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Summary Background PD-1 and PD-L1 inhibitors are active in metastatic urothelial carcinoma, but positive randomised data supporting their use as a first-line treatment are lacking. In this study we assessed outcomes with first-line pembrolizumab alone or combined with chemotherapy versus chemotherapy for patients with previously untreated advanced urothelial carcinoma. Methods KEYNOTE-361 is a randomised, open-label, phase 3 trial of patients aged at least 18 years, with untreated, locally advanced, unresectable, or metastatic urothelial carcinoma, with an Eastern Cooperative Oncology Group performance status of up to 2. Eligible patients were enrolled from 201 medical centres in 21 countries and randomly allocated (1:1:1) via an interactive voice-web response system to intravenous pembrolizumab 200 mg every 3 weeks for a maximum of 35 cycles plus intravenous chemotherapy (gemcitabine [1000 mg/m2] on days 1 and 8 and investigator's choice of cisplatin [70 mg/m2] or carboplatin [area under the curve 5] on day 1 of every 3-week cycle) for a maximum of six cycles, pembrolizumab alone, or chemotherapy alone, stratified by choice of platinum therapy and PD-L1 combined positive score (CPS). Neither patients nor investigators were masked to the treatment assignment or CPS. At protocol-specified final analysis, sequential hypothesis testing began with superiority of pembrolizumab plus chemotherapy versus chemotherapy alone in the total population (all patients randomly allocated to a treatment) for the dual primary endpoints of progression-free survival (p value boundary 0·0019), assessed by masked, independent central review, and overall survival (p value boundary 0·0142), followed by non-inferiority and superiority of overall survival for pembrolizumab versus chemotherapy in the patient population with CPS of at least 10 and in the total population (also a primary endpoint). Safety was assessed in the as-treated population (all patients who received at least one dose of study treatment). This study is completed and is no longer enrolling patients, and is registered at ClinicalTrials.gov , number NCT02853305 . Findings Between Oct 19, 2016 and June 29, 2018, 1010 patients were enrolled and allocated to receive pembrolizumab plus chemotherapy (n=351), pembrolizumab monotherapy (n=307), or chemotherapy alone (n=352). Median follow-up was 31·7 months (IQR 27·7–36·0). Pembrolizumab plus chemotherapy versus chemotherapy did not significantly improve progression-free survival, with a median progression-free survival of 8·3 months (95% CI 7·5–8·5) in the pembrolizumab plus chemotherapy group versus 7·1 months (6·4–7·9) in the chemotherapy group (hazard ratio [HR] 0·78, 95% CI 0·65–0·93; p=0·0033), or overall survival, with a median overall survival of 17·0 months (14·5–19·5) in the pembrolizumab plus chemotherapy group versus 14·3 months (12·3–16·7) in the chemotherapy group (0·86, 0·72–1·02; p=0·0407). No further formal statistical hypothesis testing was done. In analyses of overall survival with pembrolizumab versus chemotherapy (now exploratory based on hierarchical statistical testing), overall survival was similar between these treatment groups, both in the total population (15·6 months [95% CI 12·1–17·9] with pembrolizumab vs 14·3 months [12·3–16·7] with chemotherapy; HR 0·92, 95% CI 0·77–1·11) and the population with CPS of at least 10 (16·1 months [13·6–19·9] with pembrolizumab vs 15·2 months [11·6–23·3] with chemotherapy; 1·01, 0·77–1·32). The most common grade 3 or 4 adverse event attributed to study treatment was anaemia with pembrolizumab plus chemotherapy (104 [30%] of 349 patients) or chemotherapy alone (112 [33%] of 342 patients), and diarrhoea, fatigue, and hyponatraemia (each affecting four [1%] of 302 patients) with pembrolizumab alone. Six (1%) of 1010 patients died due to an adverse event attributed to study treatment; two patients in each treatment group. One each occurred due to cardiac arrest and device-related sepsis in the pembrolizumab plus chemotherapy group, one each due to cardiac failure and malignant neoplasm progression in the pembrolizumab group, and one each due to myocardial infarction and ischaemic colitis in the chemotherapy group. Interpretation The addition of pembrolizumab to first-line platinum-based chemotherapy did not significantly improve efficacy and should not be widely adopted for treatment of advanced urothelial carcinoma. Funding Merck Sharp and Dohme, a subsidiary of Merck, Kenilworth, NJ, USA.

Wide adoption of electronic health records (EHRs) has raised the expectation that data obtained during routine clinical care, termed “real-world” data, will be accumulated across health care systems and analyzed on a large scale to produce improvements in patient outcomes and the use of health care resources. To facilitate a learning health system, EHRs must contain clinically meaningful structured data elements that can be readily exchanged, and the data must be of adequate quality to draw valid inferences. At the present time, the majority of EHR content is unstructured and locked into proprietary systems that pose significant challenges to conducting accurate analyses of many clinical outcomes. This article details the current state of data obtained at the point of care and describes the changes necessary to use the EHR to build a learning health system.

Importance: This three-part study characterizes the widespread implementation of telehealth during the first year of the COVID-19 pandemic, giving us insight into the role of telehealth as we enter a stage of “new normal” healthcare delivery in the U.S. Objective: The COVID-19 Telehealth Impact Study was designed to describe the natural experiment of telehealth adoption during the pandemic. Using a large claims data stream and surveys of providers and patients, we studied telehealth in all 50 states to inform healthcare leaders. Design, Setting, Participants: In March 2020, the MITRE Corporation and Mayo Clinic founded the COVID-19 Healthcare Coalition (C19HCC), to respond to the pandemic. We report trends using a dataset of over 2 billion healthcare claims covering over 50% of private insurance activity in the U.S. (January 2019-December 2020), along with key elements from our provider survey (July-August 2020) and patient survey (November 2020 - February 2021). Main Outcomes and Measures: There was rapid and widespread adoption of telehealth in Spring 2020 with over 12 million telehealth claims in April 2020, accounting for 49.4% of total health care claims. Providers and patients expressed high levels of satisfaction with telehealth. 75% of providers indicated that telehealth enabled them to provide quality care. 84% of patients agreed that quality of their telehealth visit was good. Results: Peak levels of telehealth use varied widely among states ranging from 74.9% in Massachusetts to 25.4% in Mississippi. Every clinical discipline saw a steep rise with the largest claims volume in behavioral health. Provision of care by out-of-state provider was common at 6.5% (October-December 2020). Providers reported multiple modalities of telehealth care delivery. 74% of patients indicated they will use telehealth services in the future. Conclusions and Relevance: Innovation shown by providers and patients during this period of rapid telehealth expansion constitutes a great natural experiment in care delivery with evidence supporting widespread clinical adoption and satisfaction on the part of both patients and clinicians. The authors encourage continued broad access to telehealth over the next 12 months to allow telehealth best practices to emerge, creating a more effective and resilient system of care delivery.

OBJECTIVE To examine the role of intensive care unit (ICU) management following lateral skull base surgery for vestibular schwannoma and identify risk factors for complications warranting admission to the ICU. STUDY DESIGN Retrospective review. SETTING Tertiary referral center. PATIENTS Two hundred consecutive patients undergoing lateral skull base surgery for vestibular schwannomas. INTERVENTION Lateral skull base approach for resection of vestibular schwannoma and postoperative monitoring. MAIN OUTCOME MEASURES Patients were grouped if they sustained an ICU complication, a non-ICU complication, or no complication. Analysis was performed to determine patient or treatment factors that may be associated with ICU complications. Multivariate and three-way analysis of variance compared groups, and multivariate logistic regression determined adjusted odds ratios (aOR) for analyzed factors. RESULTS Seventeen of 200 patients sustained ICU complications (8.5%), most commonly hypertensive urgency (n = 15). Forty-six (23%) sustained non-ICU complications, and 137 (68.5%) had no complications. When controlling for age, sex, obesity, and other comorbidities, only hypertension (aOR 5.43, 95% confidence interval (CI) 1.35-21.73, p = 0.017) and tumor volume (aOR 3.29, 95% CI 1.09-9.96, p = 0.035) were independently associated with increased risk of ICU complications. CONCLUSIONS The necessity of intensive care following lateral skull base surgery is rare, with the primary ICU complication being hypertensive urgency. Preoperative hypertension and large tumor volume (>4500 mm3) were independently associated with increased risk for ICU complications. These findings may allow for risk stratification of patients appropriate for admission to stepdown units following resection of vestibular schwannomas. Further prospective, multi-center, randomized studies are necessary to validate these findings before systematic changes to current postoperative care practices.

Chlamydia suis is an important, highly prevalent, and diverse obligate intracellular pathogen infecting pigs. In order to investigate the prevalence and diversity of C. suis in the U.S., 276 whole blood samples from feral swine were collected as well as 109 fecal swabs and 60 whole blood samples from domestic pigs. C. suis-specific peptide ELISA identified anti-C. suis antibodies in 13.0% of the blood of feral swine (26/276) and 80.0% of the domestic pigs (48/60). FRET-qPCR and DNA sequencing found C. suis DNA in 99.1% of the fecal swabs (108/109) and 21.7% of the whole blood (13/60) of the domestic pigs, but not in any of the assayed blood samples (0/267) in feral swine. Phylogenetic comparison of partial C. suis ompA gene sequences and C. suis-specific multilocus sequencing typing (MLST) revealed significant genetic diversity of the C. suis identified in this study. Highly genetically diverse C. suis strains are prevalent in domestic pigs in the USA. As crowding strongly enhances the frequency and intensity of highly prevalent Chlamydia infections in animals, less population density in feral swine than in domestic pigs may explain the significantly lower C. suis prevalence in feral swine. A future study is warranted to obtain C. suis DNA from feral swine to perform genetic diversity of C. suis between commercial and feral pigs.

Acute bacterial endocarditis is a rapid, difficult to manage, and frequently lethal disease. Potent antibiotics often cannot efficiently kill Staphylococcus aureus that colonizes the heart’s valves. S. aureus relies on virulence factors to evade therapeutics and the host’s immune response, usurping the host’s clotting system by activating circulating prothrombin with staphylocoagulase and von Willebrand factor–binding protein. An insoluble fibrin barrier then forms around the bacterial colony, shielding the pathogen from immune cell clearance. Targeting virulence factors may provide previously unidentified avenues to better diagnose and treat endocarditis. To tap into this unused therapeutic opportunity, we codeveloped therapeutics and multimodal molecular imaging to probe the host-pathogen interface. We introduced and validated a family of small-molecule optical and positron emission tomography (PET) reporters targeting active thrombin in the fibrin-rich environment of bacterial colonies. The imaging agents, based on the clinical thrombin inhibitor dabigatran, are bound to heart valve vegetations in mice. Using optical imaging, we monitored therapy with antibodies neutralizing staphylocoagulase and von Willebrand factor–binding protein in mice with S. aureus endocarditis. This treatment deactivated bacterial defenses against innate immune cells, decreased in vivo imaging signal, and improved survival. Aortic or tricuspid S. aureus endocarditis in piglets was also successfully imaged with clinical PET/magnetic resonance imaging. Our data map a route toward adjuvant immunotherapy for endocarditis and provide efficient tools to monitor this drug class for infectious diseases.

After deep venous thrombosis (DVT), many patients have impaired quality of life (QOL). We aimed to assess whether pharmacomechanical catheter-directed thrombolysis (PCDT) improves short-term or long-term QOL in patients with proximal DVT and whether QOL is related to extent of DVT.The Acute Venous Thrombosis: Thrombus Removal with Adjunctive Catheter-Directed Thrombolysis (ATTRACT) trial was an assessor-blinded randomized trial that compared PCDT with no PCDT in patients with DVT of the femoral, common femoral, or iliac veins. QOL was assessed at baseline and 1 month, 6 months, 12 months, 18 months, and 24 months using the Venous Insufficiency Epidemiological and Economic Study on Quality of Life/Symptoms (VEINES-QOL/Sym) disease-specific QOL measure and the 36-Item Short Form Health Survey (SF-36) physical component summary (PCS) and mental component summary general QOL measures. Change in QOL scores from baseline to assessment time were compared in the PCDT and no PCDT treatment groups overall and in the iliofemoral DVT and femoral-popliteal DVT subgroups.Of 692 ATTRACT patients, 691 were analyzed (mean age, 53 years; 62% male; 57% iliofemoral DVT). VEINES-QOL change scores were greater (ie, better) in PCDT vs no PCDT from baseline to 1 month (difference, 5.7; P = .0006) and from baseline to 6 months (5.1; P = .0029) but not for other intervals. SF-36 PCS change scores were greater in PCDT vs no PCDT from baseline to 1 month (difference, 2.4; P = .01) but not for other intervals. Among iliofemoral DVT patients, VEINES-QOL change scores from baseline to all assessments were greater in the PCDT vs no PCDT group; this was statistically significant in the intention-to-treat analysis at 1 month (difference, 10.0; P .0001) and 6 months (8.8; P .0001) and in the per-protocol analysis at 18 months (difference, 5.8; P = .0086) and 24 months (difference, 6.6; P = .0067). SF-36 PCS change scores were greater in PCDT vs no PCDT from baseline to 1 month (difference, 3.2; P = .0010) but not for other intervals. In contrast, in femoral-popliteal DVT patients, change scores from baseline to all assessments were similar in the PCDT and no PCDT groups.Among patients with proximal DVT, PCDT leads to greater improvement in disease-specific QOL than no PCDT at 1 month and 6 months but not later. In patients with iliofemoral DVT, PCDT led to greater improvement in disease-specific QOL during 24 months.

Geological climate archives from the Holocene Epoch provide baseline information concerning natural climate variability. Temperate mountain glacier extent is sensitive to summer air temperature, thus geological records of past glacier length changes are a useful proxy for this climatic variable. Here we present a new cosmogenic 10Be chronology of glacier length changes at Dart Glacier in the Southern Alps, New Zealand. Prominent moraines deposited 321 ± 44 yr ago (n = 11) and 7.8 ± 0.3 ka (n = 5) show glaciers during the Little Ice Age were less extensive than during the early Holocene. This pattern of net Holocene glacier retreat is consistent with emerging data from other catchments in New Zealand and across the southern mid-latitudes. Using the physical framework of a transient global climate model simulation, we suggest that cool summers in the early Holocene were promoted by the local summer insolation minimum, together with low atmospheric greenhouse gas concentrations, causing an early Holocene austral glacial maximum. An insolation-driven reduction in seasonality at southern mid-latitudes may reconcile differences between early Holocene temperature reconstructions where climate proxies have different seasonal sensitivities. We suggest that rising greenhouse gas concentrations after 7 ka caused regional-scale glacier retreat and appear to be the dominant driver of multi-millennial summer temperature trends in the southern mid-latitudes during the present interglacial.

Glucose dysregulation and disruption of insulin signaling in the brain have been suggested as a possible etiology of Alzheimer’s Disease. In the present study, we show that oral delivery of MA-[D-Leu-4]-OB3 to young male Swiss Webster (SW) mice rendered hyperglycemic by intraperitoneal injection of streptozotocin (STZ), prevented insulin-induced increase in body weight gain and enhanced the effects of insulin alone on fasting blood glucose to levels approaching those of normal SW mice of the same age and sex. Novel object testing indicated that insulin treatment improved working memory in STZ-induced hyperglycemic mice, and that MA-[D-Leu-4]-OB3 given in combination with insulin significantly accelerated the time course of this improvement. Although positive results in an animal model may not be recapitulated in human pathology, our data suggest that MA-[D-Leu-4]-OB3, when added to an insulin regimen, may have application to the treatment of Alzheimer’s Disease by improving insulin sensitivity and glycemic control, thus slowing or preventing the progression of memory disruption associated with this disease.

Calcium chloride (CaCl2) has been used to accelerate strength gain in soil-cement mixtures. While its use in concrete is well established, there are few reports on dosage and temperature controls in soil-cement applications. This article provides laboratory and field data regarding the unconfined compression (UC) strength of soil-cement as a function of temperature, time, and dosage. The results indicate CaCl2 can increase the UC strength of soil-cement mixtures at curing temperatures of 2°C and 21°C while decreasing it dramatically if the initial temperature exceeds 50°C. At a 2°C curing temperature, a dosage of 1% CaCl2 (by weight of cement) increased the average 28-day UC strength from 1,618 to 1,869 kPa (+15.5%) while at 21°C the strength gain was significant at a dosage of 5% CaCl2, increasing the average 28-day UC strength from 1,916 to 2,338 kPa (+22.0%). In general, there is an optimum dosage that varies with temperature and soil type. In terms of field application, it is possible to use c...

The selective α2-adrenoreceptor agonist dexmedetomidine has shown neuroprotective, analgesic, anti-inflammatory, and sympatholytic properties that may be beneficial in neonatal encephalopathy (NE). As therapeutic hypothermia is only partially effective, adjunct therapies are needed to optimize outcomes. The aim was to assess whether hypothermia + dexmedetomidine treatment augments neuroprotection compared to routine treatment (hypothermia + fentanyl sedation) in a piglet model of NE using magnetic resonance spectroscopy (MRS) biomarkers, which predict outcomes in babies with NE, and immunohistochemistry. After hypoxia-ischaemia (HI), 20 large White male piglets were randomized to: (i) hypothermia + fentanyl with cooling to 33.5°C from 2 to 26 h, or (ii) hypothermia + dexmedetomidine (a loading dose of 2 μg/kg at 10 min followed by 0.028 μg/kg/h for 48 h). Whole-brain phosphorus-31 and regional proton MRS biomarkers were assessed at baseline, 24, and 48 h after HI. At 48 h, cell death was evaluated over 7 brain regions by means of transferase-mediated d-UTP nick end labeling (TUNEL). Dexmedetomidine plasma levels were mainly within the target sedative range of 1 μg/L. In the hypothermia + dexmedetomidine group, there were 6 cardiac arrests (3 fatal) versus 2 (non-fatal) in the hypothermia + fentanyl group. The hypothermia + dexmedetomidine group required more saline (p = 0.005) to maintain blood pressure. Thalamic and white-matter lactate/N-acetylaspartate did not differ between groups (p = 0.66 and p = 0.21, respectively); the whole-brain nucleotide triphosphate/exchangeable phosphate pool was similar (p = 0.73) over 48 h. Cell death (TUNEL-positive cells/mm2) was higher in the hypothermia + dexmedetomidine group than in the hypothermia + fentanyl group (mean 5.1 vs. 2.3, difference 2.8 [95% CI 0.6-4.9], p = 0.036). Hypothermia + dexmedetomidine treatment was associated with adverse cardiovascular events, even within the recommended clinical sedative plasma level; these may have been exacerbated by an interaction with either isoflurane or low body temperature. Hypothermia + dexmedetomidine treatment was neurotoxic following HI in our piglet NE model, suggesting that caution is vital if dexmedetomidine is combined with cooling following NE.

Type 1 Diabetes (T1D) is a chronic pro-inflammatory autoimmune disease consisting of islet-infiltrating leukocytes involved in pancreatic β-cell lysis. One promising treatment for T1D is islet transplantation; however, clinical application is constrained due to limited islet availability, adverse effects of immunosuppressants, and declining graft survival. Islet encapsulation may provide an immunoprotective barrier to preserve islet function and prevent immune-mediated rejection after transplantation. We previously demonstrated that a novel cytoprotective nanothin multilayer coating for islet encapsulation consisting of tannic acid (TA), an immunomodulatory antioxidant, and poly(N-vinylpyrrolidone) (PVPON), was efficacious in dampening in vitro immune responses involved in transplant rejection and preserving in vitro islet function. However, the ability of (PVPON/TA) to maintain islet function in vivo and reverse diabetes has not been tested. Recent evidence has demonstrated that modulation of redox status can affect pro-inflammatory immune responses. Therefore, we hypothesized that transplanted (PVPON/TA)-encapsulated islets can restore euglycemia to diabetic mice and provide an immunoprotective barrier. Our results demonstrate that (PVPON/TA) nanothin coatings can significantly decrease in vitro chemokine synthesis and diabetogenic T cell migration. Importantly, (PVPON/TA)-encapsulated islets restored euglycemia after transplantation into diabetic mice. Our results demonstrate that (PVPON/TA)-encapsulated islets may suppress immune responses and enhance islet allograft acceptance in patients with T1D.

Providing treatment to people with severe mental illnesses on an inpatient unit is fraught with challenges. Many patients are acutely ill and may be experiencing very severe symptoms that coexist with poor insight, emotional dysregulation, impulsivity, aggression, and severe disability. Moreover, many patients are involuntarily hospitalized and may be less cooperative with inpatient treatment. Some civilly committed patients may view their hospital tenure as needlessly lengthy and forced medications as impinging on their civil rights, while longing for less restrictive environments. For many practitioners, these are clinical challenges that adversely impact treatment adherence and ultimately positive treatment outcomes. There is accumulating evidence that the traditional model of decision making is insufficient in psychiatric care and may play a significant role in the reluctance of individuals who need mental health care to seek it and sustain their efforts in it. Shared decision-making, in contrast, provides a viable system of enhancing the engagement of care recipients in treatment and is an essential component of recovery-oriented practice. Inasmuch as it represents a change from the paternalistic model of traditional care, shared decision-making requires a shift in perspective and skill for both the provider and for the individual receiving mental health services. This chapter presents the concept of shared decision-making, explores provider attitudes, expectations and beliefs that may serve as barriers to its implementation, and provides practical strategies to facilitate effective shared decision-making in clinical care.

Background Chronic pain is common and challenging to treat. Although cognitive behavioral therapy (CBT) is efficacious, its benefit in disadvantaged populations is largely unknown. Objective To evaluate the efficacy of literacy-adapted and simplified group CBT versus group pain education (EDU) versus usual care. Design Randomized controlled trial. (ClinicalTrials.gov: NCT01967342). Setting Community health centers serving low-income patients in Alabama. Patients Adults (aged 19 to 71 years) with mixed chronic pain. Interventions CBT and EDU delivered in 10 weekly 90-minute group sessions. Measurements Self-reported, postintervention pain intensity (primary outcome) and physical function and depression (secondary outcomes). Results 290 participants were enrolled (70.7% of whom were women, 66.9% minority group members, 72.4% at or below the poverty level, and 35.8% reading below the fifth grade level); 241 (83.1%) participated in posttreatment assessments. Linear mixed models included all randomly assigned participants. Members of the CBT and EDU groups had larger decreases in pain intensity scores between baseline and posttreatment than participants receiving usual care (estimated differences in change scores-CBT: -0.80 [95% CI -1.48 to -0.11]; P = 0.022; EDU: -0.57 [CI, -1.04 to -0.10]; P = 0.018). At 6-month follow-up, treatment gains were not maintained in the CBT group but were still present in the EDU group. With regard to physical function, participants in the CBT and EDU interventions had greater posttreatment improvement than those receiving usual care, and this progress was maintained at 6-month follow-up. Changes in depression (secondary outcome) did not differ between either the CBT or EDU group and the usual care group. Limitations Participants represented a single health care system. Self-selection bias may have been present. Conclusion Simplified group CBT and EDU interventions delivered at low-income clinics significantly improved pain and physical function compared with usual care. Primary funding source Patient-Centered Outcomes Research Institute.

We attempted to determine how accurately members of the public can identify venomous snakes. Six different snakes indigenous to southern California were displayed in cages for 265 people to view at a street fair. These included 4 nonvenomous snakes and 2 venomous snakes. People were asked whether the snake was venomous and the name of the snake, if they knew it. Overall, people recognized whether a snake was venomous or nonvenomous 81% of the time. They were most accurate at identifying rattlesnakes as being venomous (95%) but incorrectly identified nonvenomous snakes as being venomous 25% of the time. Men were more accurate than women, and adults were more accurate than children. Subjects were less well able to identify the exact species of snakes. The results suggest that there may be no need to capture, kill, or bring a snake to the hospital for identification, at least in this geographic area.

Background: As many as 70% of veterans with chronic pain treated within the US Veterans Administration (VA) system may have posttraumatic stress disorder (PTSD), and conversely, up to 80% of those with PTSD may have pain. We describe pain experienced by US service members and veterans with symptoms of PTSD, and report on the effect of Accelerated Resolution Therapy (ART), a new, brief exposure-based therapy, on acute pain reduction secondary to treatment of symptoms of PTSD. Methods: A randomized controlled trial of ART versus an attention control (AC) regimen was conducted among 45 US service members/veterans with symptoms of combat-related PTSD. Participants received a mean of 3.7 sessions of ART. Results: Mean age was 41.0 � 12.4 years and 20% were female. Most veterans (93%) reported pain. The majority (78%) used descriptive terms indicative of neuropathic pain, with 29% reporting symptoms of a concussion or feeling dazed. Mean pre-/post-change on the Pain Outcomes Questionnaire (POQ) was � 16.9916.6 in the ART group versus � 0.7914.2 in the AC group (p � 0.0006). Among POQ subscales, treatment effects with ART were reported for pain intensity (effect size � 1.81, p � 0.006), pain-related impairment in mobility (effect size � 0.69, p � 0.01), and negative affect (effect size � 1.01, p � 0.001). Conclusions: Veterans with symptoms of combat-related PTSD have a high prevalence of significant pain, including neuropathic pain. Brief treatment of symptoms of combat-related PTSD among veterans by use of ART appears to acutely reduce concomitant pain.

The earliest or patch stage of mycosis fungoides may present diagnostic difficulty both clinically and pathologically. The present study of the polymerase chain reaction (PCR) as a diagnostic tool in early mycosis fungoides was therefore undertaken, using a rapid PCR method for the detection of gamma- and beta-chain T-cell receptor (TCR) gene rearrangements in routine formalin-fixed, paraffin-embedded histological sections. Forty-two biopsies were studied from 26 patients with mycosis fungoides. Twenty-three skin biopsies with a clinicopathological diagnosis of early, or patch stage, mycosis fungoides were investigated. Of these, 18 (78 per cent) showed TCR-gamma or both beta- and gamma-chain TCR gene rearrangements. TCR gene rearrangements were shown in seven of the 14 plaque stage lesions (50 per cent) and also in the single case of tumour stage disease. Where gene rearrangements were identified, these were identical in all biopsies from an individual patient, irrespective of the site of the lesion, the disease stage, or the time lapse between the biopsies. The PCR is therefore a highly sensitive technique, which can be performed on routine pathological material, in cases where the diagnosis of early mycosis fungoides cannot be made with certainty on conventional histopathological and immunohistochemical grounds.

Objective.To investigate the epidemiology of multidrug-resistant Enterobacteriaceae (MDRE) in hospitalized infants.Methods.From 2000 through 2005, active surveillance cultures for MDRE were performed for patients admitted to a 40-bed neonatal intensive care unit (NICU) that provides care for critically ill infants 6 months of age or younger. MDRE epidemiology and the genetic relatedness of MDRE strains determined by repetitive-sequence polymerase chain reaction were analyzed.Results.Active surveillance cultures revealed that 759 (23%) of 3,370 NICU infants (or approximately 1 in 5) developed MDRE colonization or infection and that 613 (72%) of the 853 isolates with epidemiologic data available were healthcare acquired. MDRE colonization occurred more frequently (in 653 infants [86%]) than did MDRE infection (in 106 [14%]). Of the 653 infants with MDRE colonization, 119 (18%) eventually became infected, with 29 (4%) acquiring sterile site infections. The most commonly isolated organisms were the Enterobacter species, accounting for 612 (71%) of the 862 isolates. Molecular epidemiologic analysis revealed that genetic-relatedness clustering (related clusters defined as having a genetic similarity coefficient greater than 95%) varied depending on microbial species. Clustering was detected for 36 (78%) of the 46 Enterobacter aerogenes isolates, 22 (45%) of the 49 Enterobacter cloacae isolates, and 13 (59%) of the 22 Klebsiella pneumoniae isolates.Conclusion.Hospitalized infants are at significant risk of acquiring MDRE, specifically Enterobacter species, at the study institution. Active surveillance cultures identified colonized patients who likely contributed to the institutional reservoir of MDRE. Molecular epidemiologic studies suggest that both patient-to-patient transmission and de novo acquisition of resistance play a role in the acquisition of these organisms, and that the clinical significance of such acquisition varies by species. The high percentage of E. aerogenes isolates that demonstrated genetic clustering suggests that monitoring the prevalence of this organism could serve as a useful measure of compliance with infection control procedures.

Finite element analysis of geotechnical materials is contingent on the proper constitutive model to represent the soil. These models often range in complexity from simple linear elastic to complex hardening and consolidation behavior. Even though many models have been derived, there is little guidance for the selection of input parameters for such models. In this study, four constitutive models are considered the Mohr-Coulomb and Hardening Soil from Plaxis and the Drucker-Prager and Sandler Dimaggio from PlasFEM. A series of six consolidated drained triaxial tests are used to verify constitutive model parameters for sand. The laboratory derived strength and stiffness parameters, the results of a parametric study, and limited guidance from the literature are assembled to provide a best estimate of inputs for four constitutive models. The of plots of the finite element simulations using each of the four models versus the actual triaxial tests show good agreement, respective to the model behavior. A summary table of the parameters details the results.

Item does not contain fulltext 1158 sentinel lymph nodes (SLNs), excised from patients with primary cutaneous melanoma, were assessed pathologically using histology with immunohistochemistry (IHC) on all nodes, and RT-PCR for Mart-1 and tyrosinase on 55 nodes. RT-PCR was compared with the histology and IHC assessed on the same nodes. The evaluation of progressively more detailed protocols for histology and IHC modulated by the RT-PCR results led to a procedure that consistently detects metastases in 34% of patients submitted to SLN biopsy for cutaneous melanomas with a vertical growth phase and a mean thickness of 2.02 mm (range 0.25, with regression, to 19 mm). As this technique is virtually free of false positives and produces only a marginally lower detection rate than RT-PCR, which was subject to false positives of 7% in our study, it is suggested that this extended protocol should be the basis on which further evaluation of the place of RT-PCR in SLN assessment takes place. The evolved protocol described here has been adopted by the EORTC as the standard procedure for pathological handling of sentinel lymph nodes for melanoma when SLN status is a criterion in their clinical trials or studies.

Des-tyrosine-gamma-endorphin (DT gamma E) has been reported to alleviate symptoms of schizophrenia. Attempting to replicate those reports, we administered 1 mg of DT gamma E, i.m., for 8 consecutive days to nine patients meeting the DSM-III criteria for schizophrenia. Patients in this double-blind, crossover, and placebo-controlled study showed a statistically significant, but clinically modest improvement. The improvement was detectable during the first several days of the DT gamma E treatment; the symptoms then returned to baseline level in spite of continued doses of DT gamma E. Testing the metabolism of DT gamma E in the patients' plasma, we found a high rate of formation and of degradation, but the metabolic rates were not related to clinical symptoms.

The subjects were 13 psychiatric inpatients with tardive dyskinesia. Each subject participated in two sessions. Either naloxone (10 mg) or placebo was administered intravenously during each session. In a subset of subjects (n = 7), blood samples for β-endorphin were drawn before and at 30 and 60 minutes after the injection. The Abnormal Involuntary Movement Scale was administered before and at 10, 20, 40, 60, 120, and 360 minutes after the injection. Double-blind procedures were maintained throughout the experiment. Neither naloxone nor placebo had any appreciable effect on the involuntary movements. Naloxone elicited a significant increase in the plasma β-endorphin.

Platelet aggregation in the Chandler tube was studied by continuous measurement of optical density during aggregation. Normal mean values for the duration of aggregation varied from 3.4 to 6.0 min. [rabbit platelet-rich plasma (PRP)] and 3.1 to 5.8 min. (human PRP). Mean thrombus formation time (TFT) varied from 17.1 to 20.9 min. (rabbit PRP) and from 13.5 to 16.4 min. (human PRP). Activation of Hageman factor shortened TFT and duration of aggregation, and minimized optical density changes during aggregation. Factor VIII and erythrocytes increased optical density changes during aggregation. The observations suggest that experimental and clinical states associated with an increased tendency to thrombosis may correlate with characteristic changes in optical density during aggregation in the Chandler system. Altered aggregation characteristics result from changes in plasma proteins, adenosine diphosphate release, catecholamine concentration, and the blood coagulation system.

SummaryThis case report describes a melanin-containing neurofibroma involving a spinal nerve root. Electron microscopy of the tumor shows that neoplastic Schwann cells are capable of melanogene-sis. Although this capability is suggested in the literature, few reports provide ultra-structural confirmation.The likely identity between reported “cellular blue nevi of spinal nerve roots” and nerve sheath tumors is discussed. It is possible that pigmented nerve sheath tumors behave more aggressively than nonpigmented ones, although it is debatable.

To the Editor.— Although the FTAABS test is considered to be sensitive and specific for the diagnosis of syphilis, it may be falsely positive in several disease states, including systemic lupus erythematosus (SLE). The occurrence of a false-positive FTA-ABS in drug-induced lupus has previously been reported to occur only with procainamide. 1 We wish to report a case of hydralazine-induced lupus in which the FTA-ABS was falsely positive. A 68-year-old hypertensive woman had taken hydralazine hydrochloride, 50 mg four times daily, for two years. She gave a four-week history of fever, weight loss, severe muscle weakness, skin rash, arthralgias, and pleuritic chest pain. The fluorescent antinuclear antibody (FANA) test was positive at a titer of 1:1,280, homogeneous pattern, with negative determination for anti-DNA. The C 3 , C 4 , and total hemolytic complement levels were normal. Rheumatoid factor was negative. Creatine phosphokinase and aldolase levels were normal. A muscle biopsy specimen