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Summary Rapid spread of coronavirus disease 2019 (COVID-19) is ravaging the globe. Since its first report in December 2019, COVID-19 cases have exploded to over 14 million as of July 2020, claiming more than 600,000 lives. Implementing fast and widespread diagnostic tests is paramount to contain COVID-19, given the current lack of an effective therapeutic or vaccine. This review focuses on a broad description of currently available diagnostic tests to detect either the virus (SARS-CoV-2) or virus-induced immune responses. We specifically explain the working mechanisms of these tests and compare their analytical performance. These analyses will assist in selecting most effective tests for a given application, for example, epidemiology or global pandemic research, population screening, hospital-based testing, home-based and point-of-care testing, and therapeutic trials. Finally, we lay out the shortcomings of certain tests and future needs., Graphical Abstract, Virology; Diagnostic Equipment; Infection Control in Health Technology; Analytical Chemistry

12001 Background: The purpose of this study was to test a Palliative Care Intervention for patients with solid tumors enrolled in phase I therapeutic trials. Methods: This randomized trial compared patients accrued to phase I Clinical Trials in groups of Usual Care compared to a Palliative Care Intervention (PCI) in two comprehensive cancer centers. The PCI included assessment of quality of life (QOL) and symptoms, an interdisciplinary meeting to discuss the care plan, including goals of care, and two nurse-delivered teaching sessions. Subjects (n=479) were followed for 24 weeks, with 12 weeks as the primary outcome point. Results: Outcomes revealed that relative to Usual Care, PCI subjects showed less Psychological Distress (1.9 in Intervention and 1.2 in Control pts, p=0.03) and a trend toward improved QOL (3.7 versus 1.6, p=0.07), with differences between sites. We observed high rates of symptom-management admissions (41.3%) and low rates of Advance Directive completion (39%), and use of supportive care services including hospice (30.7%, for only1.2 months duration), despite a median survival for all patients in both groups of 10.1 months from initiating a phase 1 study until death. Patient satisfaction with oncology care was already high at baseline, and we did not see clinically significant changes in those scores by week 12. Conclusions: Palliative care interventions can improve QOL outcomes and distress for patients participating in phase 1 trials. Greater integration of PC is needed to provide quality care to these patients and to support transitions from treatment to supportive care, especially at the end of life. Clinical trial information: NCT01828775 .

e17105 Background: The success of randomized phase III therapeutic trials (RP3TT) to reach their primary endpoint is critical given the enormous resources required to conduct such studies. In an era of accelerated therapeutic development in advanced kidney cancer, we aim to identify factors in such studies associated with a positive endpoint (PE) to better understand how to optimize trial design. Methods: Using PubMed and ClinicalTrials.gov, we identified all published RP3TT in patients with metastatic renal cell carcinoma between 1/2007-9/2019. Studies were considered PE if the primary endpoint was reached, and negative endpoint (NE) if otherwise. Studies were categorized as either first line only (FLO) or second line and beyond (SLB), with adjuvant and consolidation therapy studies excluded. We collected components of study design and baseline patient characteristics and analyzed with multivariate logistic regression to evaluate the associations between each factor and PE RP3TT. Results: Of the 65 studies evaluated, only 22 RP3TT (14 FLO, 8 SLB) were found to have published data and were included, with 14 PE and 8 NE. For all studies, those with larger enrollment size (OR = 1.008, 95% CI [1.001-1.015], p = 0.021) and clear cell requirements (OR = 0.077, 95% CI [0.007-0.901], p = 0.041) were associated with PE. After adjusting for sample size, only larger enrollment size remained significant (OR = 1.007, 95% CI [1.001-1.014], p = 0.032). Other baseline patient demographic and clinical characteristic variables were not associated with PE RP3TT. Subgroup analysis of only FLO or SLB studies also did not yield any significant associations with PE RP3TT. Conclusions: Higher enrollment size was identified as factor associated with PE in RP3TT. Incomplete trial data reporting was evident, particularly in earlier studies. Further efforts are needed to better characterize factors in order to optimize clinical trial design in this disease. [Table: see text]

Background: Scabies is one of the common epidemic and endemic diseases worldwide. Many topical therapeutic modalities for scabies are available. Topical ivermectin has been used effectively in treatment of scabies but there is no oral effective therapy that prevents contacts to get scabies. Objective: To evaluate the effectiveness of oral ivermectin in prevention of scabies contacts to get scabies. Patients and Methods: The study is a single-blinded therapeutic study that was conducted in the Center of Dermatology, Baghdad Teaching Hospital, Baghdad, Iraq during the period from April 2018 through October 2019.Two hundred sixty healthy scabies contacts were included in this study, their ages ranged from 5-60 years with a mean ± SD of 19.3± 1.9 years. All these contacts were screened for active scabies and they were all free. The contacts of scabies were treated by ivermectin tablet 200 microgram per kg as a single dose after 2 hours from dinner. They were seen regularly after 4 weeks to be re-examined and to record any scabies and drug side effects. Results: The response after four weeks of single dose therapy of healthy contacts showed that 245 (94%) from 260 were free of scabies and only 15(6%) contacts showed infection with scabies and this was statistically significant Chi-square (c2= 148, P-value less than 0.00000001. No any side effects were noticed in any treated contacts. Conclusion: Oral single ivermectin dose is an effective therapy to prevent scabies contacts to get infection. It an easy method of prevention which is very useful in condition of scabies outbreaks and epidemics to stop the rapid spread of the disease.

Left ventricular (LV) ejection fraction (LVEF) is the most validated and commonly used echocardiographic measure of systolic function. LVEF has a unique position in cardiology having severed as selection criteria for therapeutic trials that constitute the evidence base of today's treatment recommendations. Assessment of LV systolic function by global longitudinal strain (GLS) from speckle tracking echocardiography (STE) is a sensitive and feasible method that overcomes many of the limitations of LVEF, including reproducibility issues of serial testing and detection of LV dysfunction in pathologically remodeled hearts. This review discusses the role of STE as a complementary method to LVEF in estimation of LV systolic function.

PURPOSE OF REVIEW Myotonic dystrophies are the most frequent muscular dystrophies in adulthood; however, myotonic dystrophy type 2 (DM2) is by far less prevalent than myotonic dystrophy type 1 (DM1). Consequently, studies on large cohorts are lacking and disease-specific outcome measures have not been developed (see video abstract, Supplemental Digital Content 1, http://links.lww.com/CONR/A44).The aim of this review is to systematically evaluate the outcome measures applied in patients with DM2 and to identify tests adopted from other neuromuscular disorders potentially suitable for DM2.A systematic review of functional tests and patient reported outcomes (PROs) previously used in DM2 has been performed. In addition, we reviewed functional tests and PROs previously used in neuromuscular diseases (NMDs). Based on this approach, we propose a battery of tests to be validated in DM2. RECENT FINDINGS No outcome measures or PROs have been validated in DM2. The most used PROs in DM2 were INQoL, SF-36, MPQ, and BPI. It is not clear whether it is better to use MMT or QMT to assess muscle strength. The algometer seems to be a useful tool to assess myalgia. No currently adopted tests or PROs seem effective to assess the mild myotonia of DM2. Several outcome measures used in other NMDs (e.g. 6MWT, QMFT, GSGC) might be suitable for DM2; however, their disease-specific validity needs to be explored. SUMMARY Although DM2 has a milder and more heterogeneous phenotype than DM1, there is an urgent need to develop validated outcome measures in DM2. The current lack of validated DM2 tests will delay the start of therapeutic trials.

Around 15% of frontotemporal dementia (FTD) patients develop clinical symptoms of motor neuron dysfunction. Different studies have suggested that roughly 50% of patients with Amyotrophic Lateral Sclerosis (ALS) have some cognitive impairment, and 15% of them accomplish the diagnostic criteria for FTD. Cognitive impairment in ALS patients is key not only for therapeutic trials of this incurable disease, but also for care planning, compliance to interventions and ultimately end-of-life decisions.

Transcranial direct current stimulation (tDCS) modulates spontaneous neuronal activity that can generate long-term neuroplastic changes. tDCS has been used in numerous therapeutic trials showing significant clinical effects especially when combined with other behavioral therapies. One area of intensive tDCS research is chronic pain. Since the initial tDCS trials for chronic pain treatment using current parameters of stimulation, more than 60 clinical trials have been published testing its effects in different pain syndromes. However, as the field moves in the direction of clinical application, several aspects need to be taken into consideration regarding tDCS effectiveness and parameters of stimulation. In this manuscript, we reviewed the evidence of tDCS effects for the treatment of chronic pain and critically analyzed the literature pertaining its safety, efficacy and how to optimize tDCS clinical effects in a therapeutic setting. We discuss optimization of tDCS effects in three different domains: (i) parameters of stimulation; (ii) combination therapies and (iii) subject selection. This article aims to provide insights for the development of future tDCS clinical trials.

Human prion diseases are highly heterogeneous and rare disorders. Sporadic Creutzfeldt-Jakob disease (sCJD) is the most common form,1 with an average annual age-adjusted incidence of 1.1 cases per million individuals in the United States in 2016 (Larry Schonberger, Center for Disease Control, Atlanta, GA, personal communication, May 2, 2018). Prion diseases may, however, be underdiagnosed. An early and accurate clinical diagnosis of sCJD is challenging due to the substantial overlap with other rapidly progressive dementias. A more accurate diagnosis of sCJD strains is expected to improve surveillance efforts and selection of patients in therapeutic trials once effective drugs become available.

Positron Emission Tomography (PET), an imaging technique based on the injection of radiotracers directed against specific biological targets within brain tissues, within brain tissues, is a specific and sensitive technique which offers the unique opportunity to quantify myelin dynamics in the central nervous system. Several stilbene and benzothiazole derivatives have been repurposed to image myelin by PET. In demyelinating and dysmyelinating models, selected radiotracers were shown to reliably quantify demyelination and remyelination, allowing a translational approach in humans. A pilot study in subjects with active relapsing MS using PET and the most available benzothiazole derivative, [11C]PIB, supported the hypothesis that this technique is able to quantify myelin content in multiple sclerosis (MS) lesions and to capture dynamic demyelination and remyelination over time. This study highlighted for the first time in vivo the prognostic value of individual profiles of remyelination on the disease course. In future, the clinical application of myelin PET will be pushed forward thanks to the availability of novel fluorinated tracers for myelin, together with the setting up of non invasive quantification procedures and the use of powerful PET-MR systems. This will enable to address in vivo critical unanswered questions about the pathogenesis of remyelination, and to measure the efficacy of emerging promyelinating drugs in early-phase therapeutic trials.

The landscape of type 2 diabetes (T2D) therapy is continuously evolving. Recent therapeutic trials showing cardiovascular and mortality benefit have influenced its management in clinical practice (1,2). It is increasingly apparent that T2D is a heterogeneous entity (3). Hence, there is a need to emphasize patient-centred approaches to care (3). In current clinical practice, metabolic and biochemical targets remain the predominant drivers for diabetes management. Patient related outcome measures (PROMs) have been a topic of research interest, but its additional value in routine clinical practice remains uncertain. This editorial explores the findings from the recently published PANORAMA study and its clinical implications (4).

Multiple myeloma (MM) occurs in all races, but the incidence in non-Hispanic black patients (NHBs) is two to three times higher than in non-Hispanic white patients (NHWs). We determined the representation of minorities and elderly patients in MM clinical trials. Enrollment data from all therapeutic trials reported in ClinicalTrials.gov from 2000 to 2016 were analyzed. Enrollment fraction (EF) was defined as the number of trial enrollees divided by the 2014 MM prevalence. Participation in MM clinical trials varied significantly across racial and ethnic groups; NHWs were more likely to be enrolled in clinical trials (EF 0.18%) than NHBs (EF 0.06%, p

Background Submandibular gland (SMG) transplantation is a successful treatment approach for patients with severe dry eye. However, duct obstruction can occur post-transplant. Methods We studied nineteen patients with duct obstruction of transplanted SMGs, including five interventional modalities: stone removal; secretory stimulation (to mimic "internal irrigation" with substantial secretory flow); irrigation; surgical opening of stenosis and orifice reconstruction; cephalic vein bypass and Wharton's duct reconstruction. Results A solitary stone was found and removed in one patient. Duct blockages like mucus plug were cleared by secretory stimulation in three patients, and by normal saline irrigation in two grafts. In the remaining 13 patients, irrigation failed and surgical opening was performed. Orifice reconstruction succeeded in six of the eight patients, whose stenosis was near the orifice. Wharton's duct reconstruction was successful in two of the five cases where stenosis was located in the middle segment of the duct. Conclusion Transplanted SMGs obstruct for various reasons. Stone, which is easy to diagnose and treat, should be excluded first. Non-organic blockage and stenosis were semblable in clinic. Therefore, subsequent steps should be a diagnostic/therapeutic trial of secretory stimulation, followed by irrigation; failure of these interventions suggests the diagnosis of duct stenosis, necessitating surgical recanalization.

In this review, a current overview is provided of how optical coherence tomography and infrared oculography can aid in assessing the visual system and CNS in multiple sclerosis (MS). Both afferent and efferent visual disorders are common in MS and visual complaints can have a tremendous impact on daily functioning. Optical coherence tomography and infrared oculography can detect and quantify visual disorders with high accuracy, but could also serve as quantitative markers for inflammation, neurodegeneration and network changes including cognitive decline in MS patients. The assessment of the efferent and afferent visual pathways is relevant for monitoring and predicting the disease course, but is also potentially valuable as an outcome measure in therapeutic trials.

The Severe Paediatric Asthma Collaborative in Europe (SPACE) ERS Clinical Research Collaboration is devoted to describing phenotypes of children with severe asthma and to enhancing their participation in therapeutic trials of new drugs http://ow.ly/zxgB30m01zR

In spite of many studies, the real nature, etiology, pathobiology, and therapy of acute exacerbation (AEx) of idiopathic pulmonary fibrosis (IPF) are not clear. It seemed that AEx-IPF may be an acute acceleration of the underlying fibroproliferative process triggered by various extrinsic or unknown insults in the patients with IPF, who have a predisposition to abnormal wound healing and exaggerated fibrosis. This chapter summarizes the previous studies on etiology/triggering factors, risk factors, prognosis, and therapeutic trials with the introduction of the new consensus definition and diagnostic criteria, which remove “idiopathic” from the 2007 consensus definition, to improve the feasibility of future researches.

This study was conducted in Qassim region, central of Saudi Arabia to study the clinical signs associated with dermatophilosis in sheep and goats with therapeutic trials using two treatment regimes. Diagnosis of dermatophilosis was based on the appearance of the characteristic skin lesions on the affected animals and demonstrating the causal organism from the lesions beneath the scabs. Clinically, the examined diseased sheep and goats showed lesions in the form of exudative dermatitis and formation of thick greasy scabs. These lesions were mainly observed on the back of the infected animals. All cases were detected during November, December and January (2013 and 2014). Treatment of the infected animals using long acting oxytetracycline, 3 doses 3 days apart gave the same results as penicillin plus streptomycin administered for five consecutive days. From the technical point of view, it is recommend that long acting oxytetracycline, 3 doses 3 days apart are less demanding than penicillin plus streptomycin for five consecutive days.

Canine brain tumours are becoming established as naturally occurring models of disease to advance diagnostic and therapeutic understanding successfully. The size and structure of the dog's brain, histopathology and molecular characteristics of canine brain tumours, as well as the presence of an intact immune system, all support the potential success of this model. The limited success of current therapeutic regimens such as surgery and radiation for dogs with intracranial tumours means that there can be tremendous mutual benefit from collaboration with our human counterparts resulting in the development of new treatments. The similarities and differences between the canine and human diseases are described in this article, emphasizing both the importance and limitations of canines in brain tumour research. Recent clinical veterinary therapeutic trials are also described to demonstrate the areas of research in which canines have already been utilized and to highlight the important potential benefits of translational research to companion dogs.

Rationale and Objectives Accuracy of radiologic assessment may have a crucial impact on clinical studies and therapeutic decisions. We compared the variability of a central radiologic assessment (RECIST) and computer-aided volume-based assessment of lung lesions in patients with metastatic renal cell carcinoma (RCC). Materials and Methods The investigation was prospectively planned as a substudy of a clinical randomized phase IIB therapeutic trial in patients with RCC. Starting with the manual study diameter (SDM) of the central readers using RECIST in the clinical study, we performed computer-aided volume measurements. We compared SDM to an automated RECIST diameter (aRDM) and the diameter of a volume-equivalent sphere (effective diameter [EDM]), both for the individual size measurements and for the change rate (CR) between consecutive time points. One hundred thirty diameter pairs of 30 lung lesions from 14 patients were evaluable, forming 55 change pairs over two consecutive time points each. Results The SDMs of two different readers showed a correlation of 95.6%, whereas the EDMs exhibited an excellent correlation of 99.4%. Evaluation of CRs showed an SDM-CR correlation of 63.9%, which is substantially weaker than the EDM-CR correlation of 87.6%. The variability of SDM-CR is characterized by a median absolute difference of 11.4% points versus the significantly lower 1.8% points EDM-CRs variability (aRDM: 3.2% points). The limits of agreement between readers suggest that an EDM change of 10% or 1 mm can already be significant. Conclusions Computer-aided volume-based assessments result in markedly reduced variability of parameters describing size and change, which may offer an advantage of earlier response evaluations and treatment decisions for patients.

Background Therapeutic trials in Duchenne muscular dystrophy (DMD) often exclude non-ambulatory individuals. Here we establish optimal and reliable assessments in a multicenter trial.

Objective The purpose of this literature database search-based review was to critically consider and evaluate the findings of literature focusing on efficacy and safety of 5-HT3 antagonists in the treatment of obsessive–compulsive disorder (OCD), so as to test whether preclinical data match clinical therapeutic trials. Design The PubMed database has been searched for papers on 5-HT3 antagonists and OCD in humans and for animal models of OCD and 5-HT3 receptors. Results Of the clinically tested 5-HT3 receptor antagonists, ondansetron has been used to treat OCD in five therapeutic studies, whereas granisetron only in one recent trial. Both showed some efficacy in open studies and superiority to placebo in double-blind studies, along with fair safety. No animal OCD model directly implicated 5-HT3 receptors. Conclusions Overall, results indicate some utility, but the available literature is too scanty to allow for valid conclusions to be drawn. The mismatch between animal models of obsessive–compulsive disorder and clinical data with 5-HT3 antagonists needs more clinical data to ensure that it is not an artefact. Copyright © 2015 John Wiley & Sons, Ltd.

Inherited spinocerebellar ataxias (SCAs) are known to be genetically and clinically heterogeneous. Whether severity and survival are variable, however, is not known. We, therefore, studied survival and severity in 446 cases and 509 relatives with known mutations. Survival was 68 years [95% CI: 65–70] in 223 patients with polyglutamine expansions versus 80 years [73–84] in 23 with other mutations (P

The use of mesenchymal stem cells (MSCs) in experimental, clinical, and therapeutic trials has grown in recent years. However, the issue remains of whether these procedures are completely safe for transplant patients. Therefore, this study was designed and carried out with the aim of evaluating two different comet assay protocols for genomic damage pattern analysis in MSCs derived from adipose tissue. The analyzed and interpreted results suggest that genetic testing is needed to support clonal expansion safety in cell therapy procedures with MSCs. Furthermore, they also suggest that if the comet assay technique would be used as a genomic integrity screening assay, the protocol performed at pH = 12 (that yielded a frequency of damaged cells: tail intensity = 9.50 ± 0.60, tail moment = 0.0122 ± 0.0007; results are reported as means ± standard deviation) would be indicated as genomic damage, and that subsequent single-strand breaks occur at pH13 (frequency of damaged cells: tail intensity = 30.71 ± 4.23, tail moment = 0.0447 ± 0.0073). Our study demonstrates that, in the era of regenerative medicine, it is necessary to standardize and establish a battery of tests in order to identify genomic damage prior to MSC transplantation.

Background: Acne vulgaris is a very common skin disease among young people which might be associated with scarring that has a great impact on the emotional, psychological and social life of the patients as it will go with them for life. Subcision is a new technique for the treatment of acne scars. Objective: To assess objectively and subjectively the efficacy and safety of subcision in the treatment of depressed acne scars. Patients and Methods: This is an open-label therapeutic trial. A total of 16 patients were enrolled in this study. Twelve were males and 4 were females. Their ages ranged from 19 - 39 with a mean of 26.64 ± 5.64. The duration of scar varied between 6 months and 10 years with a mean of 4.14 ± 2.54 years. subcision was done by introducing a sterile, hypodermic, 18-gauge needle. The needle was held by a three ml syringe for better orientation of the sharp tip of the needle. It was kept horizontal to the skin surface with the bevel up, and was introduced in a high sub dermal plane. The needle was slowly advanced parallel to the skin surface. Initially, rapid, repetitive linear back-and-forth motion of the needle makes the skin free of the underlying scar. This procedure was repeated in all directions in a fan-like manner. Results: According to Modified Sharquie’s scoring system for grading acne scars, 4 (25%) patients had severe grade, 11 (68.8%) patients had moderate grade and only 1 (6.2%) patient had mild grade. Evaluation at 6 months after treatment revealed that 8 (50%) patients had mild acne scar, 7 (43.8%) had moderate acne scar and only 1 (6.2%) patient still had severe grade. This change in the grades was statistically significant (p-value = 0.01713441). The average score before treatment was 13.13 ± 2.363; it became 9.50 ± 2.944 after 6 months. By paired t-test comparison, the difference in the score was statistically highly significant (p = 0.000044). Regarding the photographic assessment, the difference in the visual analogue scale before and after treatment was statistically significant (p-value = 0.043823). All patients were satisfied regarding subcision as treatment for their acne scars with variable degrees. In general the reported side effects were transient and vanished within 3 - 7 days apart from firm bumps which resolved within 12 weeks in all patients. Conclusion: Subcision appears to be simple, safe, minimally invasive, well-tolerated, and effective surgical procedure that provides significant long-term betterment for depressed acne scars especially for the rolling type.

From the early 20th century, immunotherapy has been studied as a treatment modality for cancers, including in children. Since then, developments in monoclonal antibodies and vaccine therapies have helped to usher in a new era of cancer immunotherapeutics. However, efficacy of these types of therapies has been limited, mostly in part due to low tumor immunogenicity, cancer escape pathways, and toxicities. As researchers investigate the cellular and molecular components of immunotherapies, mechanisms to improve tumor specificity and overcome immune escape have been identified. The goal of immunotherapy now has been to modulate tumor escape pathways while amplifying the immune response by combining innate and adaptive arms of the immune system. Although several limiting factors have been identified, these recent advances in immunotherapy remain at the forefront of pediatric oncologic therapeutic trials. Immunotherapy is now coming to the forefront of precision treatment for a variety of cancers, with evidence that agents targeting immunosuppressive mechanisms for cancer progression can be effective therapy [1-3]. In this review, we review various types of immunotherapy, including the cellular biology, limitations, recent novel therapeutics, and the application of immunotherapy to pediatric oncology.

Goldmann kinetic perimetry is a commonly used method of evaluating the peripheral visual field. Ongoing gene therapy trials have targeted the central retina, but have nonetheless often included Goldmann kinetic perimetry as part of extensive preinterventional and postinterventional assessment. Future gene therapy trials may target the entire retina through intravitreal injections, as have drug therapeutic trials, further necessitating the evaluation of function across the entire retina. In the following pages, we will briefly review the necessary steps to perform and quantify the visual field, using the conventional Goldmann perimeter and the Field Digitizer software (version 4.20; Johns Hopkins Technology Ventures, Baltimore, USA), respectively.

International audience; Non-alcoholic steatohepatitis is a disease without a single, specific, diagnostic marker, hence multiple indicators are required to measure therapeutic efficacy. Moreover, drug candidates for non-alcoholic steatohepatitis target many distinct mechanisms that are believed to promote hepatic injury. Therefore, a wide range of endpoints must be reached, sequentially, as required by the drug development process. Some of these endpoints validate the mechanism of action, others are used to anticipate histological efficacy. Histological endpoints are still considered the best predictors of clinical outcome, but they can only be reliably tested in larger, late phase trials. Herein, we will review the rationale and clinical data supporting the use of specific endpoints at different stages of therapeutic trials. We will also discuss the validity and limitations of current phase IIb histological endpoints, particularly a one stage reduction in fibrosis, for their ability to predict progression to cirrhosis, which is the ultimate outcome measure in therapeutic trials.

Purpose To propose and validate a modified pediatric intracerebral hemorrhage (PICH) (mPICH) score and to compare its association with functional outcome to that of the original PICH score. Materials and Methods Data from prospectively included patients were retrospectively analyzed. Consecutive patients with nontraumatic PICH who had undergone clinical follow-up were included. The study population was divided into a development cohort (2008-2012, n = 100) and a validation cohort (2013-2016, n = 43). An mPICH score was developed after variables associated with poor outcome were identified at multivariate analysis (King's Outcome Scale for Childhood Head Injury score5a) in the development cohort. The accuracy of the score for prediction of poor outcome was evaluated (sensitivity, specificity). Discrimination and calibration of associations between the mPICH score and poor outcome cohorts were assessed (C statistics, Hosmer-Lemeshow test). Results The mPICH score assessed as follows: brain herniation, four points; altered mental status, three points; hydrocephalus, two points; infratentorial PICH, two points; intraventricular hemorrhage, one point; PICH volume greater than 2% of total brain volume, one point. An mPICH score greater than 5 was associated with severe disability or worse, with sensitivity of 97% (95% confidence interval [CI]: 83%, 100%) and specificity of 61% (95% CI: 49%, 73%). The C statistic was 0.81 (95% CI: 0.73, 0.89). In the validation cohort, sensitivity and specificity were 95.2% (95% CI: 76%, 99%) and 77% (95% CI: 55%, 92%), respectively. There was no significant difference between the observed and predicted risks of poor outcome (P = .46). Conclusion An mPICH score was developed as a simple clinical and imaging grading scale for acute prognosis in patients with PICH.

Malassezia spp in skin microbiome scalp has been implicated in seborrheic dermatitis pathogenesis. Thus, treatment based in antifungal combined to topical keratolitic agents have been indicated as well as oral isotretinoin as it reduces the sebum production, glandular's size and possesses anti-inflammatory properties. This randomized, comparative and therapeutic trial aimed toper form the genotypic identification of Malassezia species before and after low-dose oral isotretinoin or topical antifungal treatments for moderate to severe seborrhea and/or seborrheic dermatitis on scalp. Scales and sebum of the scalp were seeded in the middle of modified Dixon and incubated at 32°C. For genotypic identification polymerase chain reaction primers for the ITS and D1/D2 ribossomal DNA were used and followed by samples sequencing. The procedure was conducted before and after therapeutic and randomized intervention for moderate to severe seborrhea/seborrheic dermatitis on the scalp, including oral isotretinoin, 10 mg, every other day and anti-seborrheic shampoo (piroctone olamine), over six months. The M. globosa and M. restricta were the most frequent species isolated on the scalp before and after both treatments. Other non-Malassezia species were also identified. The Malassezia spp. were maintained in the scalp after both treatments that were equally effective for the control of seborrhea/seborrheic dermatitis clinical signs.

Folded and misfolded tau is common to many neurodegenerative conditions, collectively termed "tauopathies". In recent years, many efforts have contributed toward development of tau imaging agents to allow measurement of tau deposits in vivo using positron emission tomography (PET). The particularities of tau present some unique challenges for the development of tau imaging tracers. Most notably, these pertain to the predominantly intracellular nature of tau aggregations, the existence of six isoforms, multiple post-translational modification, and that tau is usually surrounded by larger concentrations of Aβ plaques. Nevertheless, significant progress has been made towards overcoming these issues and a number of tracers are now undergoing human trials. Once validated, tau imaging with PET will be a useful tool for the differential diagnosis and disease staging, as well as therapeutic trials of AD and non-AD tauopathies.

Despite the advantages of easy applicability and cost-effectiveness, colorectal cancer mouse models based on tumor cell injection have severe limitations and do not accurately simulate tumor biology and tumor cell dissemination. Genetically engineered mouse models have been introduced to overcome these limitations; however, such models are technically demanding, especially in large organs such as the colon in which only a single tumor is desired. As a result, an immunocompetent, genetically engineered mouse model of colorectal cancer was developed which develops highly uniform tumors and can be used for tumor biology studies as well as therapeutic trials. Tumor development is initiated by surgical, segmental infection of the distal colon with adeno-cre virus in compound conditionally mutant mice. The tumors can be easily detected and monitored via colonoscopy. We here describe the surgical technique of segmental adeno-cre infection of the colon, the surveillance of the tumor via high-resolution colonoscopy and present the resulting colorectal tumors.

An article recently published in the Lancet (1) concerned a meta-analysis of two therapeutic trials ONTARGET (2) and TRANSCEND (3). They were both designed to compare angiotensin receptor blocker (ARB) to angiotensin-converting enzyme (ACE) inhibitors (or their combination) or placebo respectively, to reduce the rate of a composite of cardiovascular death, myocardial infarction (MI), stroke and hospital admission for heart failure, among patients at high risk for cardiovascular events.

Tuberculous meningitis (TBM) is associated with significant complications of central nervous system. It is accompanied by nonspecific and heterogeneous clinical symptoms. We focused on the significance of early diagnosis and prompt treatment. We describe a case of TBM in a 19-year-old Asian female. She had a progressive motor weakness with no sensory findings. She was started on antituberculous therapy. Her magnetic resonance imaging (MRI) contrast of dorsolumbar spine showed syringomyelia. Her culture and sensitivity for Mycobacterium tuberculosis (MTB) came negative. She was given a therapeutic trial of quinolones and Steroids. She had an uneventful recovery and was followed up for the past one year.

Combination therapies targeting multiple recovery mechanisms have the potential for additive or synergistic effects, but experimental design and analyses of multimodal therapeutic trials are challenging. To address this problem, we developed a data-driven approach to integrate and analyze raw source data from separate pre-clinical studies and evaluated interactions between four treatments following traumatic brain injury. Histologic and behavioral outcomes were measured in 202 rats treated with combinations of an anti-inflammatory agent (minocycline), a neurotrophic agent (LM11A-31), and physical therapy consisting of assisted exercise with or without botulinum toxin-induced limb constraint. Data was curated and analyzed in a linked workflow involving non-linear principal component analysis followed by hypothesis testing with a linear mixed model. Results revealed significant benefits of the neurotrophic agent LM11A-31 on learning and memory outcomes after traumatic brain injury. In addition, modulations of LM11A-31 effects by co-administration of minocycline and by the type of physical therapy applied reached statistical significance. These results suggest a combinatorial effect of drug and physical therapy interventions that was not evident by univariate analysis. The study designs and analytic techniques applied here form a structured, unbiased, internally validated workflow that may be applied to other combinatorial studies, both in animals and humans.

Multiple candidate biomarkers for amyotrophic lateral sclerosis (ALS) have emerged across a range of platforms. Replication of results, however, has been absent in all but a few cases, and the range of control samples has been limited. If progress toward clinical translation is to continue, the specific biomarker needs of ALS, which differ from those of other neurodegenerative disorders, as well as the challenges inherent to longitudinal ALS biomarker cohorts, must be understood. Appropriate application of multimodal approaches, international collaboration, presymptomatic studies, and biomarker integration into future therapeutic trials are among the essential priorities going forward.

Introduction The Cl. NPhys Trial 3 showed that attributes of nerve conduction (NC) were without significant intraobserver differences, although there were significant interobserver differences. Methods: Trial 4 tested whether use of written instructions and pretrial agreement on techniques and use of standard reference values, diagnostic percentile values, or broader categorization of abnormality could reduce significant interobserver disagreement and improve agreement among clinical neurophysiologists. Results: The Trial 4 modifications markedly decreased, but did not eliminate, significant interobserver differences of measured attributes of NC. Use of standard reference values and defined percentile values of abnormality decreased interobserver disagreement and improved agreement of judgment of abnormality among evaluators. Therefore, the same clinical neurophysiologist should perform repeat NCs of therapeutic trial patients. Conclusions: Differences in interobserver judgment of abnormality decrease with use of common standard reference values and a defined percentile level of abnormality, providing a rationale for their use in therapeutic trials and medical practice. Muscle Nerve 50: 900–908, 2014

Local and centrally measured plasma HIV RNA (pVL) were assessed for agreement in two trials, ENCORE1 and SECOND-LINE. The proportion less than 200 copies/ml at week 48 was qualitatively similar [ENCORE1 2.5% (95% confidence interval, 95% CI –1.6 to 6.6); 1.9% (95% CI –1.9 to 2.1); SECOND-LINE 0.3% (95% CI –6.4 to 10.0); 1.8% (95% CI –4.7 to 8.3)]. The mean difference in log10 pVL copies/ml at weeks 0 and 48 was less than 0.2 log10 copies/ml in both trials. Our data indicate that central testing of pVL in HIV therapeutic trials is not warranted.

Objectives To review the controversial issues of the Testosterone Deficiency Syndrome (TDS) with an emphasis on the concerns about the diagnosis. Design and methods The relevant literature was reviewed with particular attention to matters related to the clinical manifestations of the syndrome, the need for biochemical assessment and questions of biological and analytical variation that have to be taken into account. Therapeutic options were also appraised. Results There are numerous difficulties with the clinical diagnosis of TDS due to the lack of specificity and subtlety of the manifestations when the degree of deficiency is not severe. Confirmation of the clinical impression requires laboratory evaluation but the choice of assays remains an unsettled issue although there is a general consensus that both free testosterone and bioavailable testosterone best reflect the degree of androgenicity. The laboratory diagnosis enjoys a great deal of credibility among clinicians but shortcomings in the interpretation of the assays need to be reiterated and the need for close collaboration between the clinician and the clinical biochemist is important for diagnostic accuracy. Even when the clinical picture is convincing, the laboratory may produce inconclusive results. The option of a therapeutic trial should be contemplated in this situation. Treatment options should be decided between the physician and the patient considering issues of availability, tolerance, efficacy and cost. Conclusions TDS is a prevalent condition but a matter of persistent controversy due to the vagaries of the clinical and laboratory diagnosis. Symptomatic men with documented T deficiency deserve treatment to improve their quality of life.

Background To insure that NIH-funded research is relevant to the population’s needs, specific emphasis on proportional representation of minority/gender groups into National Cancer Institute’s (NCI) cancer centers’ clinical research programs is reported to the NCI.

Compulsive behaviors in patients with behavioral variant frontotemporal dementia (bvFTD) occur frequently and are challenging to manage. We report three cases of probable bvFTD associated with compulsive behaviors that responded well to treatment with clomipramine at daily dosages varying from 20 to 175 mg. The titration approach involved an initial 10-mg dose that was subsequently increased in 10 mg increments on a weekly basis until symptom relief without intolerable side effects. Our case series supports the consideration for a therapeutic trial with clomipramine in bvFTD when compulsive behavior occurs in these patients. It also highlights the need for further research on pharmacological treatments in bvFTD.