Single Morning Research Articles

A single dose of dapagliflozin, an SGLT-2 inhibitor, induces higher glycosuria in GCK- and HNF1A-MODY than in type 2 diabetes mellitus

AimsSGLT2 inhibitors are a new class of oral hypoglycemic agents used in type 2 diabetes (T2DM). Their effectiveness in maturity onset diabetes of the young (MODY) is unknown. We aimed to assess the response to a single dose of 10 mg dapagliflozin in patients with Hepatocyte Nuclear Factor 1 Alpha (HNF1A)-MODY, Glucokinase (GCK)-MODY, and type 2 diabetes.MethodsWe examined 14 HNF1A-MODY, 19 GCK-MODY, and 12 type 2 diabetes patients. All studied individuals received a single morning dose of 10 mg of dapagliflozin added to their current therapy of diabetes. To assess the response to dapagliflozin we analyzed change in urinary glucose to creatinine ratio and serum 1,5-Anhydroglucitol (1,5-AG) level.ResultsThere were only four patients with positive urine glucose before dapagliflozin administration (one with HNF1A-MODY, two with GCK-MODY, and one with T2DM), whereas after SGLT-2 inhibitor use, glycosuria occurred in all studied participants. Considerable changes in mean glucose to creatinine ratio after dapagliflozin administration were observed in all three groups (20.51 ± 12.08, 23.19 ± 8.10, and 9.84 ± 6.68 mmol/mmol for HNF1A-MODY, GCK-MODY, and T2DM, respectively, p < 0.001 for all comparisons). Post-hoc analysis revealed significant differences in mean glucose to creatinine ratio change between type 2 diabetes and each monogenic diabetes in response to dapagliflozin (p = 0.02, p = 0.003 for HNF1-A and GCK MODY, respectively), but not between the two MODY forms (p = 0.7231). Significant change in serum 1,5-AG was noticed only in T2DM and it was −6.57 ± 7.34 mg/ml (p = 0.04).ConclusionsA single dose of dapagliflozin, an SGLT-2 inhibitor, induces higher glycosuria in GCK- and HNF1A-MODY than in T2DM. Whether flozins are a valid therapeutic option in these forms of MODY requires long-term clinical studies.

Human seasonal and circadian studies in Antarctica (Halley, 75°S)

Living for extended periods in Antarctica exposes base personnel to extremes of daylength (photoperiod) and temperature. At the British Antarctic Survey base of Halley, 75°S, the sun does not rise for 110 d in the winter and does not set for 100 d in summer. Photoperiod is the major time cue governing the timing of seasonal events such as reproduction in many species. The neuroendocrine signal providing photoperiodic information to body physiology is the duration of melatonin secretion which reflects the length of the night: longer in the short days of winter and shorter in summer. Light of sufficient intensity and spectral composition serves to suppress production of melatonin and to set the circadian timing and the duration of the rhythm. In humans early observations suggested that bright (>2000 lux) white light was needed to suppress melatonin completely. Shortly thereafter winter depression (Seasonal Affective Disorder or SAD) was described, and its successful treatment by an artificial summer photoperiod of bright white light, sufficient to shorten melatonin production. At Halley dim artificial light intensity during winter was measured, until 2003, at a maximum of approximately 500 lux in winter. Thus a strong seasonal and circadian time cue was absent. It seemed likely that winter depression would be common in the extended period of winter darkness and could be treated with an artificial summer photoperiod. These observations, and predictions, inspired a long series of studies regarding human seasonal and circadian status, and the effects of light treatment, in a small overwintering, isolated community, living in the same conditions for many months at Halley. We found little evidence of SAD, or change in duration of melatonin production with season. However the timing of the melatonin rhythm itself, and/or that of its metabolite 6-sulphatoxymelatonin (aMT6s), was used as a primary marker of seasonal, circadian and treatment changes. A substantial phase delay of melatonin in winter was advanced to summer phase by a two pulse 'skeleton' bright white light treatment. Subsequently a single morning pulse of bright white light was effective with regard to circadian phase and improved daytime performance. The circadian delay evidenced by melatonin was accompanied by delayed sleep (logs and actigraphy): poor sleep is a common complaint in Polar regions. Appropriate extra artificial light, both standard white, and blue enriched, present throughout the day, effectively countered delay in sleep timing and the aMT6s rhythm. The most important factor appeared to be the maximum light experienced. Another manifestation of the winter was a decline in self-rated libido (men only on base at this time). Women on the base showed lower aspects of physical and mental health compared to men. Free-running rhythms were seen in some subjects following night shift, but were rarely found at other times, probably because this base has strongly scheduled activity and leisure time. Complete circadian adaptation during a week of night shift, also seen in a similar situation on North Sea oil rigs, led to problems readapting back to day shift in winter, compared to summer. Here again timed light treatment was used to address the problem.Sleep, alertness and waking performance are critically dependent on optimum circadian phase. Circadian desynchrony is associated with increased risk of major disease in shift workers. These studies provide some groundwork for countering/avoiding circadian desynchrony in rather extreme conditions.

Hypothesis driven single cell dual oscillator mathematical model of circadian rhythms

Molecular mechanisms responsible for 24 h circadian oscillations, entrainment to external cues, encoding of day length and the time-of-day effects have been well studied experimentally. However, it is still debated from the molecular network point of view whether each cell in suprachiasmatic nuclei harbors two molecular oscillators, where one tracks dawn and the other tracks dusk activities. A single cell dual morning and evening oscillator was proposed by Daan et al., based on the molecular network that has two sets of similar non-redundant per1/cry1 and per2/cry2 circadian genes and each can independently maintain their endogenous oscillations. Understanding of dual oscillator dynamics in a single cell at molecular level may provide insight about the circadian mechanisms that encodes day length variations and its response to external zeitgebers. We present here a realistic dual oscillator model of circadian rhythms based on the series of hypotheses proposed by Daan et al., in which they conjectured that the circadian genes per1/cry1 track dawn while per2/cry2 tracks dusk and they together constitute the morning and evening oscillators (dual oscillator). Their hypothesis also provides explanations about the encoding of day length in terms of molecular mechanisms of per/cry expression. We frame a minimal mathematical model with the assumption that per1 acts a morning oscillator and per2 acts as an evening oscillator and to support and interpret this assumption we fit the model to the experimental data of per1/per2 circadian temporal dynamics, phase response curves (PRC's), and entrainment phenomena under various light-dark conditions. We also capture different patterns of splitting phenomena by coupling two single cell dual oscillators with neuropeptides vasoactive intestinal polypeptide (VIP) and arginine vasopressin (AVP) as the coupling agents and provide interpretation for the occurrence of splitting in terms of ME oscillators, though they are not required to explain the morning and evening oscillators. The proposed dual oscillator model based on Daan's hypothesis supports per1 and per2 playing the role of morning and evening oscillators respectively and this may be the first step towards the understanding of the core molecular mechanism responsible for encoding the day length.

1157 INFLAMMATION IS ASSOCIATED WITH EXCESSIVE DAYTIME SLEEPINESS AND IMPAIRED COGNITIVE PERFORMANCE IN PATIENTS WITH MILD COGNITIVE IMPAIRMENT (MCI)

It has been shown that inflammatory markers are elevated in patients with cognitive impairment and are associated with excessive daytime sleepiness (EDS). Furthermore, we have previously shown that extended sleep/sleepiness in patients with Mild Cognitive Impairment (MCI) is associated with impaired cognitive performance. The aim of this study was to assess the associations between inflammation, objective sleep, and cognition among patients with MCI. A sub-sample of 119 patients with MCI were recruited from a large, population-based cohort in the island of Crete, Greece of 3140 older adults (>60yrs). The goal of this study was to assess the prevalence and risk factors associated with cognitive impairment. All participants underwent medical history/physical examination, extensive neuropsychiatric and neuropsychological evaluation, 3-day 24-h actigraphy and a single morning IL-6 and TNFa plasma level. Associations between (a) inflammatory markers and sleep variables and (b) inflammatory markers and cognition, were assessed using Linear Regression Analysis controlling for gender, age, BMI and depression for the former, and age, gender, and education, for the later. Peripheral levels of IL-6 were 1.2 ± 0.83 pgr/ml(mean ±SD), and TNFa were 1.18 ± 0.57pgr/ml. Regression analysis found a borderline significant association between IL-6 and daytime Total Sleep Time (r=0.186,p=0.07). Furthermore, regression analyses revealed significant associations between IL-6 and a number of episodic memory indices including immediate (β = -0.279, p = 0.003) and delayed word list recall (β = -0.25, p = .013), delayed complex figure reproduction (β = -0.26, p =0 .010), and autobiographic memory (β = -0.25, p =0 .009), and between TNFa and delayed word list recall (β= -0.217, p = -0.028). These data indicate that in patients with MCI, EDS and cognitive impairment are associated with inflammation. It appears that improvement of inflammation through pharmacologic and/or behavioral i.e. exercise, interventions may improve the prognosis in patients with MCI. Thales, University of Crete, A multi-disciplinary network for the study of the Alzheimer’s disease, National Strategic Reference Framework (ESPA) 2007–2013

Sleep and CKD in Chinese Adults: A Cross-Sectional Study.

To assess the association between self-reported sleep duration and quality and odds of having CKD in Chinese adults on the basis of a community study. In this cross-sectional study, we included 11,040 Chinese adults who participated in an ongoing prospective study, the Kailuan cohort. Survey questionnaire items addressed insomnia, daytime sleepiness, snoring, and sleep duration during their 2012 interview. Overall sleep quality was evaluated by summarizing these four sleep parameters. Fasting blood samples and single random midstream morning urine samples were collected in 2012 and analyzed for serum creatinine and proteinuria. CKD was defined by eGFR<60 ml/min per 1.73 m2 or proteinuria >300 mg/dl. We also examined those at high or very high risk of having CKD, on the basis of the Kidney Disease Improving Global Outcomes recommendations. The association between sleep quality and CKD was assessed using logistic regression model. Worse overall sleep quality was associated with higher likelihood of being high or very high risk for CKD (multiadjusted odds ratio, 2.69; 95% confidence interval, 1.30 to 5.59 comparing two extreme categories; P trend <0.01), but not overall CKD (multiadjusted odds ratio, 1.58; 95% confidence interval, 0.89 to 2.80 comparing two extreme categories; P trend =0.46), after adjusting for potential confounders. Specifically, individuals with worse sleep quality were more likely to have proteinuria (multiadjusted odds ratio, 1.95; 95% confidence interval, 1.03 to 3.67 comparing two extreme categories; P trend =0.02), rather than lower eGFR level (multiadjusted mean eGFR levels were 96.4 and 93.6 ml/min per 1.73 m2 in the two extreme sleep categories, respectively; P trend =0.13). However, there was no statistically significant association between individual sleep parameters and CKD status. Worse overall sleep quality was associated with higher odds of being high or very high risk for CKD and proteinuria in Chinese adults.

Efficacy of mizoribine and prednisolone combination therapy in adult patients with IgA vasculitis.

Immunoglobulin (Ig)A vasculitis (IgAV), formerly known as Henoch-Schönlein purpura, is one of the most common vasculitis caused by an IgA-mediated immune complex. It occurs most frequently in childhood and less commonly in adulthood. As for the treatment of IgAV in adults, there are few studies dealing with the administration and efficacy of intravenous pulse steroid therapy or combination therapy using prednisolone (PSL) and immunosuppressive drugs. Mizoribine (MZB) is a newly developed immunosuppressive drug with few adverse effects; however, there are currently few studies using MZB in adult patients with IgAV. In this study, we evaluated the efficacy of MZB combined with a course of PSL in adult patients with IgAV. Five patients with adult onset IgAV were enrolled in the study. All patients received oral PSL (initial dose 30-50mg/day), and MZB was administered orally at a single morning dose of 150mg. We investigated the clinical manifestations and prognosis of these patients receiving the combination therapy of MZB and PSL retrospectively. All patients showed complete or partial remission of proteinuria and microscopic hematuria with the combination therapy of MZB and PSL. Furthermore, no significant adverse effects were observed. Although this study had an uncontrolled small group, our results indicate that the combination of MZB with PSL could be a possible new treatment for adult patients with IgAV.

What the Black Lives Matter Movement Demands of Ethnic Studies Scholars

“Come in. Sit down. Close your eyes. Be silent and listen.” Melody engulfed the room. Our bodies unwittingly swayed softly to rhythms that conjured Ancestral memories. The bald, brown-skinned, goateed, dashiki-wearing man in front of the room exuded both warmth and strength. As a fourteen year-old ninth grader, the constancy of my giggle was interrupted by the sanctity of the space. Squeaks of the crotchety wooden desks that formed a large circle joined the music that hummed from the old record player at the front of the room. Minutes felt like days. Sound transported us through time and space and as the song came to an end, Mr. Navies instructed us, in a voice that prolonged the Spirit of what we had just experienced, “Now, write down your thoughts.” Silently, we scribbled down the ideas, poems, and stories that danced out of our Souls. We were greeted this way every single morning in African American History, Black Gold English, Black Male-Female Relationships, and the dozens of classes that comprised the Black Studies Department curriculum at Berkeley High School. At the close of each week, we would share our writings with the class, inspired by “classical Black musicians” from Charlie Parker, to Thelonius Monk, to Billie Holliday. Dassine, LaRae, Trinice, and Tomorrow would share poems. Ameer, always sat directly to my left and would break up the passionate tear-eliciting prose shared by others, with stories and jokes so hilarious that Mr. Navies would sometimes have to turn his back and hurriedly race across the room to shield his laughter from the class.

Efficacy of Medical Expulsive Therapy in Renal Calculi Less than or Equal to 5 Millimetres in Size.

Natural history and modality of treatment for asymptomatic renal calculi less than or equal to 5 millimetres in size is still unknown. Many options are available ranging from medical expulsive therapy to minimally invasive surgery. Till date no study has focussed on this very common but asymptomatic issue. Hence, this study is undertaken to evaluate efficacy of medical expulsive therapy in renal calculi less than or equal to 5mm in size. A prospective, parallel group, randomized study was carried out from 1st June 2014 to 31st May 2015, with total of 100 patients, 50 patients in each group. Patients with renal stones less than or equal to 5mm were included in the study. Group A Patients were administered medical expulsive therapy which included tamsulosin 0.4 mg daily at night time, furosemide 20mg, spironolactone 50mg in a single morning dose, and syrup potassium magnesium citrate 20Meq per dose three times a day for 12 weeks while group B patients were given placebo. The primary outcome variable was number of patients achieving clearance of stone during 12-week treatment period in both groups. No statistically significant differences in age, gender, stone size, and calyceal stone location was found between the two treatment arms. A spontaneous stone expulsion rate of 50% (at 6 weeks) and 86 %( at 12 weeks) was noted in group A versus 28% (at 6 weeks) and 38 % (at 12 weeks) in group B. Less number of pain episodes and less analgesic medication was required in group A as compared to group B. Medical Expulsive therapy for 12 weeks significantly improves stone free rates in renal calyceal calculi less than or equal to 5mm.

Pragmatic approach to manage new oral anticoagulants in patients undergoing dental extractions: a prospective case-control study.

The aim of this study was to validate a standardized pragmatic approach to manage new oral anticoagulants (NOACs) in patients who undergo dental extractions. This prospective case-control study in patients undergoing dental extraction included 26 patients (mean age 76 years, 57% male) treated with dabigatran, rivaroxaban, or apixaban and 26 matched controls. Regardless of timing of extraction, drug regimen, or renal function, patients were instructed to skip only the dose on the morning of the procedure. A procedural bleeding score was recorded and early and delayed bleeding was assessed at day 1 and day 7. Bleeding events were compared with a prospectively matched control group not taking any antithrombotic drug. There was no difference in the procedural bleeding score or in early bleeding events (5 in both groups). However, delayed bleeding occurred more frequently in anticoagulated compared to non-anticoagulated patients (7 versus none, p=0.01). Skipping the morning dose of NOACs avoids excess bleeding during and early after the procedure. However, anticoagulated patients had an increased risk of delayed bleedings. Further study is needed to determine the optimal post-procedural management. This is the first prospective study for the management of patients on NOACs undergoing dental extraction. Our pragmatic approach, omitting only a single morning dose, can guide clinical practice. Both patients and physicians should be aware of the increased delayed bleeding risk.

El Gerente del Siglo XXI ante los Retos del Pensamiento Estratégico

El gerente del siglo XXI ante los retos del pensamiento estratégico, observa que las organizaciones están frente a la exploración de desafíos futuros tanto previsibles como imprevisibles, más que preparar a las mismas para un posible mañana único. De allí, que la investigación que se desarrolla constituye un artículo cuyo objetivo es reflexionar sobre la gerencia del siglo XXI basada en el pensamiento estratégico; en este sentido, se tiene que la metodología usada para el estudio fue de tipo descriptiva y documental; los resultados evidencian claramente el perfil del gerente del siglo XXI como un guía orientador, creativo, innovador, estratega, llegando a concluir que: la dinámica profesional de las organizaciones manifiestan comportamientos según el cual las que mejor se adapten al entorno serán las que perdurarán en el tiempo.

OS 03-02 STRONGER ASSOCIATIONS OF URINARY SODIUM-TO-POTASSIUM RATIO WITH BLOOD PRESSURE

Objective: To evaluate the association of systolic blood pressure (SBP) and diastolic blood pressure (DBP) with ratio for urinary sodium versus potassium in a large prospective urban and rural epidemiological study in China (PURE-China). Design and method: As the important part of global multi-center PURE study, a prospective cohort study was conducted to recruit 46,285 participants in urban and rural area of 12 provinces in China between 2005 and 2009. A single fasting morning urine specimen was collected to test sodium and potassium excretion, and the Kawasaki formula was used to estimate 24-hour urinary sodium and potassium excretion. SBP and DBP were measured with an automated device. Results: Finally, a total of 41,122 subjects were eligible for the analyses of urinary sodium and potassium and blood pressure. Means of estimated urinary sodium and potassium excretion were 5.8 ± 1.8 and 2.1 ± 0.5 gram/day, respectively, and ratio for urinary sodium versus potassium was 2.8 ± 0.8. This ratio in female is a little lower than that in men (2.7 ± 0.7 vs. 2.9 ± 0.8). Adjusted logistic regression analyses in Figure 1 showed 1.54 mmHg increase and 1.18 mmHg SBP decrease per 1-g increment, and 0.44 mmHg increase and 0.77 DBP decrease for each gram increase of estimated urinary sodium and potassium excretion, respectively. Larger increase of SBP and DBP with one unit increase of ratio for sodium versus potassium were observed (4.15 mmHg for SBP and 1.42 mmHg for DBP, P < 0.01). Conclusions: Compared to urinary sodium and potassium, the increase of ratio for sodium vs. potassium is better predictor to detect the SBP and DBP increase. Hence, this ratio should be calculated as an important index when susceptible people are screened for hypertension prevention and control.

Evaluation of clinical parameters related to methotrexate therapy in lichen planus

Background: For better management of lichen planus a clinical trial of oral methotrexate is necessary in ow· country. Objective: The objective of this study is to evaluate efficacy and safety ofmethotrexate therapy in the treatment of lichen planus.Methods: It was a prospective randomized controlled clinical trial conducted in the department of Dermatology and Venereology, BSMMU, Dhaka, from January 2009 to December 2010. Forty four patients of lichen planus were included in the study. Cases (group-A, n=23) were treated with methotrexate (10 mg) single morning dose and control (group-B, n=21) were treated with mini pulse betamethasone (5mg) single morning dose on 2 consecutive days during the period of 12 weeks. Results: Clinical parameters were measured by follow up clinical examination. Morphological lesion of lichen planus improved 95. 7% in group-A and only 28.6% improved in group-B. At the end of study 82.6% bad no complaints of itching in group-A and 100% had no complaints of itching in group-B. 16(69.6%) patients in group-A were completely cured clinically but 10(47.6%) in group-B. Anemia 3(14.2%) and edema 12(57.1 %) developed in group-B but none in group-A. In group-B, dyspepsia 15(71.4%), acne 10(47.6%),mooning face 8(38.1%), striae 8(38.1%) and hyper­trichosis 4(19.0%) developed but none in group-A lntermittenr diarrhoea, headache, nausea and fatigue complained in both groups of patients but the percentage of complaints was higher amog group-8 compared to group-A. Menstrual abnormality developed in group-B 5(71.4%) but none in group-A.Conclusion: The overall adverse effects were less in group-A than group-B. Therefore, methotrexate can be used as an alternative safer option for the treatment of lichen planus.

Increased antimüllerian hormone levels and other reproductive endocrine changes in adult male relatives of women with polycystic ovary syndrome

To investigate for differences in reproductive hormone levels in male relatives of women with polycystic ovary syndrome (PCOS). Cross-sectional study. Academic medical center. Sixty-three fathers and 66 brothers of women with PCOS as well as two groups of control men of comparable age to fathers (older control, n = 30) and brothers (younger control, n = 58). A single early morning fasting blood sample was obtained for the measurement of reproductive hormone levels. Testosterone, LH, FSH, antimüllerian hormone (AMH), inhibin B, estradiol (E2), and estrone (E1) levels were measured. The AMH, LH, and FSH levels were significantly increased in male relatives compared with their respective control groups. The levels of E2, E1, T, and inhibin B did not differ between the groups. The AMH, LH, and FSH levels were increased in adult male relatives of women with PCOS, suggesting that they may have altered testicular function and changes in neuroendocrine regulation of gonadotropin secretion. These changes may reflect effects of PCOS susceptibility genes such as the recently mapped chromosome 11p14.1 locus in the region of the FSH B polypeptide gene.

Median Urinary Iodine Concentrations Are Indicative of Adequate Iodine Status among Women of Reproductive Age in Prey Veng, Cambodia.

Iodine deficiency disorders are estimated to affect over 1.9 million people worldwide. Iodine deficiency is especially serious for women during pregnancy and lactation because of the negative consequences for both mother and infant. The aim of this cross-sectional study was to determine the median urinary iodine concentration (UIC) as a population-level indicator of iodine status among rural women farmers of reproductive age (18–45 years) in the province of Prey Veng, Cambodia. A total of 450 women provided a spot morning urine sample in 2012. Of those women, 93% (n = 420) were non-pregnant and 7% (n = 30) were pregnant at the time of collection. UIC was quantified using the Sandell-Kolthoff reaction with modifications. The median UIC of non-pregnant (139 μg/L) and pregnant women (157 μg/L) were indicative of adequate iodine status using the WHO/UNICEF/ICCIDD epidemiological criteria for both groups (median UIC between 100–199 and 150–249 μg/L, respectively). We conclude that non-pregnant and pregnant women in rural Prey Veng, Cambodia had adequate iodine status based on single spot morning urine samples collected in 2012. More research is warranted to investigate iodine status among larger and more representative populations of women in Cambodia, especially in light of recent policy changes to the national program for universal salt iodization.

Riociguat (BAY 63-2521) and aspirin: a randomized, pharmacodynamic, and pharmacokinetic interaction study.

In preclinical studies, drugs that increase cyclic guanosine monophosphate levels have been shown to influence platelet function/aggregation; however, the effect of riociguat on human platelets is unclear. Aspirin, a platelet inhibitor, is likely to be given concomitantly in patients receiving riociguat. It is therefore important to establish clinically whether (1) riociguat affects platelet function and (2) aspirin and riociguat interact. This randomized, open-label, crossover study investigated potential pharmacodynamic and pharmacokinetic interactions between these drugs in healthy male volunteers (N = 18). There were 3 treatment regimens: a single morning dose of riociguat 2.5 mg, aspirin 500 mg on 2 consecutive mornings, and both treatments together, with riociguat given on the second morning. Fifteen participants were available for pharmacodynamic/pharmacokinetic analysis. There was no effect of riociguat alone on bleeding time, platelet aggregation, and serum thromboxane B2 levels. The effects of aspirin on these parameters were not influenced by concomitant administration of riociguat. The pharmacokinetic profile of riociguat showed interindividual variability, which was independent of aspirin coadministration. Six of 17 participants available for safety evaluation reported at least 1 treatment-emergent adverse event. All adverse events were of mild severity, apart from 1 report of moderate headache. No serious adverse events occurred. In conclusion, riociguat demonstrated no clinically relevant pharmacodynamic or pharmacokinetic interactions with aspirin at the doses used in this study in healthy men; coadministration of riociguat and aspirin should therefore not require any dose adjustment for either drug.

Abstract OT2-01-03: A phase 1/2 study of once-daily oral VT-464 in patients with advanced androgen receptor (AR) positive triple negative (TNBC) or estrogen receptor (ER) positive breast cancer (BC)

Abstract VT-464, an oral dual lyase-selective CYP17 inhibitor and AR antagonist (wild-type and mutated forms [e.g., F876L and T877A]), is in multiple Phase (Ph) 2 studies as treatment for men with castration-resistant prostate cancer (CRPC). VT-464 inhibits the growth of multiple BC cell lines in vitro including MCF7 (ER(+)/AR low), tamoxifen-resistant MCF7, and MDA-MB-453 (ER(-)/AR(+)) in a dose-dependent manner and with greater potency/efficacy than enzalutamide (submitted, Ellison et al., 2015). A subset of TNBC and most ER(+) BC express AR, making them potential targets for VT-464 since it directly inhibits both androgen/estrogen synthesis and AR transcriptional activity. Objectives: The primary objective of Ph 1, now enrolling, is to establish the once-daily dose of VT-464 in women. Secondary objectives include safety, PK and efficacy endpoints, including determination of clinical benefit rate (CBR) which is the primary objective of Ph 2. Exploratory objectives include the determination of the extent of AR expression and signaling in breast tissue and to evaluate the relationship of expression with VT-464 effects on circulating tumor biomarkers, circulating hormones and clinical outcomes. Study Design: This study is an open-label, single arm, Ph 1/2 study of VT-464 in women with AR(+) TNBC or ER(+)/HER2 normal unresectable locally advanced or metastatic BC. Ph 1 will follow a modified 3+3 Fibonacci design with cohort expansion to 6 patients following a single DLT in the first 28-days of treatment. Approximately 2-3 dose-levels will be explored in Ph 1. Ph 1 start dose will be the MTD for men with CRPC. AR(+) TNBC and ER(+)/HER2 BC cohorts will be expanded in Ph 2 using the MTD from Ph 1. Ph 2 will follow a Simon's two-stage design with pre-determined futility parameters. Eligible patients will have ER≥1% BC or AR≥1% (as determined by central IHC testing using the Dako antibody) TNBC. ER(+) patients must be postmenopausal and must have received at least 1 prior line of endocrine therapy. Additional eligibility criteria include: ≥ 18 years of age, ECOG PS ≤ 1, unresectable locally advanced or metastatic BC, available representative tumor specimen to enable correlative science. Treatment Plan: Eligible patients will receive VT-464 once-nightly with dinner in a continuous dosing schedule. Adverse events and concomitant medications will be collected from the time of signing of informed consent until 30 days after end of study visit (EOS). Safety labs will be monitored monthly through EOS. Dense PK will be collected after the first dose of study drug in Ph 1 and single morning samples collected approximately every two cycles thereafter in Ph 1 and Ph 2 until EOS. Blood samples for steroids, circulating tumor DNA and circulating tumor cells will be collected through Cycle 2 and then at EOS. Tumor biopsy will be collected at baseline and at disease progression. Radiographic response will be assessed every 8 weeks and EOS. Patient Accrual: Accrual is ongoing with 12-18 patients expected to be enrolled in Ph 1. Citation Format: Gucalp A, Hudis C, Norton L, Patil S, Kurman MR, Eisner JR, Moore WR, Traina TA. A phase 1/2 study of once-daily oral VT-464 in patients with advanced androgen receptor (AR) positive triple negative (TNBC) or estrogen receptor (ER) positive breast cancer (BC). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT2-01-03.

Reduced morning cortisol concentration in saliva was associated with obesity: Evidence from community-dwelling adults in papua new guinea.

This study investigated morning salivary cortisol concentration in relation to total body fat composition among community-dwelling Papua New Guinean adults. In addition to demographic and anthropometric measurements, saliva was collected in a single morning from 478 residents in Eastern Highlands Province and Madang Province. After adjusting for age, region, and occupation, the morning salivary cortisol concentration was significantly negatively correlated with body mass index among men (B = -0.01, P < 0.05) and women (B = -0.013, P < 0.05), and waist circumference (B = -0.007, P < 0.05), waist-to-hip-ratio (B = -1.214, P < 0.05), and subscapular-to-triceps skinfold-thickness ratio (B = -0.045, P < 0.05) among men. Men with total or abdominal body fat mass known for elevated risk of non-communicable diseases displayed lower cortisol compared to men without such risk. Papua New Guinean adults with increased accumulation of body fat showed reduced cortisol concentration in morning saliva. Am. J. Hum. Biol. 28:587-590, 2016. © 2016 Wiley Periodicals, Inc.

Effectiveness of Methotrexate in prednisolone and thalidomide resistant cases of Type 2 lepra reaction: report on three cases

Type 2 lepra reactions, and its cutaneous manifestation, Erythema Nodosum Leprosum (ENL) are an immune complex mediated systemic condition, often complicating the disease and/or its treatment in cases of the lepromatous spectrum of leprosy. Prednisolone and thalidomide are the mainstay for the treatment of Type 2 lepra reactions. According to the guidelines set out by the WHO and the National Leprosy Elimination Programme (NLEP) of India cases of Type 2 lepra reaction should be managed with prednisolone, cofazimine and thalidomide. NLEP guidelines suggest that prednisolone at 1 mg/kg body wt/day is given to start with as a single morning dose after breakfast, and after the reaction/inflammation is controlled, to taper the prednisolone by 10 mg fortnightly till the dose of 20 mg/day is reached. Thereafter prednisolone is tapered by 5 mg/day, fortnightly till withdrawal. Clofazimine is given with corticosteroids in every case, starting with 100 mgs three times a day, tapering to 100 mgs after every 12 weeks. It is recommended not to exceed clofazimine beyond 12 months. Thalidomide can be used in resistant cases of ENL under strict supervision in tertiary care centres only. During the years 2009 and 2010, thalidomide was made available to our department through the kind donation of the NGO Lepra Society, India. This thalidomide was used for prednisolone/clofazimine non-responsive patients of Type 2 lepra reaction. The thalidomide schedule that we followed was, to start 100 mgs three times a day, tapered fortnightly

Analysis on the securityof preoperative oral sugar salt solution ofpatients with laparoscopic gallbladder excision

Objective To evaluate the effect of the preoperative oral sugar salt solution on patients with laparoscopic gallbladder excision. Methods A total of 178 patients with laparoscopic gallbladder excision were divided into observation group and control group with 89 cases in each. The control group adopted routine fasting way before operation. The patients in the observation group were treated with 300 ml of the sugar salt solution at the 10 o'clock on the evening before surgery. After midnight, nothing by mouth was allowed, except a single morning dose of 200 ml of the corresponding solution.The morning drink was taken at 2h before surgery. Visual analog scales(VAS) were used to score 11 different preoperative discomfort variables.Operational clinical and surgical data were recorded, which included the blood pressure, heart rate, blood glucose levels. Results The control group at different time measured blood glucose, heart rate, systolic pressure and diastolic pressure were statistically different (F=5.609, 5.771, 15.780, 12.335, P 0.05). And blood glucose after 24h, the heart rate after 6h, blood pressure after 6h time compared with other time points statistically significant differences(P 0.05). On the morning before surgery, patients in the control group mainly unwell feeling nervous, hunger, thirst, fatigue, pain, VAS score were significantly increased than those in the observation group(P<0.05). Conclusions Drinking the sugar salt solution at the 10 o'clock on the evening before surgery and 2h before surgery does not affect anesthesia intubation.and not increase the risk of regurgitation and aspiration during or after surgery and alleviatenervous, hunger, thirst, fatigue, pain. Key words: Sugar salt-solution; Fasting for solids and liquid; Celioscope operation; Laparoscopic cholecystectomy; Perioperative period

The use of child actors to simulate paediatric patients in the MRCGP Clinical Skills Assessment (CSA): developing an effective model

Role-player consistency between candidates is a crucial component of the reliability of the Objective Structured Clinical Examination (OSCE) format used for clinical skills assessment (CSA). It is particularly important in a high-stakes licensing assessment such as the Membership of the Royal College of General Practitioners' (MRCGP's) CSA. The current organisation of the CSA examination poses particular challenges for child actors. The stringent licensing process for child actors limits the working hours of children aged under 13 years considerably, making it impossible for them to perform in both the morning and afternoon circuits on examination days. Children aged nine years or younger are not able to complete even a single morning or afternoon circuit. Younger children also appear disproportionately to become fatigued and less consistent with time. All children require significant support from their adult role-player parent. Careful piloting has allowed us to develop a solution which requires the use of natural pairs of adult and child role players in two teams for the morning and afternoon circuits. A new process for training and calibrating the children the day before their performance in addition to calibration on the day appears to improve the consistency of their performance. The aim of this paper is to describe the action research-based cycle through which we developed our training procedures for child actors for the MRCGP CSA. We believe, given the challenges we have outlined, our experience will be of interest to all educators involved in the CSA process.