Does Lake Louise questionnaire interpret high-altitude headache as acute mountain sickness? Experience in the western Himalayas.

BACKGROUND OBJECTIVES: High-altitude headache (HAH) and headache in acute mountain sickness (AMS) are common among lowlanders ascending to the high altitude and are often confused with one another. A pilot study was undertaken to analyze HAH and AMS cases in Indian lowlanders ascending to Leh city (3500 m) in western Himalayas. METHODS: A total number of 1228 Indian lowlanders, who ascended (fresh and re-inductees) by air and acclimatized, participated in this pilot study. The intensity of headache was assessed by the Visual Analogue Score. The parameters of HAH as per the International Classification of Headache Disorders-3 and 2018 Revised Lake Louise Questionnaire (LLQ) were used to differentiate HAH and AMS. RESULTS: Out of 1228 cases, 78 (6.4%) cases had headache, of which 24 (1.95%) cases were HAH only, 40 (3.25%) cases AMS only and 14 (1.14%) cases were defined as both HAH and AMS. There was a significant difference in heart rate [F (2,51) = (4.756), P =0.01] between these groups. It also showed a difference in the correlation between the parameters within the groups. The Odd's Ratio of AMS in fresh and re-inductees was found to be 4.5 and for HAH it was 4.33. INTERPRETATION CONCLUSIONS: The findings of this study suggest that LLQ has a tendency of overestimating AMS by including HAH cases. Furthermore differential parameters exhibit differences when AMS and HAH are considered separately. Re-inductees showed a lower incidence of HAH and AMS.

Improved QSAR models for PARP-1 inhibition using data balancing, interpretable machine learning, and matched molecular pair analysis.

The poly (ADP-ribose) polymerase-1 (PARP-1) enzyme is an important target in the treatment of breast cancer. Currently, treatment options include the drugs Olaparib, Niraparib, Rucaparib, and Talazoparib; however, these drugs can cause severe side effects including hematological toxicity and cardiotoxicity. Although in silico models for the prediction of PARP-1 activity have been developed, the drawbacks of these models include low specificity, a narrow applicability domain, and a lack of interpretability. To address these issues, a comprehensive machine learning (ML)-based quantitative structure-activity relationship (QSAR) approach for the informed prediction of PARP-1 activity is presented. Classification models built using the Synthetic Minority Oversampling Technique (SMOTE) for data balancing gave robust and predictive models based on the K-nearest neighbor algorithm (accuracy 0.86, sensitivity 0.88, specificity 0.80). Regression models were built on structurally congeneric datasets, with the models for the phthalazinone class and fused cyclic compounds giving the best performance. In accordance with the Organization for Economic Cooperation and Development (OECD) guidelines, a mechanistic interpretation is proposed using the Shapley Additive Explanations (SHAP) to identify the important topological features to differentiate between PARP-1 actives and inactives. Moreover, an analysis of the PARP-1 dataset revealed the prevalence of activity cliffs, which possibly negatively impacts the model's predictive performance. Finally, a set of chemical transformation rules were extracted using the matched molecular pair analysis (MMPA) which provided mechanistic insights and can guide medicinal chemists in the design of novel PARP-1 inhibitors.

Biomass, carbon stock, CO2 mitigation and carbon credits of coffee-based multitier cropping model in Central India.

The present work was conducted in the forest-based ecosystem of Chhattisgarh in order to assess the varietal performance of coffee varieties along with silver oak in terms of growth, biomass, and carbon dynamics. Five coffee varieties were planted in silver oak shade in a randomized block design with four replications. The aim of the present investigation is to assess the economic and ecological feasibility of forest-based coffee plantations in the Bastar region of Chhattisgarh. Findings reflect the maximum under-storied plant height in Chandragiri Dwarf (1.85 m) which was at par with CxR (1.82 m) and San Ramon (1.71 m). The maximum above and below-ground carbon stock (48.40 and 12.09 Mg ha-1, respectively), as well as carbon dioxide (CO2) mitigation (177.63 and 44.41 Mg ha-1, respectively) from the under-storied coffee plantation, was recorded in CxR. In the upper-storied plantation, the above and below-ground biomass of silver oak recorded the maximum carbon stock (201.24 and 50.31 Mg ha-1, respectively) and CO2 mitigation (738.54 and 184.63 Mg ha-1) in S-8 intercropped lines. The highest value of carbon credit was recorded under the coffee variety S-8 and silver oak agroecosystem. The S-8, CxR, and Chandragiri Dwarf varieties performed quite well in terms of the expected value of carbon credit.

An overview of compound properties, multiparameter optimization, and computational drug design methods for PARP-1 inhibitor drugs.

Breast cancer treatment with PARP-1 inhibitors remains challenging due to emerging toxicities, drug resistance, and unaffordable costs of treatment options. How do we invent strategies to design better anti-cancer drugs? A part of the answer is in optimized compound properties, desirability functions, and modern computational drug design methods that drive selectivity and toxicity and have not been reviewed for PARP-1 inhibitors. Nonetheless, comparisons of these compound properties for PARP-1 inhibitors are not available in the literature. In this review, we analyze the physchem, PKPD space to identify inherent desirability functions characteristic of approved drugs that can be valuable for the design of better candidates. Recent literature utilizing ligand, structure-based drug design strategies and matched molecular pair analysis (MMPA) for the discovery of novel PARP-1 inhibitors are also reviewed. Thus, this perspective provides valuable insights into the medchem and multiparameter optimization of PARP-1 inhibitors that might be useful to other medicinal chemists.

Neonatal Subcutaneous BCG Vaccination Decreases Atherosclerotic Plaque Number and Plaque Macrophage Content in ApoE-/- Mice.

Bacille-Calmette Guérin (BCG) modulates atherosclerosis development in experimental animals, but it remains unclear whether neonatal BCG vaccination is pro- or anti-atherogenic. Many animal models differ fundamentally from BCG administration to human infants in terms of age, vaccine preparation, dosing schedule, and route of administration. We aimed to elucidate the effect of neonatal subcutaneous BCG vaccination­analogous to human BCG vaccination­on atherosclerosis development in ApoE−/− mice. At 2 days of age, a total of 40 ApoE−/− mice received either a weight-equivalent human dose of BCG, or saline, subcutaneously. From 4 weeks onwards, the mice were fed a Western-type diet containing 22% fat. At 16 weeks of age, mice were sacrificed for the assessment of atherosclerosis. Body weight, plasma lipids, atherosclerosis lesion size and collagen content were similar in both groups. Atherosclerosis lesion number was lower in mice that received BCG. Macrophage content was 20% lower in the BCG-vaccinated mice (p < 0.05), whereas plaque lipid content was increased by 25% (p < 0.01). In conclusion, neonatal BCG vaccination reduces atherosclerosis plaque number and macrophage content but increases lipid content in a murine model of atherosclerosis. Human epidemiological and mechanistic studies are warranted to investigate whether neonatal BCG vaccination is potentially atheroprotective.

Evaluation of global Cenchrus germplasm for key nutritional and silage quality traits.

Cenchrus is important genera of grasses inhabiting tropical pastures and the Indian grasslands system. Its forage value is well established to sustain nomadic livestock and wildlife. This study deals with the evaluation of the representative set of global Cenchrus germplasm collection with 79 accessions belonging to six species (C. ciliaris, C. setigerus, C. echinatus, C. myosuroides, C. pennisetiformis, and C. biflorus) at flowering stage. Crude protein (CP), neutral detergent fiber (NDF), acid detergent fiber (ADF), cellulose, and lignin values were in the range of 61.1-136, 640-749, 373-490, 277-375, and 35.6-75.50 g kg-1DM, respectively, while sugar contents varied from 11.6 to 101 mg g-1 DM. From the evaluated germplasm, 14 accessions of C. ciliaris having >70 mg g-1 DM sugar contents were selected and further evaluated for protein, fiber, carbohydrate and protein fractions, palatability indices, in vitro CH4 production, and ensiling traits. Protein contents were lower in EC397323 (61.8) and higher in IG96-96 (91.5), while the NDF, ADF, cellulose, and lignin contents varied between 678-783, 446-528, 331-405, and 39.6-62.0 g kg-1DM, respectively. The carbohydrate and protein fractions of selected accessions differed (p < 0.05), and the sugar contents varied (p < 0.05) between 74.6 and 89.6 mg-1g DM. Dry matter intake (DMI) and relative feed value (RFV) of accessions varied (p < 0.05) and were in the range of 1.53-1.77% and 58.2-73.8 g kg-1 DM, respectively. The total digestible nutrients (TDNs), digestible energy (DE), and metabolizable energy (ME) of selected accessions varied between 362-487 g kg-1 DM, 6.62-8.90, and 5.42-7.29 Mj kg-1 DM, respectively. In vitro gas and CH4 production (24 h) varied (p < 0.05) between 73.1 to 146 and 7.72 to 21.5 ml/g, respectively, while the degraded dry matter (g kg-1 DM) and CH4 (ml/g DDM) ranged between 399-579 and 17.4-47.2, respectively. The DM contents at ensiling, silage pH, and lactic acid contents of accessions differed (p < 0.05) and ranged between 185-345 g kg-1 DM, 5.10-6.05, and 1.39-23.3 g kg-1 DM, respectively. Wide genetic diversity existed in germplasm and selected C. ciliaris accessions for protein fiber, energy, sugar, and other nutritional traits. Silage prepared from EC397366, IG96-96, IG96-50, and EC397323 had pH and lactic acid contents acceptable for moderate to good quality silage of tropical range grasses.

Effect of topical applications of sunflower seed oil on systemic fatty acid levels in under-two children under rehabilitation for severe acute malnutrition in Bangladesh: a randomized controlled trial.

BACKGROUND: Children with severe acute malnutrition (SAM) have inadequate levels of fatty acids (FAs) and limited capacity for enteral nutritional rehabilitation. We hypothesized that topical high-linoleate sunflower seed oil (SSO) would be effective adjunctive treatment for children with SAM. METHODS: This study tested a prespecified secondary endpoint of a randomized, controlled, unblinded clinical trial with 212 children with SAM aged 2 to 24 months in two strata (2 to < 6 months, 6 to 24 months in a 1:2 ratio) at Dhaka Hospital of icddr,b, Bangladesh between January 2016 and December 2017. All children received standard-of-care management of SAM. Children randomized to the emollient group also received whole-body applications of 3 g/kg SSO three times daily for 10 days. We applied difference-in-difference analysis and unsupervised clustering analysis using t-distributed stochastic neighbor embedding (t-SNE) to visualize changes in FA levels in blood from day 0 to day 10 of children with SAM treated with emollient compared to no-emollient. RESULTS: Emollient therapy led to systematically higher increases in 26 of 29 FAs over time compared to the control. These effects were driven primarily by changes in younger subjects (27 of 29 FAs). Several FAs, especially those most abundant in SSO showed high-magnitude but non-significant incremental increases from day 0 to day 10 in the emollient group vs. the no-emollient group; for linoleic acid, a 237 µg/mL increase was attributable to enteral feeding and an incremental 98 µg/mL increase (41%) was due to emollient therapy. Behenic acid (22:0), gamma-linolenic acid (18:3n6), and eicosapentaenoic acid (20:5n3) were significantly increased in the younger age stratum; minimal changes were seen in the older children. CONCLUSIONS: SSO therapy for SAM augmented the impact of enteral feeding in increasing levels of several FAs in young children. Further research is warranted into optimizing this novel approach for nutritional rehabilitation of children with SAM, especially those < 6 months. TRIAL REGISTRATION: ClinicalTrials.gov : NCT02616289 .

Topical emollient therapy in the management of severe acute malnutrition in children under two: A randomized controlled clinical trial in Bangladesh.

BACKGROUND: Topical emollient therapy can improve neonatal health and growth and potentially provides an additional avenue for augmenting the provision of nutrition to children with severe acute malnutrition (SAM). We hypothesised that topical treatment of hospitalised children with SAM using sunflower seed oil (SSO), in addition to standard-of-care for SAM, would improve skin barrier function and weight gain, reduce risk of infection, and accelerate clinical recovery. METHODS: We conducted a randomised, two-arm, controlled, unblinded clinical trial in 212 subjects aged 2 to 24 months who were admitted for care of SAM at the 'Dhaka Hospital' of icddr,b during January 2016 to November 2017. Enrollment was age-stratified into 2 to <6 months and 6 to 24 months age groups in a 1:2 ratio. All children received SAM standard-of-care, and the SSO group was also treated with 3 g of SSO per kg body weight three times daily for 10 days. Primary outcome was rate of weight gain over the 10-day study period. Secondary endpoints included rate of nosocomial infection, time to recovery from acute illness, skin condition score, rate of transepidermal water loss (TEWL) and C-reactive protein (CRP) level. RESULTS: Rate of weight gain was higher in the SSO than the control group (adjusted mean difference, AMD = 0.90 g/kg/d, 95% confidence interval (CI) = -1.22 to 3.03 in the younger age stratum), but did not reach statistical significance. Nosocomial infection rate was significantly lower in the SSO group in the older age stratum (adjusted odds ratio (OR) = 0.41, 95% CI = 0.19 to 0.85; P = 0.017), but was comparable in the younger age stratum and overall. Skin condition score improved (AMD = -14.88, 95% CI = -24.12 to -5.65, P = 0.002) and TEWL was reduced overall (AMD = -2.59, 95% CI = -3.86 to -1.31, P < 0.001) in the SSO group. Reduction in CRP level was significantly greater in the SSO group (median: -0.28) than the control group (median 0.00) (P = 0.019) in the younger age stratum. CONCLUSIONS: Topical therapy with SSO was beneficial for children with SAM when applied as adjunctive therapy. A community-based trial with a longer intervention period is recommended to validate these results. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02616289.

Estrogen receptor (ESR1 and ESR2)-mediated activation of eNOS-NO-cGMP pathway facilitates high altitude acclimatization.

Higher levels of circulatory nitric oxide (NO) and NO metabolites reportedly facilitate high altitude acclimatization. But the underlying factors and molecular pathways promoting NO production at high altitude has been poorly characterized. Studying healthy lowlanders at sea level (C, lowlander) and high altitude (3500 m, after day 1, 4 and 7 of ascent), we report higher protein levels of eNOS and eNOSSer1177, higher plasma levels of BH4, NOx (nitrate and nitrites), cGMP and lower levels of endogenous eNOS inhibitor ADMA during healthy high altitude acclimatization. Our qRT-PCR-based gene expression studies identified higher levels of eNOS/NOS3 mRNA along with several other eNOS pathway genes like CALM1, SLC7A1 and DNM2. In addition, we observed higher mRNA levels of estrogen (E2) receptors ERα/ESR1 and ERß/ESR2 at high altitude that transcriptionally activates NOS3. We also observed higher mRNA level of membrane receptor ERBB2 that phosphorylates eNOS at Ser1177 and thus augments NO availability. Evaluating E2 biosynthesis at high altitude, we report higher plasma levels of CYP11A1, CYP19A1, E2, lower levels of testosterone (T) and T/E2 ratio as compared to sea level. Correlation studies revealed moderate positive correlation between E2 and NOx (R = 0.68, p = 0.02) after day 4 and cGMP (R = 0.69, p = 0.02) after day 7 at high altitude. These findings suggest a causative role of E2 and its receptors ESR1 and ESR2 in augmenting eNOS activity and NO availability during healthy high altitude ascent. These results will aid in better understanding of NO production during hypobaric hypoxia and help in designing better high altitude acclimatization protocols.

Intermittent normobaric hypoxia facilitates high altitude acclimatization by curtailing hypoxia-induced inflammation and dyslipidemia.

Intermittent hypoxic training (IHT) is a discrete cost-effective method for improving athletic performance and high altitude acclimatization. Unfortunately, IHT protocols widely vary in terms of hypoxia severity, duration, and number of cycles affecting physiological outcomes. In the present study, we evaluated the efficacy of a moderate normobaric IHT protocol (12% FiO2 for 4 h, 4 days) on acclimatization to high altitude (3250 m). Global plasma proteomics studies revealed that IHT elicited acute-phase response proteins like C-reactive protein (CRP), serum amyloid A-1 protein (SAA), and alpha-1-acid glycoprotein 2 (AGP 2) as well as altered levels of several apolipoproteins. On subsequent exposure to high altitude, the IH trained volunteers exhibited significant higher arterial oxygen saturation with concomitant lower incidences of acute mountain sickness (AMS) as compared to controls. Interestingly, IH trained subjects exhibited lower levels of positive acute-phase proteins like C-reactive protein (CRP), serum amyloid A-1 protein (SAA), and fibrinogen (FGA, FGB, and FGG) both after days 4 and 7 of high altitude ascent. High altitude exposure also decreased the levels of HDL, LDL, and associated proteins as well as key enzymes for assembly and maturation of lipoprotein particles like lecithin-cholesterol acyltransferase (LCAT), cholesteryl ester transfer protein (CETP), and phospholipid transfer protein (PLTP). In contrast, IHT curtailed hypoxia-induced alterations of HDL, LDL, Apo-AI, Apo-B, LCAT, CETP, and PLTP. Further validation of results also corroborated attenuation of hypoxia-induced inflammation and dyslipidemia by IHT. These results provide molecular evidences supporting the use of moderate IHT as a potential non-pharmacological strategy for high altitude acclimatization.

Effect of wrist cooling on aerobic and anaerobic performance in elite sportsmen.

BACKGROUND: Body cooling has been used to increase sporting performance and enhance recovery. Several studies have reported improvement in exercise capacities using forearm and hand cooling or only hand cooling. Wrist cooling has emerged as a portable light weight solution for precooling prior to sporting activity. The Astrand test for aerobic performance and the Wingate test for anaerobic performance are reliable and accurate tests for performance assessment. This study conducted on elite Indian athletes analyses the effects of wrist precooling on aerobic and anaerobic performance as tested by the Astrand test and the Wingate test before and after wrist precooling. METHODS: 67 elite sportsmen were administered Wingate and Astrand test under standardised conditions with and without wrist precooling using a wrist cooling device (dhamaSPORT). Paired t-test was applied to study effect on aerobic [VO2 (ml/min/kg)] and anaerobic performance [peak power (W/kg) and average power (W/kg)] and Cohen's d was used to calculate effect size of wrist precooling. RESULTS: After wrist precooling, significant increase of 0.22 (p = 0.014, 95% CI: 0.047, 0.398) in peak power (W/kg) and 0.22 (p < 0.0001, 95% CI: 0.142, 0.291) was observed in average power (W/kg). Although, an increase of 1.38 (p = 0.097, 95% CI: -0.225, 3.012) was observed in VO2 (ml/min/kg), wrist precooling was not significantly effective in aerobic performance. Wrist cooling effect size was smaller in VO2 (Cohen's d = 0.21), peak power (Cohen's d = 0.31) and it was larger in average power (Cohen's d = 0.71). CONCLUSION: Results show wrist precooling significantly improves anaerobic than aerobic performance of elite sportsmen.

Raised HIF1α during normoxia in high altitude pulmonary edema susceptible non-mountaineers.

High altitude pulmonary edema (HAPE) susceptibility is associated with EGLN1 polymorphisms, we hypothesized that HAPE-susceptible (HAPE-S, had HAPE episode in past) subjects may exhibit abnormal HIF1α levels in normoxic conditions. We measured HIF1α levels in HAPE-S and HAPE resistant (HAPE-R, no HAPE episode) individuals with similar pulmonary functions. Hemodynamic responses were also measured before and after normobaric hypoxia (Fi02 = 0.12 for 30 min duration at sea level) in both groups. . HIF1α was higher in HAPE-S (320.3 ± 267.5 vs 58.75 ± 33.88 pg/ml, P < 0.05) than HAPE-R, at baseline, despite no significant difference in baseline oxygen saturations (97.7 ± 1.7% and 98.8 ± 0.7). As expected, HAPE-S showed an exaggerated increase in pulmonary artery pressure (27.9 ± 6 vs 19.3 ± 3.7 mm Hg, P < 0.05) and a fall in peripheral oxygen saturation (66.9 ± 11.7 vs 78.7 ± 3.8%, P < 0.05), when exposed to hypoxia. HIF1α levels at baseline could accurately classify members of the two groups (AUC = 0.87). In a subset of the groups where hemoglobin fractions were additionally measured to understand the cause of elevated hypoxic response at baseline, two of four HAPE-S subjects showed reduced HbA. In conclusion, HIF 1 α levels during normoxia may represent an important marker for determination of HAPE susceptibility.

Plasma kallikrein-bradykinin pathway promotes circulatory nitric oxide metabolite availability during hypoxia.

Nitric oxide (NO) is an indispensible signalling molecule under hypoxic environment for both ethnic high altitude natives as well as lowland residents at high altitude. Several studies have reported higher levels of NO and bioactive NO products for both high altitude natives as well as healthy high altitude sojourners. But the metabolic pathways regulating the formation of NO and associated metabolites during hypoxia still remain elusive. In the present study, we profiled plasma proteomes of Ladakhi natives (3520 m) and lowland residents (post 1, 4 and 7 days stay) at the same altitude. This has resulted in the identification of 208 hypoxia responsive proteins (p < 0.05) and kininogen-plasma kallikrein-bradykinin as a major pathway regulating eNOS activity during hypoxia. In corroboration, we have also observed significant higher levels of plasma biomarkers for NO production (l-citrulline, nitrite, nitrate) for Ladakhi natives as compared to both lowland individuals healthy high altitude sojourners indicating higher NO availability. Since hypoxia-induced free radicals reduce NO availability, we also measured plasma levels of 8-isoprostanes, protein carbonyls and protein oxidation products in both Ladakhi natives and high altitude sojourners. Interestingly Ladakhi natives had significant lower levels of oxidative stress in comparison to high altitude sojourners but higher than lowland controls. These results suggest that plasma kallikrein-bradykinin-eNOS pathway along with moderate oxidative stress contributes to high altitude adaptation of Ladakhi natives.

Elevated pulmonary artery pressure and brain natriuretic peptide in high altitude pulmonary edema susceptible non-mountaineers.

Exaggerated pulmonary pressor response to hypoxia is a pathgonomic feature observed in high altitude pulmonary edema (HAPE) susceptible mountaineers. It was investigated whether measurement of basal pulmonary artery pressure (Ppa) and brain natriuretic peptide (BNP) could improve identification of HAPE susceptible subjects in a non-mountaineer population. We studied BNP levels, baseline hemodynamics and the response to hypoxia (FIo2 = 0.12 for 30 min duration at sea level) in 11 HAPE resistant (no past history of HAPE, Control) and 11 HAPE susceptible (past history of HAPE, HAPE-S) subjects. Baseline Ppa (19.31 ± 3.63 vs 15.68 ± 2.79 mm Hg, p < 0.05) and plasma BNP levels (52.39 ± 32.9 vs 15.05 ± 9.6 pg/ml, p < 0.05) were high and stroke volume was less (p < 0.05) in HAPE-S subjects compared to control. Acute hypoxia produced an exaggerated increase in heart rate (p < 0.05), mean arterial pressure (p < 0.05) and Ppa (28.2 ± 5.8 vs 19.33 ± 3.74 mm Hg, p < 0.05) and fall in peripheral oxygen saturation (p < 0.05) in HAPE-S compared to control. Receiver operating characteristic (ROC) curves showed that Ppa response to acute hypoxia was the best variable to identify HAPE susceptibility (AUC 0.92) but BNP levels provided comparable information (AUC 0.85). BNP levels are easy to determine and may represent an important marker for the determination of HAPE susceptibility.

Effect of dietary protein on intake, nutrients utilization, nitrogen balance, blood metabolites, growth and puberty in growing Bhadawari buffalo (Bubalus bubalis) heifers.

Fifteen Bhadawari buffalo heifers of 207 ± 9.78 kg mean body weight were randomly distributed into three dietary groups to evaluate the effect of protein level on nutrient utilization, nitrogen (N) balance, growth rate, blood metabolites, and puberty. All animals were offered wheat straw-berseem diets supplemented with concentrate mixtures of similar energy (2.7 Mcal/kg) and different protein levels (14.3-22%). Animals of standard-protein group (SPG) were offered protein and energy as per requirement, while animals of low-protein group (LPG) and high-protein group (HPG) were fed 20% less and 20% more protein, respectively, than SPG. Feed dry matter (DM) and metabolizable energy (ME) intake (% body wt. and g/kg w(0.75)) were similar for all three diets; however, the crude protein (CP) and digestible crude protein (DCP) intake on percent body weight and per kilogram metabolic weight was higher (P < 0.05) in HPG than in SPG or LPG. Digestibility of CP, cellulose, and hemicellulose was higher (P < 0.05) in HPG versus LPG. Fecal N excretion was similar, while urinary N excretion was highest (P < 0.05) in HPG (74.83 g/day) compared with SPG (50.03 g/day) and LPG (47.88 g/day), which resulted in lower N retention in HPG than in the other dietary groups. Level of dietary N had no effect on blood metabolites viz. glucose, urea, and N. Digestible energy (DE) and ME contents of diets were identical, while DCP contents were higher (P < 0.05) in HPG than in LPG. Feed and nutrient (CP and ME) conversion efficiency to produce a unit kilogram weight gain was identical among the dietary groups. Dietary protein level had no effect on the heifer's weight and age at puberty. The mean growth rate of heifers at 240 days was higher (P > 0.05) in SPG (330.8 g/day) than in LPG (296.7 g/day), while the animals gained more weight in January to March months and the lowest weight in May to July months. Protein level had no effect on conception rate of heifers. Results revealed that 20% higher or less protein than the ICAR requirement had no significant (P > 0.05) on feed intake, nutrient conversion efficiency for weight gain, heifer growth, and puberty; however, 20% more protein increased urinary N loss.

Long-term stay at low altitude (1,200 m) promotes better hypoxia adaptation and performance.

Acute exposure to high altitude hypoxia is known to decrease physical performance. The exercise performance increases during moderate altitude training (2000-3000 m) but benefits are overshadowed by adverse effect associated with hypoxia. Therefore, the study was designed to address whether low altitude of 1200 m could increase exercise performance without any adverse effects and a correlation with stay period (stay > 6 month) was optimized. In the present study residents of lower altitude (1200 m altitude) (LA) and sea level (SL) residents were subjected to sub-maximal exercise test and their exercise response in terms of post-exercise heart rate and change in oxygen saturation was compared. Post-exercise peak heart rate (129.89 ± 13.42 vs 146.00 ± 11.81, p < 0.05) was significantly lower and arterial oxygen saturation (SpO2) after exercise had a significant fall (95.3 ± 2.26% vs 98 ± 0% p < 0.001) in LA residents. The hematological parameters like hemoglobin (Hb) and hematocrit (Hct) taken as markers of physiological adaptation, were also found to be significantly higher in LA as compared to SL residents (Hb 16.13 ± 0.70 vs 14.2 ± 0.87, p < 0.001 and Hct 47.4 ± ?2.08 vs 44.0 ± ?0.72, p <0.001). Overall, the study highlights that physiological adaptation at 1200 m results into a better exercise response and hematological benefit compared to sea level residents.

Systematic review and meta-analysis of antimicrobial treatment effect estimation in complicated urinary tract infection.

Noninferiority trial design and analyses are commonly used to establish the effectiveness of a new antimicrobial drug for treatment of serious infections such as complicated urinary tract infection (cUTI). A systematic review and meta-analysis were conducted to estimate the treatment effects of three potential active comparator drugs for the design of a noninferiority trial. The systematic review identified no placebo trials of cUTI, four clinical trials of cUTI with uncomplicated urinary tract infection as a proxy for placebo, and nine trials with reports of treatment effect estimates for doripenem, levofloxacin, or imipenem-cilastatin. In the meta-analysis, the primary efficacy endpoint of interest was the microbiological eradication rate at the test-of-cure visit in the microbiological intent-to-treat population. The estimated eradication rates and corresponding 95% confidence intervals (CI) were 31.8% (26.5% to 37.2%) for placebo, 81% (77.7% to 84.2%) for doripenem, 79% (75.9% to 82.2%) for levofloxacin, and 80.5% (71.9% to 89.1%) for imipenem-cilastatin. The treatment effect estimates were 40.5% for doripenem, 38.7% for levofloxacin, 34.7% for imipenem-cilastatin, and 40.8% overall. These treatment effect estimates can be used to inform the design and analysis of future noninferiority trials in cUTI study populations.

Topical retapamulin ointment, 1%, versus sodium fusidate ointment, 2%, for impetigo: a randomized, observer-blinded, noninferiority study.

BACKGROUND: Retapamulin is a novel pleuromutilin antibacterial developed for topical use. OBJECTIVE: To compare the efficacy and safety of retapamulin ointment, 1% (twice daily for 5 days), with sodium fusidate ointment, 2% (3 times daily for 7 days), in impetigo. METHODS: A randomized (2:1 retapamulin to sodium fusidate), observer-blinded, noninferiority, phase III study in 519 adult and pediatric (aged > or = 9 months) subjects. RESULTS: Retapamulin and sodium fusidate had comparable clinical efficacies (per-protocol population: 99.1 and 94.0%, respectively; difference: 5.1%, 95% confidence interval: 1.1-9.0%, p = 0.003; intent-to-treat population: 94.8 and 90.1%, respectively; difference: 4.7%, 95% confidence interval: -0.4 to 9.7%, p = 0.062). Bacteriological efficacies were similar. Success rates in the small numbers of sodium-fusidate-, methicillin- and mupirocin-resistant Staphylococcus aureus were good for retapamulin (9/9, 8/8 and 6/6, respectively). Both drugs were well tolerated. CONCLUSION: Retapamulin is a highly effective and convenient new treatment option for impetigo, with efficacy against isolates resistant to existing therapies.