Investigating the prevalence of erectile dysfunction among men exposed to organophosphate insecticides.

INTRODUCTION: Erectile dysfunction (ED) poses a significant disease morbidity and contributor to male infertility, where an estimated 20-40% of men are affected annually. While several risk factors have been identified in the etiology of ED (e.g., aging, heart disease, diabetes, and obesity), the complete pathogenesis remains to be elucidated. Over the last few decades, the contribution of environmental exposures to the pathogenesis of ED has gained some attention, though population studies are limited and results are mixed. Among environmental contaminants, organophosphate (OP) insecticides represent one of the largest chemical classes, and chlorpyrifos is the most commonly used OP in the U.S. OP exposure has been implicated in driving biological processes, including inflammation, reactive oxygen species production, and endocrine and metabolism disruption, which have been demonstrated to adversely affect the hypothalamus and testes and may contribute to ED. Currently, studies evaluating the association between OPs and ED within the U.S. general population are sparse. METHODS: Data were leveraged from the National Health and Nutrition Examination Survey (NHANES), which is an annually conducted, population-based cross-sectional study. Urinary levels of 3,5,6-trichloro-2-pyridinol (TCPy), a specific metabolite of the most pervasive OP insecticide chlorpyrifos, were quantified as measures of OP exposure. ED was defined by responses to questionnaire data, where individuals who replied "sometimes able" or "never able" to achieve an erection were classified as ED. Chi-square, analysis of variance (ANOVA), and multivariable, weighted linear and logistic regression analyses were used to compare sociodemographic variables between quartiles of TCPy exposure, identify risk factors for TCPy exposure and ED, and to analyze the relationship between TCPy and ED. RESULTS: A total of 671 adult men were included in final analyses, representing 28,949,379 adults after survey weighting. Approximately 37% of our cohort had ED. Smoking, diabetes, aging, Mexican-American self-identification, and physical inactivity were associated with higher ED prevalence. Analysis of TCPy modeled as a continuous variable revealed nonsignificant associations with ED (OR = 1.02 95% CI [0.95, 1.09]). Stratification of total TCPy into quartiles revealed increased odds of ED among adults in the second and fourth quartiles, using the first quartile as the reference (OR = 2.04 95% CI [1.11, 3.72], OR = 1.51 95% CI [0.58, 3.93], OR = 2.62 95% CI [1.18, 5.79], for quartiles 2, 3, and 4, respectively). CONCLUSIONS: The results of our study suggest a potential role for chlorpyrifos and other OPs the pathogenesis of ED. Future studies are warranted to validate these findings, determine clinical significance, and to investigate potential mechanisms underlying these associations.

Improving the ACS Triage-Using High Sensitivity TroponinI and Copeptin for Early 'Rule-Out' of AMI.

Rule-out of acute myocardial infarction (AMI) in patients presenting with acute chest pain at the emergency department (ED) is a major challenge across the globe. Patients presenting very early with chest pain may provide a diagnostic challenge even when using a cardiac necrosis specific biomarker, high sensitivity troponin (hs-Tn) as they are elevated at 3-6 h after the symptom onset. Copeptin is a marker of acute hemodynamic stress which is released within few minutes of the occurrence of MI and is elevated immediately at the presentation of patients with AMI. This indicates a complementary pathophysiology and kinetics of these two biomarkers. Hence, we evaluated whether or not a protocol with combined testing of copeptin and hs-TnI at admission in patients presenting with chest pain within 6 h in low to intermediate risk and suspected ACS leads to an earlier diagnosis of AMI and thereby, aids to prevent a higher proportion of major adverse cardiac events than the current standard protocol followed in ED. A total of 148 patients as per the inclusion criterion were recruited for the study. The dual biomarker copeptin and hs-TnI allows a rule-out of AMI at presentation with a sensitivity of 100% and NPV of 99.8%. Hence, the use of dual biomarker in conjunction with clinical assessment may obviate the need for a prolonged stay in the ED and retesting hs-TnI after 2 h (for delta check) in more than two-thirds of the patients. The inclusion of these tests could have an impact on the economic burden of the ED without jeopardizing the outcome for the patient.

Remote reporting in the COVID-19 era: from pilot study to practice.

AIM: To assess the benefits and challenges of remote reporting using an intra-departmental teleradiology system. MATERIALS AND METHODS: A pilot of an in-hospital Trust radiologist reporting on in-hospital Trust patients via a remote login was undertaken. Reporting output, training impact, and quality improvement were measured. RESULTS: Reporting output increased by 140%. Trainee satisfaction was high in a qualitative survey, particularly for out-of-hours support and teaching. Clinicians found the service to be similar to the same service provided by a locally based radiologist. CONCLUSION: In the COVID-19 era, remote working has developed rapidly. This study shows that radiology departments can provide remote reporting that is equal in standard to reporting from within the hospital, and in addition, that there are advantages to output and training.

High Precision Detection of Change in Intermediate Range Order of Amorphous Zirconia-Doped Tantala Thin Films Due to Annealing.

Understanding the local atomic order in amorphous thin film coatings and how it relates to macroscopic performance factors, such as mechanical loss, provides an important path towards enabling the accelerated discovery and development of improved coatings. High precision x-ray scattering measurements of thin films of amorphous zirconia-doped tantala (ZrO_{2}-Ta_{2}O_{5}) show systematic changes in intermediate range order (IRO) as a function of postdeposition heat treatment (annealing). Atomic modeling captures and explains these changes, and shows that the material has building blocks of metal-centered polyhedra and the effect of annealing is to alter the connections between the polyhedra. The observed changes in IRO are associated with a shift in the ratio of corner-sharing to edge-sharing polyhedra. These changes correlate with changes in mechanical loss upon annealing, and suggest that the mechanical loss can be reduced by developing a material with a designed ratio of corner-sharing to edge-sharing polyhedra.

Evolution of prodromal parkinsonian features in a cohort of GBA mutation-positive individuals: a 6-year longitudinal study.

OBJECTIVES: GBA1 mutations are a frequent risk factor for Parkinson disease (PD). The aim of this study is to evaluate clinical features in a group of GBA1 mutation-positive individuals over a 6-year follow-up. METHODS: This is a longitudinal study on a cohort of GBA1-positive carriers. We enrolled 31 patients with Gaucher disease type 1 (GD), 29 GBA1 heterozygous carriers (Het GBA group) and 30 controls (HC) at baseline and followed them for 6 years. We assessed baseline motor and non-motor signs of PD in all subjects using clinical questionnaires and scales (reduced Unified Multiple System Atrophy Rating Scale (UMSARS), Montreal Cognitive assessment (MoCA), University of Pennsylvania Smell Identification Test (UPSIT), REM Sleep Behavior Disorder screening questionnaire (RBDsq), Movement Disorders Society Unified Parkinson's Disease Rating Scale motor subscale (MDS-UPDRS III) and Beck Depression Inventory (BDI). We repeated these at the 6-year follow-up alongside venous blood sampling for measurement of glucocerebrosidase enzymatic activity (GCase). We explored whether the GCase activity level was altered in leucocytes of these subjects and how it was related to development of PD. RESULTS: We observed a significant worsening in UMSARS, RBDsq, MDS-UPDRS III and BDI scores at the 6-year follow-up compared with baseline in both the GD and Het GBA groups. Intergroup comparisons showed that GD subjects had significantly worse scores in UPSIT, UMSARS, MoCA and MDS-UPDRS III than HC, while Het GBA displayed worse outcomes in UPSIT and MDS-UPDRS III compared with HC. In GBA1 mutation-positive individuals (Het GBA and GD), an UPSIT score of 23 at baseline was correlated with worse outcome at 6 years in UPSIT, MoCA, MDS-UPDRS III and BDI. CONCLUSION: In this 6-year-long longitudinal study, GBA1 mutation-positive subjects showed a worsening in motor and non-motor prodromal PD features.

Neurological effects of glucocerebrosidase gene mutations.

The association between Gaucher disease (GD) and Parkinson disease (PD) has been described for almost two decades. In the biallelic state (homozygous or compound heterozygous) mutations in the glucocerebrosidase gene (GBA) may cause GD, in which glucosylceramide, the sphingolipid substrate of the glucocerebrosidase enzyme (GCase), accumulates in visceral organs leading to a number of clinical phenotypes. In the biallelic or heterozygous state, GBA mutations increase the risk for PD. Mutations of the GBA allele are the most significant genetic risk factor for idiopathic PD, found in 5%-20% of idiopathic PD cases depending on ethnicity. The neurological consequences of GBA mutations are reviewed and the proposition that GBA mutations result in a disparate but connected range of clinically and pathologically related neurological features is discussed. The literature relating to the clinical, biochemical and genetic basis of GBA PD, type 1 GD and neuronopathic GD is considered highlighting commonalities and distinctions between them. The evidence for a unifying disease mechanism is considered.

Chemical vapor deposition of monolayer-thin WS2 crystals from the WF6 and H2S precursors at low deposition temperature.

Monolayer-thin WS2 with (0002) texture grows by chemical vapor deposition (CVD) from gas-phase precursors WF6 and H2S at a deposition temperature of 450 °C on 300 mm Si wafers covered with an amorphous Al2O3 starting surface. We investigate the growth and nucleation mechanism during the CVD process by analyzing the morphology of the WS2 crystals. The CVD process consists of two distinct growth regimes. During (i) the initial growth regime, a fast and self-limiting reaction of the CVD precursors with the Al2O3 starting surface forms predominantly monolayer-thin WS2 crystals and AlF3 crystals that completely cover the starting surface. During (ii) the steady-state growth regime, a much slower, anisotropic reaction on the bottom, first WS2 layer proceeds with the next WS2 layer growing preferentially in the lateral dimensions. We propose that the precursor adsorption reaction rate strongly diminishes when the precursors have no more access to the Al2O3 surface as soon as the WS2 layer completely covers the Al2O3 surface and that the WS2 crystal basal planes and AlF3 crystals have a low reactivity for WF6 adsorption at 450 °C. Nonetheless, a second layer of WS2 starts to form before the first WS2 layer completely covers the starting surface, albeit the surface coverage of the second layer is low (<20%, after 25 min of CVD reaction). During the steady-state growth regime, predominantly the WS2 crystals in the second monolayer continue to grow in lateral dimensions up to ∼40 nm. These crystals reach larger lateral dimensions compared to the crystals in the bottom, first layer due to low reactivity for WF6 adsorption on the WS2 basal plane compared to Al2O3. Presumably, they grow laterally by precursor species that adsorb on and diffuse across the WS2 surface, before being incorporated at the more reactive edges of the WS2 crystals in the second layer. Such a process proceeds slowly with only up to 40% surface coverage of the second WS2 layer after 150 min of CVD reaction. The CVD reaction is mediated by the starting surface: WF6 precursor preferentially adsorbs on Al2O3, whereas adsorption is not observed on SiO2. Nevertheless, WS2 grows on SiO2 in close proximity to Al2O3 in 90 nm pitch Al2O3/SiO2 line patterns. Hence, functionalization of the starting surface (e.g., SiO2 with Al2O3) can provide opportunities to grow monolayer-thin WS2 crystals at predetermined locations by selective, lateral growth with tunable crystal size, even at low deposition temperatures.

Ideal charge-density-wave order in the high-field state of superconducting YBCO.

The existence of charge-density-wave (CDW) correlations in cuprate superconductors has now been established. However, the nature of the CDW ground state has remained uncertain because disorder and the presence of superconductivity typically limit the CDW correlation lengths to only a dozen unit cells or less. Here we explore the field-induced 3D CDW correlations in extremely pure detwinned crystals of YBa2Cu3O2 (YBCO) ortho-II and ortho-VIII at magnetic fields in excess of the resistive upper critical field ([Formula: see text]) where superconductivity is heavily suppressed. We observe that the 3D CDW is unidirectional and possesses a long in-plane correlation length as well as significant correlations between neighboring CuO2 planes. It is significant that we observe only a single sharply defined transition at a critical field proportional to [Formula: see text], given that the field range used in this investigation overlaps with other high-field experiments including quantum oscillation measurements. The correlation volume is at least two to three orders of magnitude larger than that of the zero-field CDW. This is by far the largest CDW correlation volume observed in any cuprate crystal and so is presumably representative of the high-field ground state of an "ideal" disorder-free cuprate.

Characterisation of the HLA-DRB1*07:01 biomarker for lapatinib-induced liver toxicity during treatment of early-stage breast cancer patients with lapatinib in combination with trastuzumab and/or taxanes.

HLA-DRB1*07:01 allele carriage was characterised as a risk biomarker for lapatinib-induced liver injury in a large global study evaluating lapatinib, alone and in combination with trastuzumab and taxanes, as adjuvant therapy for advanced breast cancer (adjuvant lapatinib and/or trastuzumab treatment optimisation). HLA-DRB1*07:01 carriage was associated with serum alanine aminotransferase (ALT) elevations in lapatinib-treated patients (odds ratio 6.5, P=3 × 10-26, n=4482) and the risk and severity of ALT elevation for lapatinib-treated patients was higher in homozygous than heterozygous HLA-DRB1*07:01 genotype carriers. A higher ALT case incidence plus weaker HLA association observed during concurrent administration of lapatinib and taxane suggested a subset of liver injury in this combination group that was HLA-DRB1*07:01 independent. Furthermore, the incidence of ALT elevation demonstrated an expected correlation with geographic HLA-DRB1*07:01 carriage frequency. Robust ALT elevation risk estimates for HLA-DRB1*07:01 may support causality discrimination and safety risk management during the use of lapatinib combination therapy for the treatment of metastatic breast cancer.

Tumor necrosis factor family member LIGHT acts with IL-1ß and TGF-ß to promote airway remodeling during rhinovirus infection.

BACKGROUND: Rhinovirus (RV) can exacerbate allergen-driven asthma. However, it has been suggested that serial infections with RV may also lead to asthma-like features in childhood without prior allergen exposure. AIM: We sought to test the effects of RV infection in the absence of allergen challenge on lung tissue remodeling and to understand whether RV induced factors in common with allergen that promote remodeling. METHODS: We infected C57BL/6 mice multiple times with RV in the absence or presence of allergen to assess airway remodeling. We used knockout mice and blocking reagents to determine the participation of LIGHT (TNFSF14), as well as IL-1ß and TGF-ß, each previously shown to contribute to lung remodeling driven by allergen. RESULTS: Recurrent RV infection without allergen challenge induced an increase in peribronchial smooth muscle mass and subepithelial fibrosis. Rhinovirus (RV) induced LIGHT expression in mouse lungs after infection, and alveolar epithelial cells and neutrophils were found to be potential sources of LIGHT. Accordingly, LIGHT-deficient mice, or mice where LIGHT was neutralized, displayed reduced smooth muscle mass and lung fibrosis. Recurrent RV infection also exacerbated the airway remodeling response to house dust mite allergen, and this was significantly reduced in LIGHT-deficient mice. Furthermore, neutralizing IL-1ß or TGF-ß also limited subepithelial fibrosis and/or smooth muscle thickness induced by RV. CONCLUSION: Rhinovirus can promote airway remodeling in the absence of allergen through upregulating common factors that also contribute to allergen-associated airway remodeling.

Impact of ovarian metastases on survival in patients treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for peritoneal malignancy originating from appendiceal and colorectal cancer.

AIM: Ovarian metastases from gastrointestinal tract malignancies have been considered an ominous finding with poor prognosis. The aim of this project was to determine the impact on survival, and potential cure, when cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are combined to treat peritoneal malignancy in women with Krukenberg tumours. METHOD: A retrospective analysis of prospectively collected data between January 2010 and July 2015. Female patients undergoing complete CRS (macroscopic tumour removal) and HIPEC for pseudomyxoma peritonei (PMP) of appendiceal origin, or colorectal peritoneal metastases (CPM) were included. Survival was estimated using the Kaplan-Meier method and survival rates compared using the log-rank test. RESULTS: In total, 889 patients underwent surgery for peritoneal malignancy, of whom 551 were female. Of these, 504/551 (91%) underwent complete CRS and HIPEC. Overall, 405/504 (80%) had at least one involved ovary removed either during CRS and HIPEC or at their index prereferral operation. Three hundred and fifty-two patients (87%) had an appendiceal tumour and 53 (13%) had CPM. At a median follow up of 40 months, overall survival (OS) did not differ significantly between patients with or without ovarian involvement in women with a primary low-grade appendiceal tumour or CPM. In women with high-grade primary appendiceal pathology, OS was significantly lower in patients with ovarian metastases compared with those without ovarian involvement. CONCLUSION: Women with ovarian metastases from low-grade appendiceal tumours or colorectal cancer treated with CRS and HIPEC have similar survival rates to patients without ovarian metastases. Long-term survival and cure is feasible in patients amenable to complete tumour removal.

Transperineal retropubic approach in total pelvic exenteration for advanced and recurrent colorectal and anal cancer involving the penile base: technique and outcomes.

BACKGROUND: Complete pathological resection of locally advanced and recurrent anorectal cancer is considered the most important determinant of survival outcome. Involvement of the retropubic space with cancer threatening or involving the penile base poses specific challenges due to the potential for margin involvement and blood loss from the dorsal venous plexus. In the present study we evaluate a new transperineal surgical approach to excision of anterior compartment organs involved or threatened by cancer which facilitates exposure and visualisation of the bulbar urethra and the deep vein of the penis caudal to the retropubic space and penile base. METHODS: A retrospective study was performed on male patients with tumour extension into the penile base treated at our institution using the transperineal surgical approach. Descriptive data for patient demographics, radiology, operative details, postoperative histology, complications and outcomes were collated. RESULTS: Ten male patients with tumour extension into the penile base were identified. Two patients had recurrent anal cancer, 6 had locally advanced primary rectal cancer and 2 had recurrent rectal cancer. All patients had exenterative surgery with excision of the penile base utilising the transperineal approach. All patients had R0 resection. No local recurrence developed after a median follow up period of 15 months. CONCLUSIONS: The transperineal approach to the penile base and retropubic space allows for high rates of R0 resection margin status with direct visualisation of the dorsal venous plexus, thereby minimising blood loss. In our experience, this technique is the preferred approach to excision of cancers threatening and involving the penile base and also for most male patients requiring total pelvic exenteration.

Diagnostic Accuracy of Intraoperative Frozen Section in Ovarian Neoplasms: Experience in a Tertiary Oncology Centre.

Background Ovarian cancer is the second most common type of female genital tract malignancy. Treatment planning differs for benign, borderline and malignant subtypes of surface epithelial tumours and depends on accurate histopathological diagnosis. A pre-operative diagnosis of the nature of ovarian tumors is not always reliable. Frozen section is a valuable diagnostic tool in rapid intraoperative categorization of ovarian masses and thereby helps in planning the surgical management. Adequate management and treatment of ovarian carcinoma requires a complete surgical staging supported by frozen-section examination. To achieve this goal it is necessary to have a high level of accuracy. Objective To assess the accuracy of intra-operative frozen section in the diagnosis of various categories of ovarian neoplasm conducted in Rajiv Gandhi Cancer Institute and Research Centre. Method Intra-operative frozen sections for suspected ovarian neoplasm that underwent surgery as primary line of therapy at this institution were analyzed retrospectively from Jan. 2014 - Dec. 2015. The results of frozen section were compared with the final histopathology diagnosis on paraffin sections and the overall accuracy, sensitivity, specificity, positive and negative predictive values were determined. Result The study included 159 cases and the mean age of patients was 44.72±14.28 years (Range 19-75 years). The mean size of tumor was 12.5±5.9 cm. Sensitivity of frozen section for benign, borderline and malignant tumors was 98.53%, 73.33% and 94.74% respectively and the related specificities were 95.60%, 96.53% and 100% respectively. There were 150 concordant cases and 9 discordant cases. Overall diagnostic accuracy of frozen section was 94.33%. Conclusion Intra-operative frozen section diagnosis appeared to be an accurate and comparable technique for the histopathology diagnosis of ovarian tumors.

Lessons Learned: Early Termination of a Randomized Trial of Calcineurin Inhibitor and Corticosteroid Avoidance Using Belatacept.

The intent of this National Institutes of Health-sponsored study was to compare a belatacept-based immunosuppressive regimen with a maintenance regimen of tacrolimus and mycophenolate. Nineteen primary, Epstein-Barr virus-immune renal transplant recipients with a negative cross-match were randomized to one of three groups. All patient groups received perioperative steroids and maintenance mycophenolate mofetil. Patients in groups 1 and 2 were induced with alemtuzumab and maintained on tacrolimus or belatacept, respectively. Patients in group 3 were induced with basiliximab, received 3 mo of tacrolimus, and maintained on belatacept. There was one death with a functioning allograft due to endocarditis (group 1). There were three graft losses due to vascular thrombosis (all group 2) and one graft loss due to glomerular disease (group 1). Biopsy-proven acute cellular rejection was more frequent in the belatacept-treated groups, with 10 treated episodes in seven participants compared with one episode in group 1; however, estimated GFR was similar between groups at week 52. There were no episodes of posttransplant lymphoproliferative disorder or opportunistic infections in any group. Protocol enrollment was halted prematurely because of a high rate of serious adverse events. Such negative outcomes pose challenges to clinical investigators, who ultimately must weigh the risks and benefits in randomized trials.

TrueNTH sexual recovery study protocol: a multi-institutional collaborative approach to developing and testing a web-based intervention for couples coping with the side-effects of prostate cancer treatment in a randomized controlled trial.

BACKGROUND: Over half of men who receive treatment for prostate suffer from a range of sexual problems that affect negatively their sexual health, sexual intimacy with their partners and their quality of life. In clinical practice, however, care for the sexual side effects of treatment is often suboptimal or unavailable. The goal of the current study is to test a web-based intervention to support the recovery of sexual intimacy of prostate cancer survivors and their partners after treatment. METHODS: The study team developed an interactive, web-based intervention, tailored to type of treatment received, relationship status (partnered/non-partnered) and sexual orientation. It consists of 10 modules, six follow the trajectory of the illness and four are theme based. They address sexual side effects, rehabilitation, psychological impacts and coaching for self-efficacy. Each includes a video to engage participants, psychoeducation and activities completed by participants on the web. Tailored strategies for identified concerns are sent by email after each module. Six of these modules will be tested in a randomized controlled trial and compared to usual care. Men with localized prostate cancer with partners will be recruited from five academic medical centers. These couples (N = 140) will be assessed prior to treatment, then 3 months and 6 months after treatment. The primary outcome will be the survivors' and partners' Global Satisfaction with Sex Life, assessed by a Patient Reported Outcome Measure Information Systems (PROMIS) measure. Secondary outcomes will include interest in sex, sexual activity, use of sexual aids, dyadic coping, knowledge about sexual recovery, grief about the loss of sexual function, and quality of life. The impact of the intervention on the couple will be assessed using the Actor-Partner Interaction Model, a mixed-effects linear regression model able to estimate both the association of partner characteristics with partner and patient outcomes and the association of patient characteristics with both outcomes. DISCUSSION: The web-based tool represents a novel approach to addressing the sexual health needs of prostate cancer survivors and their partners that-if found efficacious-will improve access to much needed specialty care in prostate cancer survivorship. TRIAL REGISTRATION: Clinicaltrials.gov registration # NCT02702453 , registered on March 3, 2016.

Structural characterization of SnS crystals formed by chemical vapour deposition.

The crystal and defect structure of SnS crystals grown using chemical vapour deposition for application in electronic devices are investigated. The structural analysis shows the presence of two distinct crystal morphologies, that is thin flakes with lateral sizes up to 50 µm and nanometer scale thickness, and much thicker but smaller crystallites. Both show similar Raman response associated with SnS. The structural analysis with transmission electron microscopy shows that the flakes are single crystals of α-SnS with [010] normal to the substrate. Parallel with the surface of the flakes, lamellae with varying thickness of a new SnS phase are observed. High-resolution transmission electron microscopy (TEM), scanning transmission electron microscopy (STEM), first-principles simulations (DFT) and nanobeam diffraction (NBD) techniques are employed to characterise this phase in detail. DFT results suggest that the phase is a strain stabilised ß' one grown epitaxially on the α-SnS crystals. TEM analysis shows that the crystallites are also α-SnS with generally the [010] direction orthogonal to the substrate. Contrary to the flakes the crystallites consist of two to four grains which are tilted up to 15° relative to the substrate. The various grain boundary structures and twin relations are discussed. Under high-dose electron irradiation, the SnS structure is reduced and ß-Sn formed. It is shown that this damage only occurs for SnS in direct contact with SiO2 .

Postdepletion Lymphocyte Reconstitution During Belatacept and Rapamycin Treatment in Kidney Transplant Recipients.

Belatacept is used to prevent allograft rejection but fails to do so in a sizable minority of patients due to inadequate control of costimulation-resistant T cells. In this study, we report control of costimulation-resistant rejection when belatacept was combined with perioperative alemtuzumab-mediated lymphocyte depletion and rapamycin. To assess the means by which the alemtuzumab, belatacept and rapamycin (ABR) regimen controls belatacept-resistant rejection, we studied 20 ABR-treated patients and characterized peripheral lymphocyte phenotype and functional responses to donor, third-party and viral antigens using flow cytometry, intracellular cytokine staining and carboxyfluorescein succinimidyl ester-based lymphocyte proliferation. Compared with conventional immunosuppression in 10 patients, lymphocyte depletion evoked substantial homeostatic lymphocyte activation balanced by regulatory T and B cell phenotypes. The reconstituted T cell repertoire was enriched for CD28(+) naïve cells, notably diminished in belatacept-resistant CD28(-) memory subsets and depleted of polyfunctional donor-specific T cells but able to respond to third-party and latent herpes viruses. B cell responses were similarly favorable, without alloantibody development and a reduction in memory subsets-changes not seen in conventionally treated patients. The ABR regimen uniquely altered the immune profile, producing a repertoire enriched for CD28(+) T cells, hyporesponsive to donor alloantigen and competent in its protective immune capabilities. The resulting repertoire was permissive for control of rejection with belatacept monotherapy.

Neuroimaging in encephalitis: analysis of imaging findings and interobserver agreement.

AIM: To assess the role of imaging in the early management of encephalitis and the agreement on findings in a well-defined cohort of suspected encephalitis cases enrolled in the Prospective Aetiological Study of Encephalitis conducted by the Health Protection Agency (now incorporated into Public Health England). MATERIALS AND METHODS: Eighty-five CT examinations from 68 patients and 101 MRI examinations from 80 patients with suspected encephalitis were independently rated by three neuroradiologists blinded to patient and clinical details. The level of agreement on the interpretation of images was measured using the kappa statistic. The sensitivity, specificity, and negative and positive predictive values of CT and MRI for herpes simplex virus (HSV) encephalitis and acute disseminated encephalomyelitis (ADEM) were estimated. RESULTS: The kappa value for interobserver agreement on rating the scans as normal or abnormal was good (0.65) for CT and moderate (0.59) for MRI. Agreement for HSV encephalitis was very good for CT (0.87) and MRI (0.82), but only fair for ADEM (0.32 CT; 0.31 MRI). Similarly, the overall sensitivity of imaging for HSV encephalitis was ∼80% for both CT and MRI, whereas for ADEM it was 0% for CT and 20% for MRI. MRI specificity for HSV encephalitis between 3-10 days after symptom onset was 100%. CONCLUSION: There is a subjective component to scan interpretation that can have important implications for the clinical management of encephalitis cases. Neuroradiologists were good at diagnosing HSV encephalitis; however, agreement was worse for ADEM and other alternative aetiologies. Findings highlight the importance of a comprehensive and multidisciplinary approach to diagnosing the cause of encephalitis that takes into account individual clinical, microbiological, and radiological features of each patient.

Tildrakizumab (MK-3222), an anti-interleukin-23p19 monoclonal antibody, improves psoriasis in a phase IIb randomized placebo-controlled trial.

BACKGROUND: Tildrakizumab is a high-affinity, humanized, IgG1/κ, anti-interleukin (IL)-23p19 monoclonal antibody that does not bind human IL-12 or p40 is being developed for the treatment of chronic plaque psoriasis. OBJECTIVES: To evaluate the safety and efficacy of subcutaneous tildrakizumab in patients with moderate-to-severe chronic plaque psoriasis. METHODS: A three-part, randomized, double-blind, phase IIb trial was conducted in 355 adults with chronic plaque psoriasis. Participants were randomized to receive subcutaneous tildrakizumab (5, 25, 100, 200 mg) or placebo at weeks 0 and 4 (part I) and every 12 weeks thereafter until week 52 (part II). Study drug was discontinued at week 52 and participants were followed through week 72 (part III). Primary efficacy end point was Psoriasis Area and Severity Index (PASI) 75 response at week 16. Adverse events (AEs) and vital signs were monitored throughout the study. RESULTS: At week 16, PASI 75 responses were 33·3% (n = 14), 64·4% (n = 58), 66·3% (n = 59), 74·4% (n = 64) and 4·4% (n = 2) in the 5-, 25-, 100- and 200-mg tildrakizumab and placebo groups, respectively (P ≤ 0·001 for each tildrakizumab dose vs. placebo). PASI 75 response was generally maintained through week 52; only eight of 222 participants who achieved PASI 75 response at week 52 and continued to part III relapsed following discontinuation up to week 72. Possible drug-related serious AEs included bacterial arthritis and lymphoedema (part I), and melanoma, stroke, epiglottitis and knee infection (part II). CONCLUSIONS: Tildrakizumab had treatment effects that were superior to placebo, maintained for 52 weeks of treatment, and persisted for 20 weeks after cessation. Tildrakizumab was generally safe and well tolerated. These results suggest that IL-23p19 is a key target for suppressing psoriasis.

New treatments for diabetic retinopathy.

Diabetic retinopathy is the major cause of vision loss in middle-aged adults. Alteration of the blood-retinal barrier (BRB) is the hallmark of diabetic retinopathy and, subsequently, hypoxia may result in retinal neovascularization. Tight control of systemic factors such as blood glucose, blood pressure and blood lipids is essential in the management of this disease. Vascular endothelial growth factor (VEGF) is one of the most important factors responsible for alteration of the BRB. The introduction of anti-VEGF agents has revolutionized the therapeutic strategies used in people with diabetic retinopathy, and the use of laser therapy has been modified. In the present article, we examine the clinical features and pathophysiology of diabetic retinopathy and review the current status of new treatment recommendations for this disease, and also explore some possible future therapies.