based outcome study. The cost effectiveness of ambulatory rotator cuff repair relies on the discharge of patients on the day of surgery. As the impact of a peripheral nerve block in addition to general anesthesia on this outcome is unknown, we sought to elucidate this subject using population-based data., Patients and Methods: Information on patients undergoing rotator cuff surgery under general anesthesia with or without the addition of a peripheral nerve block (GN vs G) from a retrospective database provided by Premier Perspective, Inc, Charlotte, NC (http://www.premierinc.com), was analyzed. Using multilevel multivariable regressions, we evaluated the independent impact of the type of anesthesia on the outcomes hospital admission, combined major complications, and increased hospital costs., Results: We identified 27,201 patients who underwent surgical rotator cuff repair. Approximately 89% (24,240) of patients were discharged on the day of surgery, whereas 11% (2961) were admitted to the hospital. The admission rates for the GN group were 9.1% and 11.2% for the G group (P=.0001). The multivariable regression models showed that patients with the addition of a peripheral nerve block had 18% less risk of being admitted to the hospital (relative risk [RR]=0.82; 95% confidence interval [CI], 0.74-0.91; P=.0003) compared with those without this intervention. Differences in risk for combined major complications (RR=1.00; 95% CI, 0.83-1.20; P=.9751) or increased hospital costs (RR=0.97; 95% CI, 0.93-1.02; P=.2538) were nonsignificant., Discussion: For patients undergoing surgical rotator cuff repair under general anesthesia, the addition of a peripheral nerve block may be associated with a reduction in the need for postoperative hospital admission after ambulatory surgery. Although the reason for this finding has to remain speculative, better pain control may play a role., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Despite literature suggesting benefits of using regional anesthesia, the impact of neuraxial anesthesia on perioperative outcomes in patients undergoing lung surgery remains unstudied. We studied the effect of combined neuraxial/general anesthesia (vs general anesthesia) on perioperative outcome in a large national sample of patients who underwent open lung resection., Methods: We extracted data from the Premier Perspective database on patients who underwent open lung resection. The main effect of interest was anesthesia type: general and combined neuraxial/general anesthesia. Patient and health-care variables, complications, and resource use were compared between groups. Multivariable analyses assessed the independent impact of choice of anesthetic technique on outcomes., Results: For 18,943 patients, anesthesia type was known: 79% (n = 14,912) were administered general anesthesia, and 21% (n = 4,031) received neuraxial/general anesthesia. Comparing general vs neuraxial/general anesthesia, unadjusted incidences for the latter were lower for acute myocardial infarction (1.09% vs 0.67%, P = .018), pulmonary complications (20.96% vs 18.98%, P = .006), blood transfusion (14.15% vs 9.80%, P < .0001), and mechanical ventilation (11.60% vs 8.81%, P < .0001). Neuraxial/general anesthesia was associated with lower adjusted odds of blood transfusion (OR, 0.82; 95% CI, 0.69-0.98) and mechanical ventilation (OR, 0.81; 95% CI , 0.67-0.98), while higher odds were seen for DVT (OR, 1.50; 95% CI, 1.01-2.23) and pulmonary embolism (OR, 1.56; 95% CI, 1.02-2.38)., Conclusions: This study illustrates the association between adding neuraxial to general anesthesia in open lung resections among patients with cancer and perioperative outcomes. Neuraxial anesthesia use was associated with decreased risk for blood transfusion but increased thromboembolic risks. Additional studies are needed to elucidate mechanisms by which neuraxial anesthesia may affect these outcomes.

Chemotherapy resistance is a major clinical challenge for the management of locally advanced breast cancer. Accumulating evidence suggests a major role of cancer stem cells (CSCs) in chemoresistance evoking the requirement of drugs that selectively target CSCs in combination with chemotherapy. Here, we report that mithramycin A, a known specificity protein (Sp)1 inhibitor, sensitizes breast CSCs (bCSCs) by perturbing the expression of drug efflux transporters, ATP-binding cassette sub-family G, member 2 (ABCG2) and ATP-binding cassette sub-family C, member 1 (ABCC1), survival factors, B-cell lymphoma 2 (Bcl-2) and X-linked inhibitor of apoptosis (XIAP), and, stemness regulators, octamer-binding transcription factor 4 (Oct4) and Nanog, which are inherently upregulated in these cells compared with the rest of the tumor population. In-depth analysis revealed that aberrant overexpression of Sp1 in bCSCs transcriptionally upregulates (1) resistance-promoting genes to protect these cells from genotoxic therapy, and (2) stemness regulators to sustain self-renewal potential of these cells. However, mithramycin A causes transcriptional suppression of these chemoresistant and self-renewal genes by inhibiting Sp1 recruitment to their promoters. Under such antisurvival microenvironment, chemotherapeutic agent doxorubicin induces apoptosis in bCSCs via DNA damage-induced reactive oxygen species generation. Cumulatively, our findings raise the possibility that mithramycin A might emerge as a promising drug in combinatorial therapy with the existing chemotherapeutic agents that fail to eliminate CSCs. This will consequently lead to the improvement of therapeutic outcome for the treatment-resistant breast carcinomas., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Depression and anxiety are highly prevalent psychiatric disorders. However, little is known about their impact on outcomes in the perioperative setting. This study is intended to gain insight into epidemiology and effects on perioperative morbidity, mortality, length of hospital stay, discharge and cost., Methods: We obtained the National Inpatient Sample from the Hospital Cost and Utilization Project for each year between 2000 and 2008. Entries indicating the performance of primary total hip and knee arthroplasty were identified and separated into four groups: (1) those with concomitant diagnosis of depression or (2) anxiety, (3) both, and (4) none of these diagnoses. The incidence of major complications, non-routine discharge, length, and cost of hospitalization were assessed. Regression analysis was performed to identify if psychiatric comorbidity was an independent risk factor for each outcome., Results: We identified 1,212,493 patients undergoing arthroplasty between 2000 and 2008. The prevalence of depression and anxiety significantly increased over time. Patients with either condition had higher hospital charges, rates of non-routine discharges and comorbidity index. Depression or anxiety were associated with significantly decreased adjusted odds for in-hospital mortality (OR = 0.53, p = 0.0147; OR = 0.58, p = 0.0064). The risk of developing a major complication was slightly lower in patients with depression, anxiety or both (OR=0.95, p = 0.0738; OR = 0.95, p = 0.0259; OR = 0.94, p = 0.7349)., Conclusions: Patients suffering from depression, anxiety, or both require more healthcare resources in a perioperative setting. However, lower short-term mortality in spite of higher comorbidity burden and without extensive changes in perioperative complication profile indicates better outcome for this group of patients., (Copyright © 2013 The Academy of Psychosomatic Medicine. Published by Elsevier Inc. All rights reserved.)

Purpose: Lennox-Gastaut syndrome (LGS) is an epileptogenic disorder that arises in childhood and is typically characterized by multiple seizure types, slow spike-and-wave complexes on EEG and cognitive impairment. If medical treatment fails, patients can proceed to one of two palliative surgeries, vagus nerve stimulation (VNS) or corpus callosotomy (CC). Their relative seizure control rates in LGS have not been well studied. The purpose of this paper is to compare seizure reduction rates between VNS and CC in LGS using meta-analyses of published data., Methods: A systematic search of Pubmed, Ovidsp, and Cochrane was performed to find articles that met the following criteria: (1) prospective or retrospective study, (2) at least one patient diagnosed with Lennox-Gastaut syndrome, and (3) well-defined measure of seizure frequency reduction. Seizure reduction rates were divided into seizure subtypes, as well as total seizures, and categorized as 100%, >75%, and >50%. Patient groups were compared using chi-square tests for categorical variables and t-test for continuous measures. Pooled proportions with 95% confidence interval (95% CI) of seizure outcomes were estimated for total seizures and seizure subtypes using random effects methods., Results: 17 VNS and 9 CC studies met the criteria for inclusion. CC had a significantly better outcome than VNS for >50% atonic seizure reduction (80.0% [67.0-90.0%] vs. 54.1% [32.1-75.4%], p<0.05) and for >75% atonic seizure reduction (70.0% [48.05-87.0%] vs. 26.3% [5.8-54.7%], p<0.05). All other seizure types, as well as total number of seizures, showed no statistically significant difference between VNS and CC., Conclusions: CC may be more beneficial for LGS patients whose predominant disabling seizure type is atonic. For all other seizure types, VNS offers comparable rates to CC., (Copyright © 2012 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Study Objective: To analyze whether patient characteristics, ambulatory facility type, anesthesia provider and technique, procedure type, and temporal factors impact the outcome of unexpected disposition after ambulatory knee and shoulder surgery., Design: Retrospective analysis of a national database., Setting: Freestanding and hospital-based ambulatory surgery facilities., Measurements: Ambulatory knee and shoulder surgery cases from 1996 and 2006 were identified through the National Survey of Ambulatory Surgery. The incidence of unexpected disposition status was determined and risk factors for such outcome were analyzed., Main Results: Factors independently increasing the risk for unexpected disposition included procedures performed in hospital-based versus freestanding facilities [odds ratio (OR) 6.83 (95% confidence interval [CI] 4.34; 10.75)], shoulder versus knee procedures [OR 3.84 (CI 2.55; 5.77)], anesthesia provided by nonanesthesiology professionals and certified registered nurse-anesthetists versus anesthesiologists [OR 7.33 (CI 4.18; 12.84) and OR 1.80 (CI 1.09; 2.99), respectively]. Decreased risk for unexpected disposition was for procedures performed in 2006 versus 1996 [OR 0.15 (CI 0.10; 0.24)] and the use of anesthesia other than regional or general [OR 0.34 (CI 0.18; 0.68)]., Conclusions: The decreased risk for unexpected disposition associated with more recent data and with freestanding versus hospital-based facilities may represent improvements in efficiency, while the decreased odds for such disposition status associated with the use of other than general or regional anesthesia may be related to a lower invasiveness of cases. We found an increased risk of adverse disposition in cases where the anesthesia provider was a nonanesthesiology professional. No difference in this outcome was noted when an anesthesia care team provided care., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Quercetin, a flavonol group of plant flavonoid, has generated immense interest because of its potential antioxidant, anti-proliferative, chemoprotective, anti-inflammatory and gene expression modulating properties. However, the pro-oxidant chemistry of quercetin is important as it is related to the generation of mutagenic quinone-type metabolites. In the present study, 25mg/kg, 50mg/kg and 100mg/kg of quercetin given through the intra peritoneal (i.p.) route induced 2.31 ± 0.27%, 4.72 ± 0.58% and 6.38 ± 0.68% (control value=0.67 ± 0.30%) respectively, of cells with micronucleus (MN) in polychromatic erythrocytes in bone marrow cells and 10.93 ± 0.98%, 10.00 ± 0.89% and 14.27 ± 3.94% (control 2.61 ± 0.48) of cells with chromosome aberrations (CA) following 24h of the treatments. Higher frequencies of MN and CA were also observed after 48h of the treatments. To verify the effect of route of treatment on the quercetin induced damage, 100mg/kg b.w. was given through oral route which declined frequency of MN (P<0.001) as well as CA (P<0.05) as compared to the i.p. route for the same dose. Quercetin also induced higher frequency of metaphases with sticky chromosomes and C-mitosis. Pre-treatment with quercetin significantly reduced the frequency of mitomycin C (MMC) induced MN as well as CA, but no clear correlation between the dose and effect could be observed. Further studies are required to elucidate the possible interaction of quercetin with DNA as well as with other DNA damaging agents like MMC in vivo. The protective action of quercetin was not enhanced when given orally. Our findings suggest that quercetin may result in genomic instability in the tested dose range and significant reduction in MMC induced genotoxicity in the highest dose tested. These effects of quercetin are to be taken into consideration while evaluating the possible use of quercetin as a therapeutic agent., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Genotoxicity is one of the important endpoints for risk assessment of various lifestyle factors. The study is the first report on the genotoxic effect associated with sadagura, a unique smokeless tobacco prepared in southern Assam province of North-East India. Sadagura is consumed with or without betel quid and/or smoking. In the present cytogenetic monitoring study, analysis of micronuceus (MN), nuclear bud, binucleated, karyorrhectic, karyolytic and pyknotic cells tests were performed in the exfoliated buccal cells of 75 habituates and compared to controls matched for gender, age, and habit. Significant increase in the frequency of MN was found in sadagura chewers (0.48%, P < 0.001), smokers (0.46%, P < 0.01), betel quid with sadagura chewers (0.91%, P < 0.001) and smokers chewing betel quid with sadagura (0.53%, P < 0.001) as compared to the unexposed control group (0.07%). Betel quid chewers showed significant increase (1.65%, P < 0.05) in the frequency of binucleated cells as compared to the control group (0.16%). Results of this study demonstrated that sadagura consumed as a single agent or in combination with betel quid, leads to a significant induction of cytogenetic damage in the buccal epithelial cells of habituates. We suggest that analysis of other degenerative nuclear changes in addition to MN can provide valuable information while evaluating potential genotoxic agents.

Objective: Refinement of endoscopic pituitary surgery requires an understanding of the impact of demographic and surgical variables on outcomes., Methods: Multivariate logistic regression and ANOVA models were used to explore variables for association with outcomes in a consecutive series of 57 patients undergoing endoscopic pituitary surgery., Results: The mean duration of surgery was 177 min and was longer in patients with larger tumor size (p=0.03) and presentation with visual symptoms (p=0.02) in univariate analyses. The median duration of hospitalization was 3 days and was longer in patients with larger tumors (p=0.0005). Gross tumor removal was achieved in 89%. Tumor size correlated with extent of tumor removal with an almost 3-fold decrease in complete tumor removal for every 1cm increase in tumor size (p=0.047). High rates of hormonal control (90%) and improvement in visual symptoms (92%) were noted., Conclusions: High rates of gross tumor removal, hormonal cure and visual field improvement were noted in this series. Markers including tumor size and visual symptoms may be used to stratify patients.

This trial determined the safety and efficacy of the combination regimen clarithromycin (Biaxin), lenalidomide (Revlimid), and dexamethasone (BiRD) as first-line therapy for multiple myeloma. Patients received BiRD in 28-day cycles. Dexamethasone (40 mg) was given orally once weekly, clarithromycin (500 mg) was given orally twice daily, and lenalidomide (25 mg) was given orally daily on days 1 to 21. Objective response was defined by standard criteria (ie, decrease in serum monoclonal protein [M-protein] by at least 50%, and a decrease in urine M-protein by at least 90%). Of the 72 patients enrolled, 65 had an objective response (90.3%). A combined stringent and conventional complete response rate of 38.9% was achieved, and 73.6% of the patients achieved at least a 90% decrease in M-protein levels. This regimen did not interfere with hematopoietic stem-cell harvest. Fifty-two patients who did not go on to receive transplants received continued therapy (complete response, 37%; very good partial response, 33%). The major adverse events were thromboembolic events, corticosteroid-related morbidity, and cytopenias. BiRD is an effective regimen with manageable side effects in the treatment of symptomatic, newly diagnosed multiple myeloma. This trial was registered at www.clinicaltrials.gov as #NCT00151203.

Background: The ability to accurately predict clinical and pathological response and survival in patients undergoing preoperative chemotherapy may have a significant impact on treatment strategy for esophageal carcinoma. This study assessed the predictive accuracy of clinical response (CR) and positron emission tomography (PET) scanning in determining pathological downstaging and disease free survival (DFS) after chemotherapy., Methods: This is a retrospective review of patients who underwent chemotherapy prior to complete surgical resection for esophageal carcinoma between 1999 and 2005. Clinical response was correlated with pathological downstaging and survival. For PET scanning, the percent reduction in maxSUV after induction therapy was determined and we identified the optimal threshold of percent reduction in maxSUV for predicting clinical response and pathological downstaging., Results: Sixty-two patients (52 men, median age 62.3) were evaluated. Thirty-nine patients (62.9%) had either a partial (n = 32) or complete clinical response (n = 7) to induction therapy. The sensitivity, specificity, positive, and negative predictive value of an objective clinical response in predicting downstaging in T and (or) N were 85.7%, 55.9%, 61.5%, and 82.6%, respectively. There was no difference in DFS between responders and nonresponders. The PET sensitivity, specificity, positive, and negative predictive values for predicting pathologic downstaging were 77.8%, 52.9%, 56.8%, and 75%, respectively. Thirty-seven patients (59.7%) had a 50% or greater reduction in the maxSUV of their primary tumor and had a significant improvement in DFS compared with patients with a less than 50% reduction in maxSUV (median DFS time: 35.5 months vs 17.9 months, respectively, p = 0.03). Significantly, 11 patients had a 100% reduction in maxSUV despite the presence of residual tumor., Conclusions: Complete response and PET appear equivalent in predicting pathological downstaging. However, a 50% reduction in the maxSUV after induction therapy is more significantly associated with improved DFS than CR or pathological downstaging. Additionally, a complete absence of PET signal cannot be equated with a complete pathological response.

Background: Accurate response assessment is essential for evaluating new cancer treatments. We evaluated the impact of Response Evaluation Criteria in Solid Tumors (RECIST), World Health Organization (WHO) criteria and tumor shape on response assessment in patients with metastatic esophageal cancer., Patients and Methods: In 19 patients with metastatic esophageal cancer in a phase II trial of bryostatin-1 and paclitaxel, response was retrospectively assessed for 89 lesions with RECIST and WHO criteria on baseline and serial follow-up CT scans. The eccentricity factor (EF) was introduced for measuring the degree to which tumor shape diverges from a perfect sphere [EF = radical1-(LPD/MD)(2), where LPD is the largest perpendicular diameter and MD is the maximal diameter]., Results: The disagreement rate in best overall response categorization between RECIST (unidimensional) and WHO (bidimensional) criteria was 26.3%. Change in eccentricity was significantly greater (P < 0.01) for patients with disagreement (mean 0.31, range 0-0.91). When the short axis was used for unidimensional lymph node measurement, disagreement between WHO and RECIST lessened., Conclusions: Response assessment by WHO and RECIST differs substantially. Greater change in eccentricity is associated with greater discordance between WHO and RECIST. The discordance between WHO and RECIST may impact on how effective a therapy is judged to be.

Background and Objective: Most advanced cancer patients have multiple tumors. Because the multiple tumors are from the same patient, the tumor sizes are expected to be correlated and the information contained in each additional tumor might not always have significant 'added value' toward the response assessment. Needing to measure only a subset of tumors would reduce workload for the study radiologist but is expected to increase the variability in response outcome. We compute this increment in variability and find a procedure for choosing the minimum number (m) of tumors among some fixed maximum number (M) of correlated tumors that must be considered to ensure precision of at least as high as a specified proportion of the precision obtained if one were to measure all M tumors., Method: The ratio V(m)(R)/V(M)(R) = M2[m + (m2 - m)rho(ICC)]/m2[M + (M2 - M)rho(ICC)] quantifies the percentage increment in variance of the response R, where rho(ICC) is the intra-class between tumors within patient correlation coefficient. The procedure for choosing the minimum number of tumors is demonstrated using data for 42 cancer patients with 10 or more tumors., Results: Using the criterion that >20% increase in variability due to selection of a subset out of M of 10 tumors is unacceptable, we find that m of 9, 6, 5, 3, and 2 tumors are needed when rho(ICC)=0.0 (no correlation), 0.2, 0.4, 0.6, and 0.8, respectively. If the criterion is made stricter to >10%, the number of tumors needed rise to 10, 8, 6, 4, and 3, respectively. For the example, 6 tumors out of 10 are found to provide sufficiently stable response categorization confirming the theoretical result., Conclusion: If cancer research community can agree on a percentage of variability in response outcome that is unacceptable, it is mathematically possible to recommend a minimum number of tumors that should be used for response assessment.

Background: The purpose of this study was to retrospectively analyze the relationship between neo-adjuvant chemotherapy (NAC) and outcome in patients with high-grade extremity sarcomas., Patients and Methods: Inclusion criteria were high-grade, deep, >5 cm extremity soft tissue sarcomas. Patients diagnosed between 1990 and 2001 were treated with surgery only (n=282) or NAC containing doxorubicin/ifosfamide/mesna (AIM) (n=74). The stratified Cox proportional hazards model was used to test the effect of NAC on disease-specific survival and recurrence while adjusting for known prognostic factors., Results: NAC was associated with improved disease-specific survival for this cohort of patients (P=0.02). This overall improvement appears to be driven by the benefit of NAC on disease-specific survival for patient with tumors >10 cm. The 3-year disease-specific survival for tumors >10 cm was 0.62 (95% CI: 0.53-0.71) for patients not receiving NAC and 0.83 (95% CI: 0.72-0.95) for patients receiving NAC., Conclusion: NAC with AIM was associated with a significant improvement in disease-specific survival in patients with high-grade extremity soft tissue sarcomas >10 cm. These data emphasize the need for further prospective clinical studies of neo-adjuvant or adjuvant chemotherapy for patients with large high-grade extremity sarcomas.

Objective: Tumor shrinkage has been adopted as an end point for evaluating the effectiveness of new anticancer agents. The WHO (World Health Organization) criterion suggested measuring the tumor shrinkage by the change in the product of maximal diameter (MD) and the corresponding largest perpendicular diameter (LPD). The RECIST (Response Evaluation Criteria In Solid Tumor) guideline proposed using the change in MD only, based on the observation that this measure is more linearly related to tumor cell kill than the cross product (MD*LPD). Both criteria classify patients into four categories of response: complete response (CR: total disappearance), partial response (PR), stable disease (SD), and progressive disease (PD) but the criteria used in the definition of PD vary. It was anticipated that patients' actual response categorization would not be considerably affected by utilizing the RECIST criteria instead of WHO. Empirical evidence supporting this fact was provided by retrospective analysis of several large datasets., Study Design and Setting: A statistical simulation is performed to generate tumor measurements and patient response data under meaningful probability distributions with parameters based on data from 130 patients on clinical trials at a cancer center. Concordance measures between the two response criteria (Kappa coefficient and percentage disagreement per response category) are assessed systematically over various combinations of the percentage of elliptical tumors at baseline and the percentage of tumors changing shape from baseline to follow-up., Results: The overall percentage of disagreement between the two methods of response assessment is found to be in the range of 14-20%. The patients categorized by WHO in the PR, SD, and PD groups fall into a different category when assessed by RECIST between 8-16%, 3-12%, and 32-35% of the times, respectively. The kappa coefficient ranges between 0.68-0.77. The proportion of elliptical tumors at baseline does not greatly impact the concordance, but the magnitude of the change in the aspect ratio has a large impact., Conclusion: Response assessment as measured by RECIST, with both a change in the underlying metric and change in definition of progression, often results in different categorization of response compared to WHO. The difference in response categorization may be problematic when new experimental therapies are compared to conventional agents whose response rates have been established in historical trials. The apparent lower rate of disease progression with RECIST may mean that more patients remain on therapy. Higher percentages of patients with SD need to be interpreted cautiously by distinguishing those due to the change in the response criterion as opposed to those induced by drugs using pathways such as angiogenesis where disease stabilization is expected rather than shrinkage of tumor.

Methotrexate (MTX) transport was examined in 27 patients with untreated acute lymphocytic leukemia (ALL) and 31 patients with relapsed ALL using a previously described fluorescent MTX analog (PT430) displacement assay (Blood 80:1158, 1992). Only 13% of untreated patients were considered to have impaired MTX transport, whereas more than 70% of relapsed patients had evidence of impaired MTX transport. To further characterize the basis for this defect, Northern analyses for the reduced folate carrier (RFC) were performed on the RNA available from the leukemic blasts of 24 patients in whom MTX transport had been measured. Six of nine samples with impaired MTX transport had decreased RFC expression (one had no detectable RFC expression), while three had no decrease in RFC expression. None of 15 samples with normal MTX transport had decreased RFC expression. A reverse-transcriptase polymerase chain reaction (RT-PCR) assay was developed to quantitate RFC mRNA expression more accurately. Decreased RFC expression was demonstrated in six of the nine samples with impaired MTX transport, confirming the results obtained by Northern blot. These data indicate decreased RFC expression associated with impaired MTX transport is observed in relapsed ALL following treatment with MTX-containing therapy.

Although dihydrofolate reductase (DHFR) gene amplification is a common mechanism of resistance to methotrexate (MTX) in tumor cell lines, with the exception of a few case reports, the incidence of this phenomenon as a mechanism of MTX resistance in the clinic has not been reported. We studied 38 untreated patients and 29 patients in relapse with acute lymphoblastic leukemia (ALL) for gene amplification and p53 gene mutations. Three patients were studied both at diagnosis and at each of two relapses after treatment with MTX. Nine of 29 relapsed patients (31%) had low-level DHFR gene amplification (two to four gene copies) associated with increased levels of DHFR mRNA and enzyme activity. Of significance was a correlation of gene amplification with p53 mutations in seven of nine relapsed patients (P < .001). Low-level DHFR gene amplification may be an important cause of MTX resistance in ALL and strengthens the concept that mutations in the p53 gene may lead to gene amplification as a consequence of defective cell cycle control.