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Summary: We have identified a non‐steroidal selective androgen receptor modulator (SARM), termed LY305, that is bioavailable through a transdermal route of administration while highly cleared via hepatic metabolism to limit parent compound exposure in the liver. Selection of this compound and its transdermal formulation was based on the optimization of skin absorption properties using both in vitro and in vivo skin models that supported PBPK modeling for human PK predictions. This molecule is an agonist in perineal muscle while being a weak partial agonist in the androgenic tissues such as prostate. When LY305 was tested in animal models of skeletal atrophy it restored the skeletal muscle mass through accelerated repair. In a bone fracture model, LY305 remained osteoprotective in the regenerating tissue and void of deleterious effects. Finally, in a small cohort of healthy volunteers, we assessed the safety and tolerability of LY305 when administered transdermally. LY305 showed a dose‐dependent increase in serum exposure and was well tolerated with minimal adverse effects. Notably, there were no statistically significant changes to hematocrit or HDL after 4‐week treatment period. Collectively, LY305 represents a first of its kind de novo development of a non‐steroidal transdermal SARM with unique properties which could find clinical utility in hypogonadal men. [ABSTRACT FROM AUTHOR]

Background Scoring systems for assessing the signs of atopic dermatitis ( AD) are complex and difficult to interpret. Severity strata are helpful to interpret these assessments properly. Objectives To confirm previously reported strata for the Eczema Area and Severity Index ( EASI), Scoring Atopic Dermatitis ( SCORAD) and the objective component of SCORAD ( oSCORAD), and to develop strata for the modified EASI ( mEASI), Atopic Dermatitis Severity Index ( ADSI) and body surface area ( BSA) for use in adults with AD. Methods Skin examination was performed in 673 adolescents and adults (age ≥ 13 years) with diagnosed AD, in a dermatology practice setting. Strata were selected using an anchoring approach based on a four-point Investigator's Global Assessment of severity (clear of active skin lesions, mild, moderate or severe disease). Results We determined potential severity strata for EASI (0 clear, 0·1-5·9 mild, 6·0-22·9 moderate, 23·0-72 severe; κ = 0·69), mEASI (0-0·9 clear, 1-8·9 mild, 9·0-29·9 moderate, 30·0-90 severe; κ = 0·71), oSCORAD (0-7·9 clear, 8·0-23·9 mild, 24·0-37·9 moderate, 38·0-83 severe; κ = 0·70), SCORAD (0-9·9 clear, 10·0-28·9 mild, 29·0-48·9 moderate, 49·0-103 severe; κ = 0·68), ADSI (0-1·9 clear, 2-5·9 mild, 6·0-8·9 moderate, 9·0-15 severe; κ = 0·55) and BSA (0 clear, 0·1-15·9 mild, 16·0-39·9 moderate, 40·0-100 severe; κ = 0·66). oSCORAD values > 0 were found in clear skin due to the presence of xerosis, which is scored in oSCORAD. Similarly, SCORAD values > 0 were found in clear skin due to the scoring of xerosis, pruritus and sleeplessness. Similarly, mEASI and ADSI scores > 0 occurred in patients with clear skin due to scoring of pruritus. Conclusions We recommend using these strata for interpretation of their respective measures in clinical trials of AD. There are important differences between the five assessments, which profoundly impact the interpretation of their scores. [ABSTRACT FROM AUTHOR]

Dominant SCN1B mutations are known to cause several epilepsy syndromes in humans. Only 2 epilepsy patients to date have been reported to have recessive mutations in SCN1B as the likely cause of their phenotype. Here, we confirm the recessive inheritance of 2 novel SCN1B mutations in 5 children from 3 families with developmental epileptic encephalopathy. The recessive inheritance and early death in these patients is consistent with the Dravet-like phenotype observed in Scn1b−/− mice. The 'negative' clinical exome in one of these families highlights the need to consider recessive mutations in the interpretation of variants in typically dominant genes. [ABSTRACT FROM AUTHOR]

We describe the third family in the world, after Arabian and Turkish ones, displaying an autosomal recessive autoimmune disease (AID), mimicking systemic lupus erythematosus (SLE), with unusual manifestations due to a homozygous frame-shift variant in DNASE1L3. SLE is a complex AID characterized by multiple organ involvement. Genetic risk variants identified account for only 15% of SLE heritability. Rare Mendelian forms have been reported, including DNASE1L3-related SLE. Through specific genetic tests we identified a homozygous 2 bp-deletion c.289_290delAC (NM_004944.2) in DNASE1L3, predicting frameshift and premature truncation (p.Thr97Ilefs*2). The same mutation was previously reported in three sisters, born from consanguineous parents and affected with hypocomplementemic urticarial vasculitis syndrome (HUVS). As approximately 50% of individuals affected with HUVS develop SLE, it is still unclear whether it is a SLE sub-phenotype or a separate condition. [ABSTRACT FROM AUTHOR]

To conduct surveillance and determine the safety profile of new hepatitis C virus treatments in real-world clinical practice. Hepatic decompensation and other serious adverse events were investigated in an observational cohort study of 511 patients treated with regimens containing sofosbuvir, December 2013-June 2014. Among 499 previously stable patients (no history of hepatic decompensation during the previous 12 months), a nested case-control study was performed to identify predictors of decompensation/serious adverse event. Cases and controls were matched 1:5 based on treatment regimen and duration. Matched conditional logistic regression was used for analysis. Providers scored the likelihood that events were treatment-related (scale = 0-4). The cumulative incidence of decompensation/events was 6.4% for the total cohort. Among 499 previously stable patients, the incidence of decompensation/events was 4.5%; the mortality rate was 0.6%. Sixteen of the 499 experienced one or more serious complications considered to be at least potentially treatment-related, and the sustained virological response rate was 7/16 (44%). Two cases, both on sofosbuvir/simeprevir (without interferon or ribavirin), had complications consistent with autoimmune events (score 3, 'likely treatment-related'), and one experienced a flare of autoimmune hepatitis. Compared to controls, cases had higher baseline median model for end-stage liver disease scores (14 vs 8, P < 0.01). Decompensation/events was independently associated with lower baseline albumin ( OR = 0.12/g/dL, P = 0.01) and higher total bilirubin ( OR = 4.31/mg/dL, P = 0.01). Reduced hepatic function at baseline increased the risk of liver decompensation/events. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the complications associated with anterior pelvic external fixation and the success of this device in maintaining reduction when used in conjunction with sacroiliac screws. Methods: Through a retrospective clinical study at an academic Level I Trauma Center, 129 patients fit the criteria for inclusion with a mean duration of anterior pelvic external fixation of 62 days and mean follow-up of 360 days. Charts were reviewed for complications postoperatively. The symphysis diastasis, vertical displacement and posterior displacement of each hemipelvis were quantified from pelvic radiographs. Results: Of the 129 patients receiving anterior pelvic external fixation, 14 (10.9 %) presented to an emergency department for problems with their anterior pelvic external fixation. Of these 14 patients, 7 (5.4 %) required readmission, all for infectious concerns necessitating IV antibiotics. 6 (4.7 %) required formal operative debridement and device removal. 13 patients (10.1 %) had superficial pin site infections successfully treated with oral antibiotics. Reduction was maintained (rated as fair, good or excellent) in all patients with radiographic follow-up ( n = 74, average radiographic follow-up of 216 days) following removal of their anterior pelvic external fixation. 38 patients (30.4 %) had their anterior pelvic external fixation removed in clinic, while 87 (69.6 %) had formal removal in the operating room. Conclusion: While previous data suggest high complication rates in definitive anterior pelvic external fixation, we present the largest cohort of patients receiving anterior pelvic external fixation and sacroiliac screws, demonstrating a low complication rate while maintaining reduction of the pelvic ring. In addition, we found that these devices could be reliably removed in a clinic setting. [ABSTRACT FROM AUTHOR]

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Purpose: Autosomal dominant hyper-IgE syndrome (AD-HIES), caused by mutations in Signal Transducer and Activator of Transcription 3 (STAT3) is associated with defective STAT3 signaling and Th17 differentiation and recurrent bacterial and fungal infections. Most patients suffer significant morbidity and premature mortality. Hematopoietic stem cell transplantation (HSCT) has been reported in a small number of cases, with mixed outcomes. We report successful haploidentical donor HSCT in a patient with AD-HIES. Methods: Evaluation of lymphocyte subsets, STAT3 signaling, and Th17 cells was performed pre- and post-HSCT. Results: A 14-year old female with AD-HIES developed recurrent methicillin-resistant Staphylococcus aureus (MRSA) abscesses. Immunologic analysis showed elevated IgE (4331 kU/L), absent Th17 cells, and markedly decreased STAT3 phosphorylation in cytokine stimulated peripheral blood mononuclear cells. She had breakthrough abscesses despite clindamycin and trimethoprim-sulfamethoxazole prophylaxis, and developed steroid refractory autoimmune hemolytic anemia. She underwent T-cell depleted haploidentical HSCT from her father following reduced intensity conditioning. She developed one MRSA hand abscess after transplant. Twenty-four months post transplant, she had complete donor chimerism (>95 % donor), normal absolute T cell numbers, and a normal percentage of Th17 cells. IgE was normal at 25 kU/L. She remains well 42 months after transplantation off all antibacterial prophylaxis. Conclusions: Haploidentical HSCT led to successful bone marrow engraftment, normalization of STAT3 signaling in hematopoietic cells, normalization of IgE, and restoration of immune function in this patient with AD-HIES. [ABSTRACT FROM AUTHOR]

The objective of this study was to determine the pattern of presentation, response to treatment, and outcome in patients with systemic lupus erythematosus (SLE) and thrombocytopaenia (TCP). A retrospective review of the records of patients with SLE and TCP and a matched control group of SLE patients without TCP, seen in the rheumatology department in Durban, South Africa, was performed. The demographic data, clinical findings, laboratory findings, treatment and outcome were recorded. There were 54 patients and an equal number of controls. They comprised 30 Indians and 24 African Blacks, median age of 33 years and female to male ratio 5.8:1. A group of eight patients who initially presented with idiopathic thrombocytopaenic purpura (ITP) and subsequently developed SLE were analysed separately. An acute presentation was noted in 31 patients (57%). Patients with an acute presentation had an increased prevalence of renal disease (77% vs 43.5%; p = 0.01) and an increased number of deaths (38.7% vs 4.4%; p = 0.004). The majority of patients responded to corticosteroids (68.5%) and splenectomy. There was an increased prevalence of renal disease (p = 0.03) and deaths (p = 0.004) among patients with TCP. The majority of deaths had an acute presentation ((12/13; 92.3%) (p = 0.004)), and were due to infection and active lupus. TCP with an acute presentation is associated with a high mortality and predicts survival in SLE. [ABSTRACT FROM AUTHOR]

Objectives. To study factors that predict changes in management with digital breast tomosynthesis (DBT). Methods. The Institutional Review Board approved this HIPAA compliant study. 996 patients had DBT with full field digital mammography (FFDM). Univariate analysis evaluated predictors of management change and cancer detection. Results. DBT changed management in 109 of 996 (11%); 77 (71%) required less imaging. Recalled patients after abnormal FFDM screen were most likely to have management change--25% (24 of 97 patients) compared to 8% (13/163) of symptomatic patients and 10% (72/736) of screening patients (P < 0.001). Dense breasted patients had a higher likelihood of having DBT change management: 13% (68/526) compared to 9% (41/470) (P = 0.03). Of the 996 patients, 19 (2%) were diagnosed with breast cancer. 15 cancers (83%) were seen on FFDM and DBT; 3 (17%) were diagnosed after DBT (0.3%, 95% CI: 0.1-0.9%). One recurrence was in the skin and was not seen on DBT nor was it seen on FFDM. The increase in cancer detection rate was 17% for asymptomatic patients, 0% for symptomatic patients, and 100% for recalled patients. Conclusions. DBT increased cancer detection rate by 20% and decreased the recall rate in 8-25%. Advances in Knowledge. DBT led to a doubling of the cancer detection rate in recalled patients. [ABSTRACT FROM AUTHOR]

Aims To conduct a pilot study evaluation of an interprofessional education tool that could improve healthcare professional confidence, knowledge and quality of inpatient diabetes care. Methods Diabetes specialists designed an education tool for use in the hospital environment to educate qualified pharmacists, nurses, healthcare assistants and junior doctors. The interprofessional learning enabled professionals to learn from and about each other. The education tool was piloted at four hospitals. Diabetes specialists delivered the education programme to 31 healthcare professionals over 8 h either as three individual teaching blocks or a whole day. Healthcare professionals completed a multiple choice questionnaire before and after the education intervention to evaluate acquisition of knowledge. The maximum score was 20. Confidence was evaluated using categorical questions. Diabetes specialists used a clinical audit form before and after the education programme, to evaluate the quality of diabetes care. Results Healthcare professional's confidence improved from 58 to 94% ( P < 0.05) and knowledge improved from 12.4 ± 0.6 to 15.0 ± 0.6 (mean ± sem, P < 0.05). There was a reduction in management errors from 74 to 44% ( P < 0.05) and improvement in appropriate blood glucose monitoring from 67 to 92% ( P < 0.05). The number of patients with documented foot assessment improved from15 to 33% ( P < 0.05). Improvement in the number of appropriate diabetes referrals and reduction in prescribing errors did not reach statistical significance. Conclusion The education tool improved healthcare professional confidence, knowledge and may improve the quality of inpatient diabetes care. [ABSTRACT FROM AUTHOR]

The article discusses a study which investigated the effectiveness of smart-phone applications (apps) for assessing the risk of type 2 diabetes. It carried out a literature review and found no studies describing the development, validation and implementation of these apps. It concluded that the evidence base for the existing apps for assessing type 2 diabetes risk is lacking; however, it suggested that smart-phone apps may increase the uptake to screening and may motivate behaviour change.

Microbubble measurement of hepatic vein transit times (HVTT) may have the potential to assess severity of hepatitis C virus (HCV)-related liver disease, where there is a shorter HVTT with more severe disease. We investigated the utility of this test as a marker of response to antiviral treatment. Thirty-seven patients with biopsy-proven HCV-related disease undergoing antiviral treatment were studied. All had baseline scans and then repeat scans 6 months after the end of treatment. HVTT using Levovist were obtained from the right and middle hepatic veins, and the shorter time was used for analysis. The aspartate aminotransferase to platelet ratio index (APRI) scores were calculated retrospectively. There were seven patients with mild hepatitis, 23 with moderate/severe hepatitis and seven with cirrhosis. The mean baseline HVTT in responders ± SE increased from 27.3 ± 2.29 s to 33.5 ± 2.8 s posttreatment ( P = 0.01). In the 10 nonresponders, the HVTT remained the same; 43.3 ± 9 s baseline compared to 44 ± 7.8 s posttreatment ( P = 0.84). This trend was also seen with the APRI score where in responders, the mean score decreased from 1.1 ± 0.2 to 0.74 ± 1 ( P = 0.03) and in nonresponders, the score remained unchanged; 0.88 ± 0.2 compared to 0.84 ± 0.2 ( P = 0.31). HVTT measurement lengthened, while APRI scores decreased in patients who responded to antiviral treatment while both remained the same, shortened (HVTT) or increased (APRI), respectively, in patients who were nonresponders. These results are encouraging and indicate that these tests could be potentially used as markers of response to treatment and could obviate the need for serial biopsies in antiviral future treatment studies. [ABSTRACT FROM AUTHOR]

Combinations of noninvasive markers may improve discrimination of chronic liver disease severity. The aims of this study were to compare four validated serum and ultrasound-based markers of hepatic disease severity head-to-head with liver biopsy and to assess optimal combinations with consideration of cost. A total of 67 patients with biopsy-proven chronic hepatitis C underwent all four techniques on the same visit [aspartate aminotransferase (AST) to platelet ratio index (APRI); Enhanced Liver Fibrosis (ELF) panel; transient elastography (TE) and ultrasound microbubble hepatic transit times (HTT)]. Markers were combined according to increasing financial cost and ordinal regression used to determine contributions. APRI, ELF, TE and HTT predicted cirrhosis with diagnostic accuracy of 86%, 91%, 90% and 83% respectively. ELF and TE were the most reliable tests with an intra-class correlation of 0.94 each. Either ELF or TE significantly enhanced the prediction of fibrosis stage when combined with APRI, but when combined together, did not improve the model further. Addition of third or fourth markers did not significantly improve prediction of fibrosis. Combination of APRI with either ELF or TE effectively predicts fibrosis stage, but combinations of three or more tests lead to redundancy of information and increased cost. [ABSTRACT FROM AUTHOR]

AimTo assess the value of the modified international classification system in screening high-risk patients with bilateral age-related maculopathy (ARM) from those with lower risk characteristics.MethodsIn total, 164 digital images of 106 patients with either bilateral ARM (group A) or the fellow eyes of unilateral exudative age-related macular degeneration (AMD) (Group B) were included. Patients with no signs of ARM in both eyes or those with bilateral late AMD were excluded. The images were randomised and then graded by two masked ophthalmologists based on the modified International Classification of ARM.ResultsThe interobserver consistency between the two graders was high with a Kappa value of 0.82 (SE 0.34, P<0.0001). There were no significant differences in the distribution of the stages of ARM between the two subgroups. Stage 3 was the most common stage in each group for both graders followed by stage 2a in the bilateral drusen group. Stages 1a, 2a and 2b were equally the next common stage in the fellow eye of chordial neovascularisation group.ConclusionA screening system based on clinical characteristics would be of value in risk prediction in a clinical setting. Type of Drusen alone, as identified by the modified International grading system, may not be reliably predictive in screening for patients who are at high risk of developing choroidal neovascularisation.Eye (2006) 20, 199–202. doi:10.1038/sj.eye.6701852; Published online 4 March 2005 [ABSTRACT FROM AUTHOR]

Objective: The objective was to develop and assess the validity and reliability of a target board test (TBT) for quantifying ataxia and measuring dysmetria in the presence of tremor. Design: Each subject was instructed to reach out and mark a target placed at arm's length with a pen (10 times with each hand). Ten patients performed the test twice. Setting: A hospital-based multiple sclerosis (MS) unit. Subjects: Fifty-three patients with MS and upper limb tremor/ataxia and 20 healthy control subjects. The MS patients were classified into four subgroups: MS control group (n = 13), MS tremor group (n = 9), MS dysmetria group (n = 6), MS mixed (tremor and dysmetria) group (n = 25). Main outcome measures: The main outcome measures were the average radial distance away from the target (mean R) and the mean directional error (mean V) of the 10 contact points from the target. From these a dysmetria tremor index (DTI) was calculated by dividing mean V by mean R. Also used were a dysmetria scale, a dysdiadochokinesia scale and a fingertapping test. Results: Mean R correlated significantly with dysmetria, dysdiadochokinesia, kinetic tremor and (inversely) with the finger-tapping test (all p< 0.005). The median difference between two measurements of mean R for all 10 contact points was 11.3% and 19.0% and for mean V 48.3% and 63.4% and DTI 57.2% and 50.5% for the right- and left-hand sides respectively, indicating the considerable directional variability within ataxia. Conclusion: The TBT provides simple quantitative objective measurements of upper limb ataxia. [ABSTRACT FROM AUTHOR]

The effects of hormone replacement therapy in hypertensive women are controversial. This randomised placebo controlled trial assessed the effect of tibolone 2.5 mg on blood pressure and fasting plasma lipids in 29 hypertensive postmenopausal women over 6 months using a 2:1 randomisation to tibolone. The primary clinical end-point was mean office blood pressure. At 6 months systolic blood pressure declined by 5.30 ± 2.87% vs 4.94 ± 3.37% whilst diastolic blood pressure declined 5.38 ± 2.65% vs 0.85 ± 3.69% on tibolone and placebo respectively. These differences were not statistically significant. Triglycerides decreased by 33.3 ± 6.1% vs 7.6 ± 7.9% (P < 0.01) and high-density lipoprotein (HDL)-cholesterol by 21.7 ± 3.8% vs 2.4 ± 2.6% (P < 0.01) with tibolone as opposed to placebo. No significant differences were observed in total cholesterol, low-density lipoprotein (LDL)-cholesterol and lipoprotein (a). Fibrinogen levels were reduced by 13.6 ± 6.8% on tibolone compared to a 19.3 ± 15.4% rise (P < 0.05) on placebo. This study suggests that tibolone has no deleterious effect on blood pressure in women with hypertension but has contrasting effects on biochemical risk factors. Large-scale studies are required to determine the overall effect of tibolone on cardiovascular morbidity and mortality. [ABSTRACT FROM AUTHOR]

Vibrio species are ubiquitous in the marine environment and can cause severe infections in cirrhotic patients. Patients with liver disease should be warned about the potential dangers of consuming raw or undercooked seafood, and avoiding exposure of wounds to seawater. We report a case of severe sepsis from Vibrio cholerae non-O1 in a patient with cirrhosis awaiting orthotopic liver transplant. This case is aimed to advise clinicians about the importance of V. cholerae subtypes, and non-cholera Vibrio species infections in cirrhotic patients, highlighting the need to educate these patients to stay away from undercooked seafood. [ABSTRACT FROM AUTHOR]

A 60-year-old male with chronic lymphatic leukemia (CLL) after 6 months of fludarabine therapy was admitted with status epilepticus and developed left hemiplegia. His magnetic resonance imaging revealed multiple T2 hyperintense lesions in the right frontal and left parieto-occipital lesion, simulating progressive multifocal leucoencephalopathy (PML). Cerebrospinal fluid Polymerase Chain Reaction (PCR) for JC virus was negative. We suggest the possible role of fludarabine in producing PML-like lesions in patients with Chronic Lymphocytic Leukemia (CLL). INSET: 14. [ABSTRACT FROM AUTHOR]

Background: Children with moderate-to-severe asthma continue to have disease complications despite the receipt of standard-of-care therapy. The monoclonal antibody dupilumab has been approved for the treatment of adults and adolescents with asthma as well as with other type 2 inflammatory diseases.Methods: In this 52-week phase 3, randomized, double-blind, placebo-controlled trial, we assigned 408 children between the ages of 6 and 11 years who had uncontrolled moderate-to-severe asthma to receive a subcutaneous injection of dupilumab (at a dose of 100 mg for those weighing ≤30 kg and 200 mg for those weighing >30 kg) or matched placebo every 2 weeks. All the children continued to receive a stable dose of standard background therapy. The primary end point was the annualized rate of severe asthma exacerbations. Secondary end points included the change from baseline in the percentage of predicted prebronchodilator forced expiratory volume in 1 second (ppFEV1) at week 12 and in the score on the Asthma Control Questionnaire 7 Interviewer-Administered (ACQ-7-IA) at week 24. End points were evaluated in the two primary efficacy populations who had either a type 2 inflammatory asthma phenotype (≥150 blood eosinophils per cubic millimeter or a fraction of exhaled nitric oxide of ≥20 ppb at baseline) or a blood eosinophil count of at least 300 cells per cubic millimeter at baseline.Results: In patients with the type 2 inflammatory phenotype, the annualized rate of severe asthma exacerbations was 0.31 (95% confidence interval [CI], 0.22 to 0.42) with dupilumab and 0.75 (95% CI, 0.54 to 1.03) with placebo (relative risk reduction in the dupilumab group, 59.3%; 95% CI, 39.5 to 72.6; P<0.001). The mean (±SE) change from baseline in the ppFEV1 was 10.5±1.0 percentage points with dupilumab and 5.3±1.4 percentage points with placebo (mean difference, 5.2 percentage points; 95% CI, 2.1 to 8.3; P<0.001). Dupilumab also resulted in significantly better asthma control than placebo (P<0.001). Similar results were observed in the patients with an eosinophil count of at least 300 cells per cubic millimeter at baseline. The incidence of serious adverse events was similar in the two groups.Conclusions: Among children with uncontrolled moderate-to-severe asthma, those who received add-on dupilumab had fewer asthma exacerbations and better lung function and asthma control than those who received placebo. (Funded by Sanofi and Regeneron Pharmaceuticals; Liberty Asthma VOYAGE ClinicalTrials.gov number, NCT02948959.). [ABSTRACT FROM AUTHOR]