Search

Early response after 2 to 4 weeks of antidepressant therapy has been shown to predict remission by 8 to 12 weeks. Most of the work to date on early response has been done using data from randomized controlled trials.This naturalistic study uses archival data from a national tele-mental health company. The positive and negative predictive values as well as sensitivity and specificity were calculated using different drops in baseline Patient Health Questionnaire 9 scores at various periods. Demographic and clinical characteristics were compared between early responders versus those lacking early response. Binary logistic regression analyses determined if early response was predictive of remission, response, and greater than minimal improvement at 14 weeks. For those who do not show early improvement, treatments were investigated using binary logistic regression to see if changes predicted later outcomes.Positive predictive values for all endpoints improved with the strength of early response but did not improve much with the time allowed for that response to occur. In contrast, negative predictive values increased substantially with time. Using a definition of 30% drop in Patient Health Questionnaire 9 score at week 4, 56.5% of patients were early responders. Early responders were ~3.2 times more likely to achieve remission than those lacking early response. Of nonresponders by week 4, those prescribed atypical antipsychotics (+SSRI) had significantly reduced odds of response at week 14, whereas those prescribed a norepinephrine and dopamine reuptake inhibitor had increased odds.Early response may be associated with better outcomes at 14 weeks. In those with lack of response by week 4, patients prescribed a norepinephrine and dopamine reuptake inhibitor may achieve superior outcomes.

Recurrent Clostridioides difficile infection, associated with dysbiosis of gut microbiota, has substantial disease burden in the USA. RBX2660 is a live biotherapeutic product consisting of a broad consortium of microbes prepared from human stool that is under investigation for the reduction of recurrent C. difficile infection.A randomized, double-blind, placebo-controlled, phase III study, with a Bayesian primary analysis integrating data from a previous phase IIb study, was conducted. Adults who had one or more C. difficile infection recurrences with a positive stool assay for C. difficile and who were previously treated with standard-of-care antibiotics were randomly assigned 2:1 to receive a subsequent blinded, single-dose enema of RBX2660 or placebo. The primary endpoint was treatment success, defined as the absence of C. difficile infection diarrhea within 8 weeks of study treatment.Of the 320 patients screened, 289 were randomly assigned and 267 received blinded treatment (n = 180, RBX2660; n = 87, placebo). Original model estimates of treatment success were 70.4% versus 58.1% with RBX2660 and placebo, respectively. However, after aligning the data to improve the exchangeability and interpretability of the Bayesian analysis, the model-estimated treatment success rate was 70.6% with RBX2660 versus 57.5% with placebo, with an estimated treatment effect of 13.1% and a posterior probability of superiority of 0.991. More than 90% of the participants who achieved treatment success at 8 weeks had sustained response through 6 months in both the RBX2660 and the placebo groups. Overall, RBX2660 was well tolerated, with manageable adverse events. The incidence of treatment-emergent adverse events was higher in RBX2660 recipients compared with placebo and was mostly driven by a higher incidence of mild gastrointestinal events.RBX2660 is a safe and effective treatment to reduce recurrent C. difficile infection following standard-of-care antibiotics with a sustained response through 6 months.NCT03244644; 9 August, 2017.Clostridioides difficile is a diarrhea-causing bacterium that is associated with potentially serious and fatal consequences. Antibiotics used to treat or prevent infections have a side effect of damaging the healthy protective gut bacteria (microbiota). Damage to the gut microbiota can allow C. difficile to over-grow and produce toxins that injure the colon. Paradoxically, the standard of care treatment of C. difficile infection (CDI) is antibiotics. Although initially effective for the control of diarrhea, antibiotics can leave a patient at risk for CDI recurrence after antibiotic treatment is stopped. Live biotherapeutic products are microbiota-based treatments used to repair the gut microbiota. These products have been shown to reduce the recurrence of CDI. RBX2660 is an investigational microbiota-based live biotherapeutic. RBX2660 contains a diverse set of microorganisms. RBX2660 has been developed to reduce CDI recurrence in adults following antibiotic treatment for recurrent CDI. This study was conducted to demonstrate that RBX2660 is effective and safe in treating patients with recurrent CDI. Treatment was considered successful in participants who did not experience CDI recurrence within 8 weeks after administration. Overall, statistical modeling demonstrated that 70.6% of participants treated with RBX2660 and 57.5% of participants treated with placebo remained free of CDI recurrence through 8 weeks. A 13.1 percentage point increase in treatment success was observed with RBX2660 treatment compared with placebo. In participants who achieved treatment success at 8 weeks, more than 90% remained free of CDI recurrence through 6 months. The most common side effects with RBX2660 treatment were abdominal pain and diarrhea. No serious treatment-related side effects were reported. The current data from the comprehensive clinical development program support a positive benefit-risk profile for RBX2660 in the reduction of CDI recurrence in adults following antibiotic therapy for recurrent CDI.

Migraine affects over 40 million Americans and is the world’s second most disabling condition. As the majority of medical care for migraine occurs in primary care settings, not in neurology nor headache subspecialty practices, healthcare system interventions should focus on primary care. Though there is grade A evidence for behavioral treatment (e.g., biofeedback, cognitive behavioral therapy (CBT), and relaxation techniques) for migraine, these treatments are underutilized. Behavioral treatments may be a valuable alternative to opioids, which remain widely used for migraine, despite the US opioid epidemic and guidelines that recommend against them. Identifying and removing barriers to the use of headache behavioral therapy could help reduce the disability as well as the personal and social costs of migraine. These techniques will have their greatest impact if offered in primary care settings to the lower socioeconomic status groups at greatest risk for migraine. We review the societal and cultural challenges that impose barriers to optimal use of non-pharmacological treatment services. These barriers include insufficient knowledge of migraine/headache behavioral treatments and insufficient availability of clinicians trained in non-pharmacological treatment delivery; limited access in underserved communities; financial burden; and stigma associated with both headache and mental health diagnoses and treatment. For each barrier, we discuss potential approaches to minimizing its effect and thus enhancing non-pharmacological treatment utilization. Case Example A 25-year-old graduate student with a prior history of headaches in college is attending school in the evenings while working a full-time job. Now, his headaches have significant nausea and photophobia. They are twice weekly and are disabling enough that he is unable to complete homework assignments. He does not understand why the headaches occur on Saturdays when he pushes through all week to get through his examinations that take place on Friday evenings. He tried two different migraine preventive medications, but neither led to the 50% reduction in headache days his doctor had hoped for. His doctor had suggested cognitive behavioral therapy (CBT) before initiating the medications, but he had been too busy to attend the appointments, and the challenges in finding an in-network provider proved difficult. Now with the worsening headaches, he opted for the CBT and by the fifth week had already noted improvements in his headache frequency and intensity.

The global burden of malaria remains substantial. Circumsporozoite protein (CSP) has been demonstrated to be an effective target antigen, however, improvements that offer more efficacious and more durable protection are still needed. In support of research and development of next-generation malaria vaccines, Walter Reed Army Institute of Research (WRAIR) has developed a CSP-based antigen (FMP013) and a novel adjuvant ALFQ (Army Liposome Formulation containing QS-21). We present a single center, open-label, dose-escalation Phase 1 clinical trial to evaluate the safety and immunogenicity of the FMP013/ALFQ malaria vaccine candidate. In this first-in-human evaluation of both the antigen and adjuvant, we enrolled ten subjects; five received 20 μg FMP013 / 0.5 mL ALFQ (Low dose group), and five received 40 μg FMP013 / 1.0 mL ALFQ (High dose group) on study days 1, 29, and 57. Adverse events and immune responses were assessed during the study period. The clinical safety profile was acceptable and there were no serious adverse events. Both groups exhibited robust humoral and cellular immunological responses, and compared favorably with historical responses reported for RTS,S/AS01. Based on a lower reactogenicity profile, the 20 μg FMP013 / 0.5 mL ALFQ (Low dose) was selected for follow-on efficacy testing by controlled human malaria infection (CHMI) with a separate cohort. Trial Registration:Clinicaltrials.gov Identifier NCT04268420 (Registered February 13, 2020).

Background Malaria remains the top infectious disease threat facing the U.S. military in many forward operating environments. Compliance with malaria chemoprophylaxis remains a critical component in preventing malaria in the deployed Service Member. Studies of previous military operations show that compliance is consistently higher with weekly versus daily dosing regimens. Current FDA approved weekly chemoprophylaxis options have contraindications that can limit prescribing. The combination of chloroquine (CQ) with azithromycin (AZ) has previously been shown to be an efficacious treatment option for malaria, has pharmacokinetics compatible with weekly dosing, and has shown synergy when combined in vitro. Methods In this open label study, 18 healthy volunteers, aged 18–50 years (inclusive), were randomly assigned to receive either 300 mg CQ or 300 mg CQ and 2 gm azithromycin (CQAZ) of directly observed therapy, weekly for 3 weeks prior to undergoing mosquito bite challenge with chloroquine-resistant Plasmodium falciparum. Volunteers that remained asymptomatic and had no evidence of parasitaemia continued to receive weekly post-exposure chemoprophylaxis for 3 weeks following malaria challenge. The primary endpoint was the number of volunteers that remained asymptomatic and had no evidence of parasitaemia 28 days after the malaria challenge. Results All 6 (100%) volunteers randomized to the CQ control group became symptomatic with parasitaemia during the 28-day post-challenge period. Only 1/12 (8.3%) of volunteers in the CQAZ group developed symptoms and parasitaemia during the 28-day post-challenge period. However, after chemoprophylaxis was discontinued an additional 6 volunteers developed parasitaemia between days 28–41 after challenge, with 4 of 6 experiencing symptoms. 80% of subjects in the CQAZ group experienced treatment related gastrointestinal adverse events (including 13% that experienced severe nausea) compared to 38% in the CQ group. A comparison of the pharmacokinetics in the CQAZ group demonstrated higher azithromycin Cmax (p = 0.03) and AUC (p = 0.044) levels in those volunteers who never became parasitaemic compared to those who did. Conclusion Given the high rate of side effects and poor efficacy when administered for 3 weeks before and after challenge, the combination of weekly chloroquine and azithromycin is a suboptimal regimen combination for weekly malaria chemoprophylaxis. Trial registration ClinicalTrials.gov NCT03278808

Background Rapid, preoperative identification of patients with the highest risk for medical complications is necessary to ensure that limited infrastructure and human resources are directed towards those most likely to benefit. Existing risk scores either lack specificity at the patient level or utilise the American Society of Anesthesiologists (ASA) physical status classification, which requires a clinician to review the chart. Methods We report on the use of machine learning algorithms, specifically random forests, to create a fully automated score that predicts postoperative in-hospital mortality based solely on structured data available at the time of surgery. Electronic health record data from 53 097 surgical patients (2.01% mortality rate) who underwent general anaesthesia between April 1, 2013 and December 10, 2018 in a large US academic medical centre were used to extract 58 preoperative features. Results Using a random forest classifier we found that automatically obtained preoperative features (area under the curve [AUC] of 0.932, 95% confidence interval [CI] 0.910–0.951) outperforms Preoperative Score to Predict Postoperative Mortality (POSPOM) scores (AUC of 0.660, 95% CI 0.598–0.722), Charlson comorbidity scores (AUC of 0.742, 95% CI 0.658–0.812), and ASA physical status (AUC of 0.866, 95% CI 0.829–0.897). Including the ASA physical status with the preoperative features achieves an AUC of 0.936 (95% CI 0.917–0.955). Conclusions This automated score outperforms the ASA physical status score, the Charlson comorbidity score, and the POSPOM score for predicting in-hospital mortality. Additionally, we integrate this score with a previously published postoperative score to demonstrate the extent to which patient risk changes during the perioperative period.

Antigen-based tests for SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), are inexpensive and can return results within 15 minutes (1). Antigen tests have received Food and Drug Administration (FDA) Emergency Use Authorization (EUA) for use in asymptomatic and symptomatic persons within the first 5-12 days after symptom onset (2). These tests have been used at U.S. colleges and universities and other congregate settings (e.g., nursing homes and correctional and detention facilities), where serial testing of asymptomatic persons might facilitate early case identification (3-5). However, test performance data from symptomatic and asymptomatic persons are limited. This investigation evaluated performance of the Sofia SARS Antigen Fluorescent Immunoassay (FIA) (Quidel Corporation) compared with real-time reverse transcription-polymerase chain reaction (RT-PCR) for SARS-CoV-2 detection among asymptomatic and symptomatic persons at two universities in Wisconsin. During September 28-October 9, a total of 1,098 paired nasal swabs were tested using the Sofia SARS Antigen FIA and real-time RT-PCR. Virus culture was attempted on all antigen-positive or real-time RT-PCR-positive specimens. Among 871 (79%) paired swabs from asymptomatic participants, the antigen test sensitivity was 41.2%, specificity was 98.4%, and in this population the estimated positive predictive value (PPV) was 33.3%, and negative predictive value (NPV) was 98.8%. Antigen test performance was improved among 227 (21%) paired swabs from participants who reported one or more symptoms at specimen collection (sensitivity = 80.0%; specificity = 98.9%; PPV = 94.1%; NPV = 95.9%). Virus was isolated from 34 (46.6%) of 73 antigen-positive or real-time RT-PCR-positive nasal swab specimens, including two of 18 that were antigen-negative and real-time RT-PCR-positive (false-negatives). The advantages of antigen tests such as low cost and rapid turnaround might allow for rapid identification of infectious persons. However, these advantages need to be balanced against lower sensitivity and lower PPV, especially among asymptomatic persons. Confirmatory testing with an FDA-authorized nucleic acid amplification test (NAAT), such as RT-PCR, should be considered after negative antigen test results in symptomatic persons, and after positive antigen test results in asymptomatic persons (1).

Previous studies of secular change in cranial size among black South Africans have produced conflicting results.We re-examined cranial size change in this population during the 19th and 20th century by evaluating its relationship with individual year-of-birth, and the significance of trends among eight decennial cohorts.This study is based on 102 male and 89 female adults born between 1865 and 1959. Linear regressions were employed to evaluate possible relationships between year-of-birth and cranial dimensions; ANOVAs were used to evaluate the significance of long-term trends among decennial cohorts.No analysis revealed a secular change in cranial length in either sex; however, the ANOVA for cranial length in the combined sex sample was significant. There is no secular trend in female cranial breadth, but males display a negative trend in this dimension. This results in a secular trend for increased male dolichocephaly.The factors that underlie the negative secular trend in male cranial breadth and the absence of a secular trend in overall cranial size in this population are unclear. Nevertheless, these observations accord with findings related to stature and long bone strength in this population and are consistent with observations for other sub-Saharan African populations.

Prediction models of post-liver transplant mortality are crucial so that donor organs are not allocated to recipients with unreasonably high probabilities of mortality. Machine learning algorithms, particularly deep neural networks (DNNs), can often achieve higher predictive performance than conventional models. In this study, we trained a DNN to predict 90-day post-transplant mortality using preoperative variables and compared the performance to that of the Survival Outcomes Following Liver Transplantation (SOFT) and Balance of Risk (BAR) scores, using United Network of Organ Sharing data on adult patients who received a deceased donor liver transplant between 2005 and 2015 (n = 57,544). The DNN was trained using 202 features, and the best DNN’s architecture consisted of 5 hidden layers with 110 neurons each. The area under the receiver operating characteristics curve (AUC) of the best DNN model was 0.703 (95% CI: 0.682-0.726) as compared to 0.655 (95% CI: 0.633-0.678) and 0.688 (95% CI: 0.667-0.711) for the BAR score and SOFT score, respectively. In conclusion, despite the complexity of DNN, it did not achieve a significantly higher discriminative performance than the SOFT score. Future risk models will likely benefit from the inclusion of other data sources, including high-resolution clinical features for which DNNs are particularly apt to outperform conventional statistical methods.

Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New Background The authors tested the hypothesis that deep neural networks trained on intraoperative features can predict postoperative in-hospital mortality. Methods The data used to train and validate the algorithm consists of 59,985 patients with 87 features extracted at the end of surgery. Feed-forward networks with a logistic output were trained using stochastic gradient descent with momentum. The deep neural networks were trained on 80% of the data, with 20% reserved for testing. The authors assessed improvement of the deep neural network by adding American Society of Anesthesiologists (ASA) Physical Status Classification and robustness of the deep neural network to a reduced feature set. The networks were then compared to ASA Physical Status, logistic regression, and other published clinical scores including the Surgical Apgar, Preoperative Score to Predict Postoperative Mortality, Risk Quantification Index, and the Risk Stratification Index. Results In-hospital mortality in the training and test sets were 0.81% and 0.73%. The deep neural network with a reduced feature set and ASA Physical Status classification had the highest area under the receiver operating characteristics curve, 0.91 (95% CI, 0.88 to 0.93). The highest logistic regression area under the curve was found with a reduced feature set and ASA Physical Status (0.90, 95% CI, 0.87 to 0.93). The Risk Stratification Index had the highest area under the receiver operating characteristics curve, at 0.97 (95% CI, 0.94 to 0.99). Conclusions Deep neural networks can predict in-hospital mortality based on automatically extractable intraoperative data, but are not (yet) superior to existing methods.

Summary Background Clostridium difficile infection is the most common health-care-associated infection in the USA. We assessed the safety and efficacy of ridinilazole versus vancomycin for treatment of C difficile infection. Methods We did a phase 2, randomised, double-blind, active-controlled, non-inferiority study. Participants with signs and symptoms of C difficile infection and a positive diagnostic test result were recruited from 33 centres in the USA and Canada and randomly assigned (1:1) to receive oral ridinilazole (200 mg every 12 h) or oral vancomycin (125 mg every 6 h) for 10 days. The primary endpoint was achievement of a sustained clinical response, defined as clinical cure at the end of treatment and no recurrence within 30 days, which was used to establish non-inferiority (15% margin) of ridinilazole versus vancomycin. The primary efficacy analysis was done on a modified intention-to-treat population comprising all individuals with C difficile infection confirmed by the presence of free toxin in stool who were randomly assigned to receive one or more doses of the study drug. The study is registered with ClinicalTrials.gov, number NCT02092935. Findings Between June 26, 2014, and August 31, 2015, 100 patients were recruited; 50 were randomly assigned to receive ridinilazole and 50 to vancomycin. 16 patients did not complete the study, and 11 discontinued treatment early. The primary efficacy analysis included 69 patients (n=36 in the ridinilazole group; n=33 in the vancomycin group). 24 of 36 (66·7%) patients in the ridinilazole group versus 14 of 33 (42·4%) of those in the vancomycin group had a sustained clinical response (treatment difference 21·1%, 90% CI 3·1–39·1, p=0·0004), establishing the non-inferiority of ridinilazole and also showing statistical superiority at the 10% level. Ridinilazole was well tolerated, with an adverse event profile similar to that of vancomycin: 82% (41 of 50) of participants reported adverse events in the ridinilazole group and 80% (40 of 50) in the vancomycin group. There were no adverse events related to ridinilazole that led to discontinuation. Interpretation Ridinilazole is a targeted-spectrum antimicrobial that shows potential in treatment of initial C difficile infection and in providing sustained benefit through reduction in disease recurrence. Further clinical development is warranted. Funding Wellcome Trust and Summit Therapeutics.

Background/objectives Nonpharmacological interventions, such as biofeedback, cognitive behavioral therapy, and relaxation techniques are Level-A evidence-based treatments for headache. The impact of these interventions is often equivalent to or greater than pharmacological interventions, with fewer side effects. Despite such evidence, the rate of participation in nonpharmacological interventions for headache remains low. Once obstacles to optimizing use of behavioral interventions, such as local access to nonpharmacological treatment and primary headache providers are traversed, identification of barriers contributing to low adherence is imperative given the high levels of disability and cost associated with treating headache disorders. In this review of factors in adults associated with underuse of nonpharmacological interventions, we discuss psychological factors relevant to participation in nonpharmacological treatment, including attitudes and beliefs, motivation for change, awareness of triggers, locus of control, self-efficacy, acceptance, coping styles, personality traits, and psychiatric comorbidities associated with treatment adherence. Finally, future prospects and approaches to optimizing treatment matching and minimizing adherence issues are addressed. Methods An interdisciplinary team conducted this narrative review. Neuropsychologists conducted a literature search during the month of July 2017 using a combination of the keywords ("headache" or "migraine") and ("adherence" or "compliance") or "barriers to treatment" or various "psychological factors" discussed in this narrative review. Content experts, a psychiatrist, and a complementary and integrative health specialist provided additional commentary and input to this narrative review resulting in integration of additional noteworthy studies, book chapters and books. Results Various psychological factors, such as attitudes and beliefs, lack of motivation, poor awareness of triggers, external locus of control, poor self-efficacy, low levels of acceptance, and engagement in maladaptive coping styles can contribute to nonadherence. Conclusions To maximize adherence, clinicians can assess and address an individual's level of treatment acceptance, beliefs that may present as barriers, readiness for change, locus of control, self-efficacy and psychiatric comorbidities. Identification of barriers to adherence as well as the application of relevant assessment and intervention techniques have the potential to facilitate adherence and ultimately improve treatment success.

Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New Background With appropriate algorithms, computers can learn to detect patterns and associations in large data sets. The authors’ goal was to apply machine learning to arterial pressure waveforms and create an algorithm to predict hypotension. The algorithm detects early alteration in waveforms that can herald the weakening of cardiovascular compensatory mechanisms affecting preload, afterload, and contractility. Methods The algorithm was developed with two different data sources: (1) a retrospective cohort, used for training, consisting of 1,334 patients’ records with 545,959 min of arterial waveform recording and 25,461 episodes of hypotension; and (2) a prospective, local hospital cohort used for external validation, consisting of 204 patients’ records with 33,236 min of arterial waveform recording and 1,923 episodes of hypotension. The algorithm relates a large set of features calculated from the high-fidelity arterial pressure waveform to the prediction of an upcoming hypotensive event (mean arterial pressure < 65 mmHg). Receiver-operating characteristic curve analysis evaluated the algorithm’s success in predicting hypotension, defined as mean arterial pressure less than 65 mmHg. Results Using 3,022 individual features per cardiac cycle, the algorithm predicted arterial hypotension with a sensitivity and specificity of 88% (85 to 90%) and 87% (85 to 90%) 15 min before a hypotensive event (area under the curve, 0.95 [0.94 to 0.95]); 89% (87 to 91%) and 90% (87 to 92%) 10 min before (area under the curve, 0.95 [0.95 to 0.96]); 92% (90 to 94%) and 92% (90 to 94%) 5 min before (area under the curve, 0.97 [0.97 to 0.98]). Conclusions The results demonstrate that a machine-learning algorithm can be trained, with large data sets of high-fidelity arterial waveforms, to predict hypotension in surgical patients’ records.

OBJECTIVE Emerging evidence suggests that peripheral neuropathy begins in the early stages of diabetes pathogenesis. Our objective was to describe the prevalence of peripheral neuropathy and nerve dysfunction according to glucose tolerance and metabolic syndrome status and examine how these conditions are associated with neurological changes in individuals at risk for type 2 diabetes. RESEARCH DESIGN AND METHODS We studied 467 individuals in the longitudinal PROMISE (Prospective Metabolism and Islet Cell Evaluation) cohort. Peripheral neuropathy was defined by Michigan Neuropathy Screening Instrument (MNSI) scores (>2), and the severity of nerve dysfunction was measured objectively by vibration perception thresholds (VPTs) using a neurothesiometer. Metabolic syndrome was defined using the International Diabetes Federation/American Heart Association harmonized criteria. RESULTS The prevalence of peripheral neuropathy was 29%, 49%, and 50% for normal glycemia, prediabetes, and new-onset diabetes, respectively (P < 0.001 for trend). The mean VPT was 6.5 V for normal glycemia, 7.9 V for prediabetes, and 7.6 V for new-onset diabetes (P = 0.024 for trend). Prediabetes was associated with higher MNSI scores (P = 0.01) and VPTs (P = 0.004) versus normal glycemia, independent of known risk factors. Additionally, progression of glucose intolerance over 3 years predicted a higher risk of peripheral neuropathy (P = 0.007) and nerve dysfunction (P = 0.002). Metabolic syndrome was not independently associated with MNSI scores or VPTs. CONCLUSIONS In individuals with multiple risk factors for diabetes, prediabetes was associated with similar risks of peripheral neuropathy and severity of nerve dysfunction as new-onset diabetes. Prediabetes, but not metabolic syndrome, was independently associated with both the presence of peripheral neuropathy and the severity of nerve dysfunction.

Objectives We aimed to compare the associations of directly measured plasma free 25-hydroxyvitamin D [25(OH)D] and total 25(OH)D concentrations with insulin sensitivity (SI) and β-cell function in nondiabetic Hispanics and African Americans. We hypothesized that directly measured free 25(OH)D would be more strongly associated with these measures of glucose homeostasis and that associations would differ by race. Design We studied 1189 nondiabetic participants in the Insulin Resistance Atherosclerosis Study Family Study using data from baseline examinations from 2000 to 2002. SI, acute insulin response, and disposition index (DI) were determined from frequently sampled intravenous glucose tolerance tests. Plasma free and total 25(OH)D concentrations were measured by enzyme-linked immunosorbent assay and radioimmunoassay, respectively. Results The median concentrations of plasma free 25(OH)D were 3.46 pg/mL for Hispanics and 2.17 pg/mL for African Americans (P < 0.0001), whereas the median concentrations of plasma total 25(OH)D were 16 ng/mL for Hispanics and 10 ng/mL for African Americans (P < 0.0001). Plasma free and total 25(OH)D were both positively associated with SI and DI in generalized estimating equations adjusted for demographic and lifestyle factors. After further adjustment with body mass index, the associations were no longer statistically significant, except for a significant association between plasma free 25(OH)D and SI. There was no effect modification by ethnicity on any of the exposure-outcome associations. Conclusions Our data showed that plasma free 25(OH)D had a slightly stronger association with SI compared with plasma total 25(OH)D, although the difference was modest and there were no marked differences in the associations between Hispanics and African Americans.

BACKGROUND: Physical exercise has been proven to be an effective method for improving cognition and mood, but little is known about its benefits among individuals with traumatic brain injury. OBJECTIVE: This pilot study investigated the feasibility of a combined exercise and self-affirmation intervention (IntenSati) for enhancing cognition and mood in individuals with TBI. It was hypothesized that this intervention would improve individuals' cognition and mood following the completion of the program. METHOD: This intervention was held at an outpatient rehabilitation department in an urban medical center. A wait-list control design was conducted. Twenty-one adult participants-at least 12-months post-TBI-enrolled in the study. Twelve of them completed the study. Assessment was conducted at three time-points throughout the study using neuropsychological and self-report measures to evaluate participants' cognition and mood. Following initial evaluation, participants were assigned into either the immediate intervention group or the waitlist control group. During the intervention, participants attended the program twice a week over the course of 8 weeks. Debriefing was conducted following the completion of the program. RESULTS: Both independent t tests and paired t tests were utilized. RESULTS indicated that the intervention group experienced less depressive symptoms following the completion of the IntenSati program compared to the waitlist control group. Participants also reported having less depressive symptoms, experienced more positive affect, and had a higher quality of life following the completion of the program. Moderate-to-large effect sizes were found on decrease in negative affect. However, results associated with cognitive benefits were mixed. The participants tolerated the program well and reported satisfaction with the program. CONCLUSIONS: Results from this study indicated that the IntenSati exercise program is a feasible and beneficial intervention for individuals with TBI as supported by the positive impact on their mood and quality of life. Language: en

Background Social cognitive theory describes a process in which behavior can be disengaged from moral self control through eight different mechanisms. These mechanisms were used for the development of a new scale for measuring moral disengagement (Moral Disengagement Inventory, or MDI) in pharmacists. Objectives The objectives of this study were to assess the reliability and validation of a scale to measure pharmacists' moral disengagement toward patients who exhibit behaviors directly or indirectly leading to their disease condition, such as an asthmatic patient who smokes or a non-compliant asthmatic patient. Methods A self-administered survey called the Moral Disengagement Instrument (MDI) was developed for this study. Once the MDI was designed, the items were evaluated for content validity, readability and face validity. The reliability of the developed measures was assessed. The convergent and discriminant validity of the moral disengagement constructs were tested using confirmatory factor analysis. Results The reliability coefficient for the MDI for the asthmatic smoker was 0.814 and reliability coefficient for the MDI for the non-compliant asthmatic patient was 0.782. Evidence supporting validity of the MDI was provided in a confirmatory factor analysis. Conclusions The Moral Disengagement Instrument (MDI), developed as a tool for measuring pharmacists' disengagement beliefs for a smoker asthmatic patient and a non-compliant asthmatic patient, was found to be reliable and valid.

Social support has been shown to act as a buffer for cardiovascular responses to stress. However, little is known about how social support and networks are related to cardiovascular responses to immigration stress recall. The current study evaluated the impact of structural and functional support on cardiovascular reaction following immigrant stress recall provocation as well as the moderation effect of interdependent self-construal among first-generation Chinese immigrants. One hundred fifty Chinese immigrants were recruited in the New York Chinatown area. Participants completed questionnaires assessing their levels of social support and networks, and interdependent self-construal. Following adaptation, participants recalled a recent post-immigration stress-provoking situation. Cardiovascular measures were taken during adaptation, stressor task, and recovery period. Hierarchical multiple regression analysis was performed. Social network size and type, as well as perceived emotional support were positively predictive of systolic blood pressure (SBP) reactivity changes. Instrumental support seeking was a positive predictor of SBP and diastolic blood pressure (DBP) reactivity. The moderation effect between instrumental support seeking and interdependent self-construal were significantly predictive of DBP reactivity and recovery, suggesting that perceptions about themselves in relation to others is a crucial factor for determining whether support seeking is beneficial or not. Social support was not a direct buffer on cardiovascular responses to stress among Chinese immigrants. Chinese values of interdependence and collectivism may partly explain the disconfirming results. Still, when interdependent self-construal was taken into account, Chinese immigrants who had less interdependent self-construal, but solicited more instrumental support, had faster adaptation to stress over the long term.

Previous research on the association between fish consumption and incident type 2 diabetes has been inconclusive. In addition, few studies have investigated how fish consumption may be related to the metabolic abnormalities underlying diabetes. Therefore, we examined the association of fish consumption with measures of insulin sensitivity and beta-cell function in a multi-ethnic population.We examined the cross-sectional association between fish consumption and measures of insulin sensitivity and secretion in 951 non-diabetic participants in the Insulin Resistance Atherosclerosis Study (IRAS). Fish consumption, categorized as2 vs. ≥2 portions/week, was measured using a validated food frequency questionnaire. Insulin sensitivity (S(I)) and acute insulin response (AIR) were determined from frequently sampled intravenous glucose tolerance tests. Higher fish consumption was independently associated with lower S(I)-adjusted AIR (β = -0.13 [-0.25, -0.016], p = 0.03, comparing ≥2 vs.2 portions/week). Fish consumption was positively associated with intact and split proinsulin/C-peptide ratios, however, these associations were confounded by ethnicity (multivariable-adjusted β = 0.073 [-0.014, 0.16] for intact proinsulin/C-peptide ratio, β = 0.031 [-0.065, 0.13] for split proinsulin/C-peptide ratio). We also observed a significant positive association between fish consumption and fasting blood glucose (multivariable-adjusted β = 2.27 [0.68, 3.86], p = 0.005). We found no association between fish consumption and S(I) (multivariable-adjusted β = -0.015 [-0.083, 0.053]) or fasting insulin (multivariable-adjusted β = 0.016 [-0.066, 0.10]).Fish consumption was not associated with measures of insulin sensitivity in the multi-ethnic IRAS cohort. However, higher fish consumption may be associated with pancreatic beta-cell dysfunction.

OBJECTIVE We aimed to identify factors that are independently associated with the metabolic clearance rate of insulin (MCRI) and to examine the association of MCRI with incident type 2 diabetes in nondiabetic Hispanics and African Americans. RESEARCH DESIGN AND METHODS We investigated 1,116 participants in the Insulin Resistance Atherosclerosis Study (IRAS) Family Study with baseline examinations from 2000 to 2002 and follow-up examinations from 2005 to 2006. Insulin sensitivity (SI), acute insulin response (AIR), and MCRI were determined at baseline from frequently sampled intravenous glucose tolerance tests. MCRI was calculated as the ratio of the insulin dose over the incremental area under the curve of insulin. Incident diabetes was defined as fasting glucose ≥126 mg/dL or antidiabetic medication use by self-report. RESULTS We observed that SI and HDL cholesterol were independent positive correlates of MCRI, whereas fasting insulin, fasting glucose, subcutaneous adipose tissue, visceral adipose tissue, and AIR were independent negative correlates (all P < 0.05) at baseline. After 5 years of follow-up, 71 (6.4%) participants developed type 2 diabetes. Lower MCRI was associated with a higher risk of incident diabetes after adjusting for demographics, lifestyle factors, HDL cholesterol, indexes of obesity and adiposity, and insulin secretion (odds ratio 2.01 [95% CI 1.30–3.10], P = 0.0064, per one-SD decrease in loge-transformed MCRI). CONCLUSIONS Our data showed that lower MCRI predicts the incidence of type 2 diabetes.

Background Clinical trials to date have not provided definitive evidence regarding the effects of glucose lowering on the incidence of congestive heart failure (CHF). We synthesized available prospective epidemiological data on the association between glycaemia measured by haemoglobin A1c (HbA1c) and incident CHF in individuals with diabetes. Methods and results We searched electronic databases and reference lists of selected articles for relevant prospective epidemiological studies. We abstracted data from relevant studies using standardized forms and obtained additional data from investigators when required. We pooled study-specific relative risk estimates using random-effects model meta-analysis. Of the 1044 citations identified, we included 10 studies comprising 178 929 participants with diabetes and 14 176 incident CHF cases. Five studies included only patients with type 2 diabetes, four studies had predominantly patients with type 2 diabetes, and one study included only patients with type 1 diabetes. All studies except one showed an increased risk of CHF with higher HbA1c. The overall adjusted risk ratio (RR) for CHF was 1.15 [95% confidence interval (CI) 1.10–1.21] for each percentage point higher HbA1c. There was substantial heterogeneity across the 10 studies (I2: 83%; 95% CI 69–91%; P < 0.001) not explained by available study-level characteristics such as study design or average HbA1c level. In seven studies reporting RRs with more than one degree of adjustment, the association was minimally altered after adjustment for several cardiovascular risk factors. Conclusions In observational studies of individuals with diabetes, a higher HbA1c level was associated with a significantly increased incidence of CHF.

Aims Cross-sectional evidence indicates that abdominal adiposity, hypertension, dyslipidaemia and glycaemia are associated with reduced metabolic clearance rate of insulin (MCRI). Little is known about the progression of MCRI and whether components of metabolic syndrome are associated with the change in MCRI. In this study, we examined the association between components of metabolic syndrome and the 5-year change of MCRI. Methods At baseline and 5-year follow-up, we measured fasting plasma triglycerides (TG), high-density lipoprotein (HDL) cholesterol, blood pressure (BP), waist circumference (WC) and fasting blood glucose (FBG) in 784 non-diabetic participants in the Insulin Resistance Atherosclerosis Study. MCRI, insulin sensitivity (SI) and acute insulin response (AIR) were determined from frequently sampled intravenous glucose tolerance tests. Results We observed a 29% decline of MCRI at follow-up. TG, systolic BP and WC at baseline were inversely associated with a decline of MCRI regression models adjusted for age, sex, ethnicity, smoking, alcohol consumption, energy expenditure, family history of diabetes, BMI, SI and AIR [β = −0.057 (95% confidence interval, CI: −0.11, −0.0084) for TG, β = −0.0019 (95% CI: −0.0035, −0.00023) for systolic BP and β = −0.0084 (95% CI: −0.013, −0.0039) for WC; all p

Background APOBEC3B is a cytosine deaminase implicated in immune response to viral infection, cancer predisposition and carcinogenesis. Germline APOBEC3B deletion is more common in East Asian women and confers a modest risk to breast cancer in both East Asian and Caucasian women. Analysis of tumour samples from women of European descent has shown that germline APOBEC3B deletion is associated with an increased propensity to develop somatic mutations and with an enrichment for immune response-related gene sets. However, this has not been examined in Asian tumour samples, where population differences in genetic and dietary factors may have an impact on the immune system. Methods In this study, we determined the prevalence of germline APOBEC3B deletion and its association with breast cancer risk in a cross-sectional hospital-based Asian multi-ethnic cohort of 1451 cases and 1442 controls from Malaysia. We compared gene expression profiles of breast cancers arising from APOBEC3B deletion carriers and non-carriers using microarray analyses. Finally, we characterised the overall abundance of tumour-infiltrating immune cells in breast cancers from TCGA and METABRIC using ESTIMATE and relative frequency of 22 immune cell subsets in breast cancers from METABRIC using CIBERSORT. Results The minor allelic frequency of APOBEC3B deletion was estimated to be 0.35, 0.42 and 0.16 in female populations of Chinese, Malay and Indian descent, respectively, and that germline APOBEC3B deletion was associated with breast cancer risk with odds ratios of 1.23 (95 % CI: [1.05, 1.44]) for one-copy deletion and 1.38 (95 % CI: [1.10, 1.74]) for two-copy deletion compared to women with no deletion. Germline APOBEC3B deletion was not associated with any clinicopathologic features or the expression of any APOBEC family members but was associated with immune response-related gene sets (FDR q values

Many parents are reluctant to educate their Asian American adolescents on sexual health topics because sexuality is taboo in most Asian cultures. A survey was conducted with Chinese, Filipina, Korean, and Vietnamese college females ages 18-25 to assess sources of abstinence and birth control education and age of sexual debut. Parents were the least reported source of sex education for all four ethnic groups, with the majority of respondents reporting school as their source of sex education. Respondents who reported family as their source of abstinence education had a sexual debut of 6 months later than those who did not. Females who reported family as their source of birth control education began having sex more than 7 months later than those who reported other sources. Disaggregation of data by Asian ethnic groups and examining differences in delivery of sex education among ethnic groups may improve school curricula and sexual health.

Social support and coping strategies are important determinants of health, especially for those in the immigrant community adjusting to a new environment.This study assessed the buffering effects of perceived social support and different coping styles on cardiovascular reactivity to stress among Chinese immigrants in the New York City Chinatown area.Participants (N = 50, 76% women, and 22-84 years old) completed questionnaires assessing their perceived social support and coping strategy preferences. They were then asked to recall a stress-provoking event related to their immigration experience in a semi-structured interview format.Hierarchical multiple regression analyses confirmed the interaction effect between perceived social support and problem-focused, emotion-focused, or reappraisal coping on heart rate reactivity. Additionally, Chinese immigrants who upheld more Chinese values were highly correlated with stronger perceived availability of social support and were more likely to incorporate the use of problem-focused and reappraisal coping styles.Findings suggest that high level of social support and the use of reappraisal coping strategies were associated with attenuated cardiovascular responses to stress.

To the Editor: More than 65% of adult Americans are overweight or obese, with obesity comprising about half of all overweight adults (1). As a result, many people are turning to herbal dietary supplements (HDSs), which promise to “burn fat” and “lose weight fast”. National surveys have shown a steady increase of dietary supplement use, with some estimates as high as 70% among US adults (2,3). In parallel, the number of reports of drug-induced liver injury (DILI) due to HDSs has been rising (3,4,5). Multi-ingredient HDSs that are marketed for bodybuilding or weight loss account for the majority of cases of HDS-induced liver injury (3).

Single-parenting students face unique challenges that may adversely affect their mental health, which have not been explored in community college settings.The authors conducted secondary analysis of Spring 2013 data from the American College Health Association-National College Health Assessment to examine difficulties facing single-parent community college students and the association between single parenting and negative mental health (depression, self-injury, suicide attempt).Participants were 6,832 California community college students, of whom 309 were single parents.Demographic and mental health data were characterized using univariate descriptive analyses. Bivariate analyses determined whether single parents differed from other students regarding negative mental health or traumatic/difficult events.Finances, family, and relationship difficulties disproportionally affected single parents, who reported nearly twice as many suicide attempts as their counterparts (5.3% vs. 2.7%; p.0001).Single-parenting students face a higher prevalence of mental health stressors than other community college students.

BACKGROUND: Although studies have reported large reductions in the risks of AIDS and death since the introduction of potent anti-retroviral therapies, few have evaluated whether this has been similar for all AIDS-defining diseases. We wished to evaluate changes over time in the risk of specific AIDS-defining diseases, as first events, using data from individuals with known dates of HIV seroconversion. METHODS: Using a competing risks proportional hazards model on pooled data from 20 cohorts (CASCADE), we evaluated time from HIV seroconversion to each first AIDS-defining disease (16 groups) and to death without AIDS for four calendar periods, adjusting for exposure category, age, sex, acute infection, and stratifying by cohort. We compared results to those obtained from a cause-specific hazards model. RESULTS: Of 6,941, 2,021 (29%) developed AIDS and 437 (6%) died without AIDS. The risk of AIDS or death remained constant to 1996 then reduced; relative hazard = 0.89 (95% CI: 0.77-1.03); 0.90 (95% CI: 0.81-1.01); and 0.32 (95% CI: 0.28-0.37) for 1979-1990, 1991-1993, and 1997-2001, respectively, compared to 1994-1996. Significant risk reductions in 1997-2001 were observed in all but two AIDS-defining groups and death without AIDS in a competing risks model (with similar results from a cause-specific model). There was significant heterogeneity in the risk reduction across events; from 96% for cryptosporidiosis, to 17% for death without AIDS (P < 0.0001). CONCLUSION: These findings suggest that studies reporting a stable trend for particular AIDS diseases over the period 1979-2001 may not have accounted for the competing risks among other events or lack the power to detect smaller trends.

Factors predictive of death at South Australian major trauma services were investigated among 8,654 patients who had experienced severe trauma from 1997 to 2000.Univariate and multivariate analyses of age, sex, injury severity, presence of comorbid conditions, and calendar year of presentation were performed.Multiple logistic regression indicated that factors predictive of death were older age; higher injury severity as indicated by the New Injury Severity Score and the Revised Trauma Score; and accompanying chronic liver disease, ischemic heart disease, and chronic renal failure. A decrease in risk of death by calendar year was statistically significant (p = 0.001). Using 1997 as the reference, the relative odds of death were 0.86 (95% confidence limits) (0.53, 1.39) for 1998, 0.60 (0.36, 0.99) for 1999, and 0.45 (0.27, 0.76) for 2000.Results show a decrease in risk of death of patients attending South Australian major trauma services, from injuries of equivalent severity, during the first 4 years of operation of the State Trauma System.

Background Variation in clinical practice in the perioperative environment and intensive care unit is a major challenge facing modern medicine. The objective of the present study was to analyse intraoperative crystalloid administration practices at two academic medical centres in the USA. Methods We extracted clinical data from patients undergoing intra-abdominal procedures performed at UC Irvine (UCI) and Vanderbilt University (VU) Medical Centres. Limiting data to uncomplicated elective surgery with minimal blood loss, we quantified variability in fluid administration within individual providers, between providers, and between types of procedures using a corrected coefficient of variation (cCOV). Regression was performed using a general linear model to determine factors most predictive of fluid administration. Results For provider analysis and model building, 1327 UCI and 4585 VU patients were used. The average corrected crystalloid infusion rate across all providers at both institutions was 7.1 (sd 4.9) ml kg−1 h−1, an overall cCOV of 70%. Individual providers ranged from 2.3 (sd 3.7) to 14 (sd 10) ml kg−1 h−1. The final regression model strongly favoured personnel as predictors over other patient predictors. Conclusions Wide variability in crystalloid administration was observed both within and between individual anaesthesia providers, which might contribute to variability in surgical outcomes.

Ovarian cancer is a leading cause of cancer deaths among women. Effective targets to treat advanced epithelial ovarian cancer (EOC) and biomarkers to predict treatment response are still lacking because of the complexity of pathways involved in ovarian cancer progression. Here we show that miR-181a promotes TGF-β-mediated epithelial-to-mesenchymal transition via repression of its functional target, Smad7. miR-181a and phosphorylated Smad2 are enriched in recurrent compared with matched-primary ovarian tumours and their expression is associated with shorter time to recurrence and poor outcome in patients with EOC. Furthermore, ectopic expression of miR-181a results in increased cellular survival, migration, invasion, drug resistance and in vivo tumour burden and dissemination. In contrast, miR-181a inhibition via decoy vector suppression and Smad7 re-expression results in significant reversion of these phenotypes. Combined, our findings highlight an unappreciated role for miR-181a, Smad7, and the TGF-β signalling pathway in high-grade serous ovarian cancer., Ovarian cancer is often diagnosed at a late stage when metastasis has already occurred. In this study, Parikh et al. show that mir-181a is involved in mediating the epithelial-to-mesenchymal transition in ovarian cancer, leading to activation of the TGF-β signalling pathway and metastasis.

OBJECTIVE To investigate the association between dietary n-3 long-chain polyunsaturated fatty acids (n-3 LC-PUFAs) and the degree and development of albuminuria in type 1 diabetes. RESEARCH DESIGN AND METHODS We analyzed longitudinal data from 1,436 participants in the Diabetes Control and Complications Trial. We defined the average intake of eicosapentaenoic and docosahexaenoic acid from diet histories. Urinary albumin excretion rates (UAERs) were measured over 24 h; incident albuminuria was considered the first occurrence of an UAER >40 mg/24 h sustained for ≥1 year in normoalbuminuric individuals. RESULTS In a mean follow-up of 6.5 years, we observed a lower mean UAER (difference 22.7 mg/24 h [95% CI 1.6–43.8)]) in the top versus the bottom third of dietary n-3 LC-PUFAs, but we found no association with incident albuminuria. CONCLUSIONS Dietary n-3 LC-PUFAs appear inversely associated with the degree but not with the incidence of albuminuria in type 1 diabetes. These findings require further investigation in prospective studies.

AIM—This study describes the long term follow up of haemophilic patients infected with hepatitis C virus (HCV) between 1961 and 1985. METHODS—Clinical and treatment records from 310 patients with inherited coagulation disorders treated with blood product before 1985 were reviewed. Standard survival analysis methods were used to model progression to liver failure and death. RESULTS—A total of 298/305 (98%) patients tested were anti-HCV positive. Twenty seven (9%) individuals consistently HCV polymerise chain reaction negative were considered to have cleared the virus. By 1 September 1999, 223/310 (72%) were alive, 26 (8%) had died a liver related death, and 61 (20%) had died from other, predominantly human immunodeficiency virus (HIV) related, causes. Kaplan-Meier progression rates to death from any cause and liver related deaths 25 years after exposure to HCV were 47% (95% confidence intervals (CI) 34-60) and 19% (95% CI 10-27), respectively. After 13.3 years from 1985, by which time all patients had seroconverted to HIV, progression rates to death from any cause and liver related deaths were, respectively, 8% (95% CI 4-13) and 3% (95% CI 0.4-6) for those HIV negative, and 57% (95% CI 48-66) and 21% (95% CI 13-31) for those HIV positive (p=0.0001). Using Cox proportional hazard models, the adjusted relative hazard of death for individuals coinfected with HIV compared with those infected with HCV alone was 19.47 (95% CI 9.22-41.10), 0.99 (95% CI 0.39-2.53), 3.47 (95% CI 1.40-8.63), and 9.74 (95% CI 3.91-24.26) for the age groups at infection 10-19 years, 20-29 years, and >30 years, respectively, compared with the age group

A 26-year-old Brazilian man was admitted to The Toronto Hospital with a headache and visual scintillation. His last travel to Brazil was five years previously. A computed tomography (CT) scan of the head showed an occipital mass with surrounding vasogenic edema. Occipital brain biopsy revealed Schistosoma mansoni eggs. The patient was treated with two doses of praziquantel (20 mg/kg) and dexamethasone (10 mg). His symptoms and occipital mass resolved. Cerebral schistosomiasis is, in part, caused by the host's inflammatory response to Schistosoma. Modes of treatment have included surgical resection, the antiparasitic drugs oxamniquine or praziquantel, and corticosteroids. Corticosteroids may diminish granulomatous inflammation, thereby preventing further tissue destruction, and there is evidence that they also reduce ova deposition. Our review of the literature supports prompt medical therapy in patients with cerebral schistosomiasis. While the minimally or asymptomatic individual may be treated with praziquantel alone, clinicians should consider adjunctive therapy with corticosteroids for patients with prominent neurologic signs or symptoms or mass lesions with evidence of surrounding edema on a CT scan or by magnetic resonance imaging.

A 37-year-old woman with a known history of longstanding neurocysticercosis presented with a three-day history of new onset headache. Several years prior to her current presentation, she had undergone cysticidal treatment and was assumed to be cured of active disease. Computed tomography and magnetic resonance imaging studies done three months prior to presentation showed multiple intracerebral calcified lesions consistent with resolved neurocysticercosis. Physical and laboratory findings were noncontributory. Imaging studies showed the same previously calcified lesions, but they were now surrounded by large amounts of edema. This case represents a unique report of reactivation of neurocysticercosis and raises interesting questions about the natural history of this infection.

SummaryBackground Higher white blood cell count (WBC) is associated with incident type 2 diabetes; however, little is known about the potential relationship of WBC subtypes with metabolic abnormalities underlying diabetes. Design Cross-sectional analysis. Participants Six hundred and fifty-six nondiabetic participants in the Prospective Metabolism and Islet Cell Evaluation cohort. Measurements Granulocytes (basophils, neutrophils and eosinophils), lymphocytes and monocytes were measured in fasting blood samples. Neutrophil lymphocyte ratio (NLR) is the ratio of neutrophil to lymphocyte. Insulin resistance was measured by insulin sensitivity index (ISOGTT) and homeostasis model assessment of insulin resistance (HOMA-IR). Beta-cell dysfunction was measured by insulinogenic index (IGI) divided by HOMA-IR (IGI/IR) and Insulin Secretion Sensitivity Index-2 (ISSI-2). Results All WBC subtypes were inversely associated with ISOGTT [β = −0·12 (−0·15, −0·083) for granulocytes, β = −0·23 (−0·31, −0·15) for lymphocytes, β = −0·67 (−1·00, −0·34) for monocytes] and positively associated with HOMA-IR [β = 0·11 (0·074, 0·15) for granulocytes, β = 0·22 (0·14, 0·30) for lymphocytes, β = 0·64 (0·33, 0·97) for monocytes]. Granulocytes and lymphocytes were inversely associated with IGI/IR [β = −0·10 (−0·15, −0·047), β = −0·23 (−0·35, −0·11), respectively] and ISSI-2 [β = −0·048 (−0·074, −0·022), β = −0·14 (−0·19, −0·089), respectively]. BMI attenuated the associations of monocytes with IGI/IR and ISSI-2, and those of NLR with ISOGTT and HOMA-IR. NLR was not associated with IGI/IR and ISSI-2. Conclusions All WBC subtypes were independently associated with insulin resistance, whereas granulocytes and lymphocytes, but not monocytes, were associated with β-cell dysfunction. NLR was not associated with β-cell dysfunction, and its association with insulin resistance was confounded by obesity.

SummaryAllogenic proteins that contaminate intermediate purity clotting factor concentrates may activate the immune system of HIV-infected haemophilic patients. In 37 haemophilic patients infected with HIV who had originally been treated with intermediate purity factor VIII concentrate and then changed to monoclonally-purified high purity factor VIII concentrate the rates of CD4+ decline (109/1 per year) were 0.06 before and 0.02 after a switch to high purity products (p = 0.01). The median follow-up of patients after the switch to high purity products was 1.7 years (range 0.2 to 3 years). This significant change in the rate of CD4 decline was independent of the starting CD4 count, age and antiretroviral therapy. This result is consistent with those from randomised trials of the introduction of high-purity concentrate. Given the strong association between the CD4+ count and survival, treatment with high purity rather than intermediate purity clotting factor concentrate may confer a survival benefit for HIV-infected haemophilic patients.

The objective of this study was to evaluate a novel flashlamp emitting light device which represents the first light-based device for skin rejuvenation with the ability to shift the wavelength spectrum depending on the application. Three distinct programs adjust the wavelengths to accommodate the melanin and hemoglobin absorption, and also adjust the pulse width and cooling depending on the needs of the patient. Patients received treatment on the left side of the face or other body part; the untreated side served as the control.

The purpose of this clinical case report was to describe the kinematic variables of movement that best discriminated between asymmetrical and symmetrical mandibular excursion patterns in a patient with myogenic temporomandibular dysfunction. Two mandibular movements (deemed to be asymmetrical and symmetrical by both patient and physiotherapist) were each recorded six times on three occasions at six, twelve, and 15 weeks after commencement of an exercise programme. The mandibular movements were captured with a 12-camera Motion Analysis System (Motion Analysis Corp., Santa Rosa, CA) with kinematic variables expressed in six degrees-of-freedom. A two-way analysis of variance (ANOVA) for repeated measures was used to analyze the data. The asymmetrical pattern was characterized by increased axial rotation and decreased sagittal rotation but with no differences in translation values when compared to those of the symmetrical pattern. The results support the clinician's and patient's judgment regarding differences in quality of mandibular excursion patterns made over the course of time.

Purpose: Angiogenesis is increased in aggressive histology non–Hodgkin's lymphoma and may be a target with selective cyclooxygenase-2 inhibition and metronomic chemotherapy. Experimental Design: We assessed response, toxicity, and biomarkers of angiogenesis to low-dose cyclophosphamide (50 mg p.o. o.d.) and high-dose celecoxib (400 mg p.o. b.i.d.) in adult patients with relapsed or refractory aggressive non–Hodgkin's lymphoma in a multicenter phase II prospective study. Results: Thirty-two of 35 patients (median age, 62 years) are evaluable for response. Patients had primarily relapsed diffuse large B-cell lymphoma (63%) were heavily pretreated (median of three regimens) and high risk (79% international prognostic index, ≥2) and 34% were relapsed after autologous stem cell transplant. With a median follow-up of 8.4 months, the overall best response rate is 37% (2 complete clinical response/complete clinical response unconfirmed and 9 partial response), with 22% achieving stable disease. Median overall and progression-free survivals are 14.4 and 4.7 months, respectively. The median response duration was 8.2 months. The most common toxicity was skin rash (40%); myelosuppression and gastrointestinal side effects were uncommon. Three patients developed deep vein thromboses and two heavily pretreated patients developed treatment-related acute myelogenous leukemia or myelodysplasia after 3.7 and 12 months of therapy. Circulating endothelial cells and their precursors declined and remained low in responders, whereas plasma vascular endothelial growth factor trended to decline in responding patients but increase in nonresponders. Trough celecoxib levels achieved targeted “antiangiogenic” levels. Conclusions: Low-dose cyclophosphamide and high-dose celecoxib is well tolerated and active in pretreated aggressive non–Hodgkin's lymphoma. Close surveillance for arterial and venous thrombotic events is recommended. The decline in circulating endothelial cells and their precursors suggests that this combination may be working by inhibiting angiogenesis but should be validated in a larger patient sample.

Objectives. To describe the results of laparoscopic management of adnexal masses in women with a history of nongynecologic malignancy. Methods. We conducted a retrospective review of 262 patients with history of prior nongynecologic malignancy who underwent laparoscopy for management of an adnexal mass between 1/1992 and 6/2004. Results. Median patient age at laparoscopy was 55 years (range, 20–91 years), and median BMI was 25 kg/m 2 (range, 14–41 kg/m 2 ). Of the 262 patients, 145 (55.3%) had prior abdominal/pelvic surgery. Prior cancer history included breast (202, 77.1%), lymphoma/leukemia (16, 6.1%), colorectal (8, 3.0%), lung (7, 2.7%), multiple myeloma (5, 1.9%), head/neck (5, 1.9%), genitourinary (5, 1.9%), upper gastrointestinal (4, 1.5%), and other (10, 3.8%). Median ovarian mass diameter measured on radiologic imaging was 3.8 cm (range, 0.2–13.5 cm); median CA-125 was 17.0 U/mL (range, 1–7000 U/mL). In all, 49 (18.7%) patients had malignancy identified at laparoscopy, with 30/49 (61.2%) diagnosed with metastatic malignancy to the ovary and 19/49 (38.8%) having a new primary ovarian malignancy . Median tumor diameter and CA-125 were significantly higher in women found to have a malignancy (4.7 vs. 3.7 cm, and 35 vs. 14 U/mL, respectively). Overall, conversion to laparotomy occurred in 34 (12.9%) cases. Twenty-one of 49 (42.9%) patients with malignancy were converted to laparotomy compared with 13/213 (6.1%) when benign disease was noted ( P Conclusions. Approximately 1 in 5 patients with a history of nongynecologic malignancy who were selected for laparoscopic management of an adnexal mass was found to have malignancy, with 60% being metastatic from other primaries. The majority of cases were managed laparoscopically even if malignancy was identified.

Noninvasive techniques for skin rejuvenation are quickly being established as a new standard in the treatment of mild rhytides and overall skin toning. Multiple laser wavelengths and modalities have been tried for this procedure with varying degrees of success. These lasers include 532 nm, 585 nm, 1064 nm, 1320 nm, 1450 nm, and 1540 nm wavelengths. This study evaluates a combination technique by using a long-pulsed 532 nm potassium titanyl phosphate (KTP) laser and a long-pulsed 1064 nm Neodynium:yttrium aluminum garnet (Nd:YAG) laser, both separately and combined, for noninvasive photorejuvenation and skin toning/collagen enhancement, and establishes efficacy and degree of success. A total of 150 patients were treated with the long-pulsed KTP 532 nm (Aura; Laserscope, San Jose, CA) and long-pulsed Nd:YAG 1064 nm (Lyra; Laserscope) lasers both separately and combined. Patients included skin types I through V. The fluences varied between 7 and 15 J/cm2 at 7 to 20 ms pulse duration with a 2-mm handpiece, and 6 to 15 J/cm2 and 30 to 50 ms with a 4-mm handpiece for KTP. The Nd:YAG fluences were set at 24 to 30 J/cm2 for a 10-mm handpiece and 30 J/cm2 for a SmartScan Plus scanner (Laserscope, San Jose, CA). These energies were delivered at 30 to 65 ms pulse durations. All patients were treated at least 3 times and at most 6 times at monthly intervals, and were observed for up to 18 months after the last treatment. All 150 patients exhibited a mild to moderate degree of improvement in the appearance of rhytides, moderate degree of improvement in skin toning and texture, and great improvement in the reduction of redness and pigmentation. The KTP used alone was superior to the Nd:YAG laser in terms of results. The KTP and Nd:YAG laser combination was superior to either laser used alone.

The aim of this study was to assess the relationships among the detection of p24 antigen, human immunodeficiency virus (HIV) RNA level, CD4 cell count, and disease progression in 111 males with hemophilia who were infected with HIV for less than or equal to 20 years. Sixty-four individuals (58%) developed p24 antigenemia a median of 11.6 years after seroconversion. The time to first detection of p24 antigen was shorter among those who were older (P=.04) and those with a high initial HIV RNA level (P=.006). The median HIV RNA level and CD4 cell count at the time of the detection of p24 antigen were 4.95log(10) copies/mL and 100 cells/mm(3), respectively. In univariate analyses, p24 antigenemia was associated with more-rapid progression to AIDS (relative hazard [RH], 5.50; P=.0001). The effect was reduced (RH, 1.85; P =.06) after adjusting for CD4 cell counts and HIV RNA levels during follow-up, age, and calendar year. A significant relationship between p24 antigenemia and death was nonsignificant after adjusting for CD4 cell count.

BACKGROUND/AIMS: Small, uncontrolled studies of ribavirin for patients with chronic hepatitis C have reported efficacy in chronic hepatitis C. We have evaluated the efficacy and safety of a 24-week course of oral ribavirin in patients with chronic hepatitis C, compared to placebo. METHODS: A total of 114 patients were randomised to ribavirin or placebo. Ribavirin was administered in doses of 1000 or 1200 mg/day for 24 weeks. Efficacy was determined in the intention-to-treat population: 76 received ribavirin and 38 placebo. RESULTS: Ribavirin was significantly more effective than placebo in reducing and normalising serum ALT levels: 42/76 (55%) of ribavirin-treated patients vs 2/38 (5%) placebo recipients had either normalisation of the ALT levels or a reduction from baseline of at least 50% (p < 0.001). ALT levels were normal in 22/76 (29%) of ribavirin-treated patients vs 0/38 placebo recipients (p < 0.001). Twenty-four weeks after stopping ribavirin, the majority of patients had abnormal ALT levels. There was no difference between the treatment groups in reduction or disappearance of HCV-RNA levels. HCV RNA disappeared during treatment in 3% of ribavirin-treated patients and 3% of placebo recipients. More ribavirin than placebo patients showed improvement in total Knodell score (45% vs 31%), but these differences were not statistically significant. Analysis of each component of a histology activity index revealed no statistically significant differences between treatment groups. Ribavirin patients had fewer lymphoid aggregates than did placebo recipients at the post-treatment assessment (p = 0.05). Ribavirin was associated with reversible haemolytic anaemia: a fall in haemoglobin occurred in 3% of placebo- and 32% (25/78) of ribavirin-treated patients, respectively (p < 0.001). CONCLUSIONS: These data indicate that ribavirin was no more effective than placebo in reducing or eliminating HCV-RNA levels, and was not significantly more effective than placebo in improving hepatic histology after 6 months of treatment. The role of a 6-month treatment of chronic hepatitis C with ribavirin alone, without a significant effect on HCV RNA, is therefore limited

We have studied morbidity and mortality related to hepatitis C virus infection in haemophilic patients treated at our centre. 11/255 HCV seropositive patients have developed hepatic decompensation. 20 years after first exposure to lyophilized clotting factor concentrate the risk of hepatic decompensation is estimated to be 10.8% (95% CI 3.8-17.8%). There is a significantly increased risk associated with HIV infection, and also with increased age. For HIV seropositive patients the rates of decline in CD4 lymphocyte count and the development of p24 antigenaemia are significant risk factors for hepatic decompensation. Cirrhosis was seen in 9/19 HIV seropositive patients at post mortem. There was an association of cirrhosis with increased age but not with CD4 count, p24 antigenaemia, or AIDS. In conclusion, HCV infection is associated with serious liver disease in haemophilic patients, but so far this has been restricted to a minority of those at risk. HIV co-infection accelerates progression to hepatic decompensation, and we speculate that this is probably due to enhanced HCV replication in the presence of immune deficiency.

An audit of upper gastrointestinal endoscopy in HIV infected patients with gastrointestinal symptoms assessed the frequency of disease detected by endoscopy and routine laboratory analysis of surveillance biopsy specimens. Sixty nine consecutive endoscopies were performed in 59 HIV infected patients. Endoscopic biopsy specimens were taken from the lower oesophagus, gastric antrum, and third part of the duodenum for virology, histopathology, parasitology, bacteriology, and mycobacterial culture. Endoscopic appearances detected disease in 25/59 (42.4%) patients (oesophageal candida, 14; oesophageal ulcer, 3; Kaposi's sarcoma, 4; others, 4), but only 4/43 (9.3%) specimens showed evidence of disease in the absence of endoscopic abnormality. Virology for cytomegalovirus (detection of early antigenic fluorescent foci and culture) was positive in 6/59 (10.2%) patients, but parasitology and mycobacterial culture were negative in all cases. Histopathology was abnormal in 11/52 (21%) oesophageal biopsy specimens, 13/47 (28%) gastric biopsy specimens, and 4/65 (6%) duodenal biopsy specimens. Abnormal findings were found predominantly in those with advanced HIV disease (CDC Stage IV) (21/33 patients (64%)) compared with those with early HIV disease (CDC Stage II) (5/26 (19%)). In conclusion, upper gastrointestinal endoscopy detects macroscopic disease in AIDS patients and those with low CD4 counts, but routine surveillance biopsy specimens of apparently normal bowel in early HIV disease (or where CD4 counts are greater than 0.2 x 10(9)/1) are of little value.

A cohort of haemophilic patients who seroconverted to HIV-1 between October 1979 and July 1985 has been followed to 1 January 1992. The median age at initial seropositivity was 24 years with a range of 2-77 years. By January 1992, 38/111 (34%) had developed AIDS and 39/111 (35%) had died (four of liver failure including one hepatoma). Using Kaplan-Meier plots, the calculated progression to AIDS at 12 years is 45% (95% CI 31, 58): for age > 25 years 63% (95% CI 45, 82), age < 25 years 32% (95% CI 15, 48) P = 0.0001; CMV positive 68% (95% CI 48, 87) CMV -ve 20% (95% CI 8, 32) P = 0.0009. The 12-year progression rate to CD4 + 0.2 or AIDS is 66% (95% CI 55, 76). 21/34 (63%) of patients who are p24 antigen positive have developed AIDS compared to 17/77 (22%) who are p24 antigen negative (= 0.0001). 19/34 (56%) and 20/77 (23%) of those p24 positive and negative respectively have died (P = 0.007). Before antiviral and prophylactic treatment for asymptomatic patients there were nine AIDS cases in 3.84 years experience with CD4+ < 0.05 (1/0.43 years) and since treatment, 10 AIDS cases in 18.22 years (1/1.8 years). Age, CMV status and p24 remain strongly predictive of disease progression. Treatment appears to reduce the incidence of AIDS.

Liver biopsy specimens previously taken from 16 haemophilic patients with chronic non-A, non-B hepatitis were reviewed. The degree of fibrosis correlated with serum procollagen III peptide (sPIIIP) concentrations, measured both at the time of biopsy and 4.25 years later. Two patients with extremely high sPIIIP concentrations had collateral veins on computed tomography, suggesting portal hypertension. Twenty eight of 47 patients (60%) had splenomegaly on computed tomography, and of 28 patients in whom intravenous contrast medium was used, seven (25%) had collateral oesophageal veins. Serum procollagen III peptide estimations and computed tomography, both non-invasive investigations, indicated that hepatic fibrosis and portal hypertension had developed in a proportion of haemophilic patients with non-A, non-B hepatitis. Infection with the human immunodeficiency virus (HIV) may modify the course of this presumably cytopathic virus infection of the liver.

This report describes a carrier of haemophilia A who developed fulminant non-A, non-B hepatitis after transfusion with cryoprecipitate. She survived, but developed chronic active hepatitis.