Assessing the effect of soil cultivation methods and genotypes on crop yield components, yield and soil properties in wheat (Triticum aestivum L.) and Rice (Oryza sativa L.) cropping system.

BACKGROUND: The rice-wheat cropping system is the prevailing agricultural method in the North-Western states of India, namely in the Indo-Gangetic plains. The practice of open burning of rice residue is frequently employed for expedient land preparation, but it has significant adverse impacts on both the environment and human health. These include the emission of greenhouse gases, loss of nutrients, elevated concentrations of particulate matter (PM), and disruption of the biological cycle. This research aims to investigate the implementation of effective management strategies in the rice-wheat cropping system, namely via the use of tillage-based crop cultivation techniques, stubble retention, and integration approaches. The objective is to enhance soil health features in order to augment crop yield and improve its attributes. RESULTS: The research was carried out using a split plot experimental design, consisting of three replications. The main plot consisted of four different cultivation methods, while the subplot included three genotypes of both rice and wheat. The research demonstrates the enhanced efficacy of residue application is significantly augmenting soil nutrient concentrations compared to standard tillage practices (P < 0.05). This was accomplished by an analysis of soil nutrient levels, namely nitrogen (N), phosphorus (P), potassium (K), and organic carbon (OC), at a depth of 0-15 cm. The implementation of natural farming, zero tillage, and reduced tillage practices resulted in decreases in rice grain yields of 34.0%, 16.1%, and 10.8%, respectively, as compared to conventional tillage methods. Similarly, the implementation of natural farming, zero tillage, and reduced tillage resulted in reductions in wheat grain yields of 59.4%, 10.9%, and 4.6% respectively, in comparison to conventional tillage practices. CONCLUSION: Regarding the individual crop genotypes investigated, it was continuously observed that Him Palam Lal Dhan 1 and HPW 368 displayed considerably greater grain yields for both rice and wheat during the two-year experimental period. Furthermore, when considering different cultivation methods, conventional tillage emerged as the most effective approach for obtaining higher productivity in both rice and wheat. Additionally, Him Palam Lal Dhan 1 and HPW 368 exhibited superior performance in terms of various crucial yield components for rice (such as panicle density, grains per panicle, panicle weight, and test weight) and wheat (including effective tiller density, grains per spike, spike weight, and 1000-grain weight).

Cancer insights from magnetic resonance spectroscopy of cells and excised tumors.

Multinuclear ex vivo magnetic resonance spectroscopy (MRS) of cancer cells, xenografts, human cancer tissue, and biofluids is a rapidly expanding field that is providing unique insights into cancer. Starting from the 1970s, the field has continued to evolve as a stand-alone technology or as a complement to in vivo MRS to characterize the metabolome of cancer cells, cancer-associated stromal cells, immune cells, tumors, biofluids and, more recently, changes in the metabolome of organs induced by cancers. Here, we review some of the insights into cancer obtained with ex vivo MRS and provide a perspective of future directions. Ex vivo MRS of cells and tumors provides opportunities to understand the role of metabolism in cancer immune surveillance and immunotherapy. With advances in computational capabilities, the integration of artificial intelligence to identify differences in multinuclear spectral patterns, especially in easily accessible biofluids, is providing exciting advances in detection and monitoring response to treatment. Metabolotheranostics to target cancers and to normalize metabolic changes in organs induced by cancers to prevent cancer-induced morbidity are other areas of future development.

Benefit of prompt initiation of single-inhaler fluticasone furoate, umeclidinium, and vilanterol (FF/UMEC/VI) in patients with COPD in England following an exacerbation: a retrospective cohort study.

BACKGROUND: Triple therapy is recommended for patients with chronic obstructive pulmonary disease (COPD) who remain symptomatic despite dual therapy. The optimal timing of triple therapy following an exacerbation of COPD is unknown. The outcomes of prompt (≤ 30 days) vs. delayed (31-180 days) initiation of single-inhaler triple therapy with fluticasone furoate, umeclidinium, and vilanterol (FF/UMEC/VI) following an exacerbation of COPD were examined. METHODS: This was a retrospective cohort study of linked English primary (Clinical Practice Research Datalink) and secondary (Hospital Episode Statistics) care data. Patients aged ≥ 35 years with COPD were indexed on the first and/or earliest date of exacerbation between November 15, 2017 and March 31, 2019 with subsequent FF/UMEC/VI initiation within 180 days. Patients were required to be continuously registered with a general practitioner for ≥ 12 months prior to and following index. Subsequent exacerbations, direct medical costs, and hospital readmissions were compared between prompt and delayed initiators. Inverse probability of treatment weighting was used to adjust for measured confounders between cohorts. RESULTS: Overall, 1599 patients were included (prompt: 393, delayed: 1206). After weighting, prompt initiators had numerically lower moderate/severe exacerbations compared with delayed initiators (rate ratio: 0.87, 95% confidence interval [CI]: 0.76-1.01, p = 0.0587). Both all-cause and COPD-related 30-day hospital readmissions were significantly lower among patients with prompt initiation compared with delayed initiators (all-cause: 23.6% vs. 34.6%, odds ratio [95% CI]: 0.58 [0.36-0.95], p = 0.0293; COPD-related: 20.3% vs. 30.6%, odds ratio [95% CI]: 0.58 [0.35-0.96], p = 0.0347). Prompt initiators also had numerically lower all-cause total costs and significantly lower COPD-related costs per-person-per year compared with delayed initiators (COPD-related: £742 vs. £801, p = 0.0016). CONCLUSION: Prompt initiation of FF/UMEC/VI following a moderate/severe exacerbation was associated with fewer subsequent exacerbations, fewer hospital readmissions, and lower COPD-related medical costs compared with delayed initiation.

Triple therapy with an inhaled corticosteroid (ICS), a long-acting muscarinic antagonist (LAMA), and a long-acting ß2-agonist (LABA) is recommended for patients with chronic obstructive pulmonary disease (COPD) who still experience symptoms while taking dual therapy (LABA/LAMA or ICS/LABA). Triple therapy can be taken using single or multiple inhalers. The best time to start triple therapy for patients who may benefit from it following a short-term worsening (flare-up) of their COPD symptoms is unknown. This study assesses the effect of starting treatment with triple therapy sooner compared with later in patients with COPD.Patients who experienced a flare-up of their COPD symptoms were split into two groups ­ those who started taking triple therapy (via a single inhaler) within 30 days of their symptom flare-up and those who started taking triple therapy 31­180 days following their symptom flare-up. Over the 12 months following the initial flare-up, patients who started triple therapy earlier (within 30 days) had fewer subsequent symptom flare-ups, fewer hospital admissions, and lower healthcare costs compared with patients who started triple therapy later (31­180 days). These findings suggest that doctors should consider prescribing triple therapy (via a single inhaler) to their patients with COPD straight away if they experience a flare-up of their symptoms.

Graphitic carbon nitride (g-C3N4)-assisted materials for the detection and remediation of hazardous gases and VOCs.

Graphitic carbon nitride (g-C3N4)-based materials are attracting attention for their unique properties, such as low-cost, chemical stability, facile synthesis, adjustable electronic structure, and optical properties. These facilitate the use of g-C3N4 to design better photocatalytic and sensing materials. Environmental pollution by hazardous gases and volatile organic compounds (VOCs) can be monitored and controlled using eco-friendly g-C3N4- photocatalysts. Firstly, this review introduces the structure, optical and electronic properties of C3N4 and C3N4 assisted materials, followed by various synthesis strategies. In continuation, binary and ternary nanocomposites of C3N4 with metal oxides, sulfides, noble metals, and graphene are elaborated. g-C3N4/metal oxide composites exhibited better charge separation that leads to enhancement in photocatalytic properties. g-C3N4/noble metal composites possess higher photocatalytic activities due to the surface plasmon effects of metals. Ternary composites by the presence of dual heterojunctions improve properties of g-C3N4 for enhanced photocatalytic application. In the later part, we have summarised the application of g-C3N4 and its assisted materials for sensing toxic gases and VOCs and decontaminating NOx and VOCs by photocatalysis. Composites of g-C3N4 with metal and metal oxide give comparatively better results. This review is expected to bring a new sketch for developing g-C3N4-based photocatalysts and sensors with practical applications.

Effect of low-level laser therapy plus exercise therapy on pain, range of motion, muscle strength, and function in knee osteoarthritis - a systematic review and meta-analysis.

BACKGROUND: Knee osteoarthritis (KOA) is commonly associated with multiple musculoskeletal impairments. OBJECTIVE: The purpose of this review was (1) to investigate the effectiveness of LLLT plus ET on pain, ROM, muscle strength, and function in KOA immediately after therapy and (2) whether the effectiveness of LLLT plus ET could be sustained at follow-up (4 - 32 weeks). METHODS: Six databases were systematically searched upto December 2021 to find relevant articles. Included studies were RCTs written in English, which compared LLLT plus ET with placebo LLLT plus ET in KOA. Three independent reviewers extracted data and assessed the quality of included studies. Standard mean difference (SMD) was used in meta-analysis using random effect model. RESULT: Of the 6307 articles, 14 RCTs (820 patients) met the inclusion criteria. The results demonstrated that there was a significant difference in pain immediately after therapy (SMD: -0.58, p = 0.001) and at follow-up (SMD: -1.35, p = 0.05) in LLLT plus ET group. There were no significant differences in knee ROM, muscle strength, and knee function outcomes immediately and at follow-up. CONCLUSION: Our findings indicate that LLLT plus ET could be considered to alleviate pain in the KOA. LLLT reduces pain at 4-8J with a wavelength of 640-905nm per point applied for 10-16 sessions at a frequency of 2 sessions/week. An exercise therapy program at prescribed dosage involving major muscle groups might help. However, LLLT plus ET is no more effective than placebo LLLT plus ET in improving ROM, muscle strength, and function in KOA.

Blood flow restriction therapy with exercise are no better than exercise alone in improving athletic performance, muscle strength, and hypertrophy: a systematic review and meta-analysis.

BACKGROUND: The benefits of Blood Flow Restriction Therapy (BFRT) have gained attention in recent times. OBJECTIVE: This review aimed to evaluate the immediate (up to 24 hours), intermediate (up to 6 weeks), and long term (6-10 weeks) effects of BFRT plus exercises (EX) compared to EX only on athletic performance (sprint and jump performance), muscle strength, and hypertrophy in athletes and physically active population. METHODS: A literature search was conducted to select randomized controlled trials across four electronic databases from inception till April 2021. The search yielded twenty-seven studies in total. RESULTS: Based on eligibility criteria, twenty-one studies were analyzed. No differences were found between both groups for immediate (standardized mean difference [SMD] -0.02, 95% confidence interval [CI] -0.31, 0.27) and long-term effects (SMD -0.30, 95%CI -0.90, 0.30) on sprint performance. For jump performance, no significant effect was observed immediately (SMD -0.02 (95% CI -1.06, 1.02) and long term (SMD -0.40 (95% CI -1.46, 0.67). Similarly, muscle torque at intermediate (SMD 0.90 (95% CI -1.01, 2.81) and long term (SMD -0.54 (95% CI -1.19, 0.12), muscle strength at intermediate (SMD 1.12 (95% CI 0.20, 2.04) , and long term (SMD -0.07 (95% CI -0.56, 0.42) also showed non-significant effects. Muscle hypertrophy at intermediate (SMD 0.16 (95% CI -0.31, 0.63) and long term (SMD -0.20 (95% CI -0.90, 0.50) were not statistically significant. CONCLUSIONS: There was no significant difference observed in BFRT plus EX group compared to the EX-group on athletic performance, muscle strength, and muscle hypertrophy.

'It's helped me to learn to deal with it': a mixed methods service evaluation of a multicomponent fibromyalgia service.

OBJECTIVES: To evaluate the Royal London Hospital for Integrated Medicine (RLHIM) multicomponent fibromyalgia service. METHODS: Mixed methods approach consisting of the completion of validated quantitative outcome measures (Patient Health Questionnaire-9; Generalised Anxiety Disorder-7; Pain Catastrophising Scale; Patient Self-Efficacy Questionnaire) pre- and post-treatment to explore the impact of treatment; and qualitative focus groups with patients at their follow-up appointments to explore patients' experiences and perspectives on the service. RESULTS: 138 fibromyalgia patients attended the RLHIM group fibromyalgia service during the period of the evaluation. Baseline scores demonstrate that patients were significantly impaired pre-treatment according to all outcome measures. At the end of the course of treatment, scores for all outcome measures showed clinically and statistically significant improvements. These improvements were maintained at both 6- and 9-month follow-up appointments. Qualitative analysis indicated that those participating valued the multicomponent treatment approach, and perceived the service as having a positive impact on their fibromyalgia and overall quality of life, enabling patients to effectively manage their condition. CONCLUSIONS: Patients attending the RLHIM multicomponent fibromyalgia service appear to have demonstrable improvements in presenting symptoms, and quality of life. The findings support a multicomponent approach to the treatment of fibromyalgia.

Dose-response and temporal ergogenic effects of ginseng supplementation in athletes and active participants: A systematic review and meta-analysis.

This review sought to assess the dose-response, i.e., low (<300 mg/day) and high (>300 mg/day), and temporal effects of ginseng, i.e., immediate, short-term (up to 4 weeks) and long-term (>4 weeks) in comparison to placebo on physical performance [visual analogue scale (VAS) level, vertical jump(VJ), rating of perceived exertion (RPE), peak power output (PPO)] and physiological measures [VO2 max, creatine kinase(CK), heart rate(HR)], in athletes and active participants. Search in four databases with English language constraints yielded 492 studies. Fourteen studies were shortlisted through PEDro scale by methodological quality evaluation. Ginseng exhibited significant short-term effect at high dosage for VJ improvement (SMD: -8.17, 95% CI: -16.28 to -0.06, p= 0.05). Ginseng had no effect on VAS (SMD: -0.65, 95% CI: -1.35 to 0.06, p= 0.07), RPE (SMD: -1.11, 95% CI: -2.57 to 0.35, p= 0.14), PPO (SMD: -0.70, 95% CI: -1.78 to 0.38, p= 0.20), HR (SMD: -0.54, 95% CI: -2.05 to 0.96, p= 0.48), CK (SMD: 0.33, 95% CI: -0.18 to 0.84, p= 0.21) and VO2 max (SMD: 0.08, 95% CI: -0.69 to 0.85, p= 0.08).The ginseng supplementation was found to have significant short-term effect at high dose only for VJ in athletic and active participants. Methodologically strong research is warranted to further consolidate these findings.

Outcome of Atypical & Complex Clubfoot Managed by Modified Ponseti Method-A Prospective Study.

Atypical or complex clubfoot constitutes a small number of cases. Due to the difference in complexity of anatomy, standard deformity correction by Ponseti is not effective. Hence a modified Ponseti method was advised which focuses on deformity differences for treatment. We conducted a prospective study to analyze the outcome in atypical or complex clubfoot treated with the modified Ponseti method. All the children of age less than 1 year were included in the study with atypical or complex clubfoot. Every case was treated according to the modified Ponseti method and tenotomy. Pirani scores were measured at pretreatment, each visit, before application of a brace, and at the latest follow-up. Statistical analysis of all continuous and categorical variables was done. A total of 30 patients (47 feet) were included in the study. Mean Pirani score improved from 5.69 at presentation to 0.45 at time of brace application and latest follow-up 0.34 (p < .001). Six patients (9 feet) had a relapse which was managed with recasting. The mean Pirani score of relapse was 0.72, which after correction reduced to 0.11 (p = .008). Six patients had cast-related complications which were managed with conservative treatment. With an increase in popularity of the Ponseti method, a greater number of complex clubfoot cases are seen due to inadequate reduction or slippage of cast or improper cast application techniques. All these need to be identified at an early age. This helps in proper treatment and improves the quality of life as well as foot appearance.

A randomised controlled trial of the effect of a connected inhaler system on medication adherence in uncontrolled asthmatic patients.

Suboptimal adherence to maintenance therapy contributes to poor asthma control and exacerbations. This study evaluated the effect of different elements of a connected inhaler system (CIS), comprising clip-on inhaler sensors, a patient-facing app and a healthcare professional (HCP) dashboard, on adherence to asthma maintenance therapy.This was an open-label, parallel-group, 6-month, randomised controlled trial in adults with uncontrolled asthma (asthma control test (ACT) score less than 20) on fixed-dose inhaled corticosteroids/long-acting ß-agonist maintenance therapy (n=437). All subjects received fluticasone furoate/vilanterol ELLIPTA dry-powder inhalers for maintenance and salbutamol/albuterol metered-dose inhalers for rescue, with a sensor attached to each inhaler. Participants were randomised to one of five CIS study arms (allocation ratio 1:1:1:1:1) reflecting the recipient of the data feedback from the sensors, as follows: 1) maintenance use to participants and HCPs (n=87); 2) maintenance use to participants (n=88); 3) maintenance and rescue use to participants and HCPs (n=88); 4) maintenance and rescue use to participants (n=88); and 5) no feedback (control) (n=86).For the primary endpoint, observed mean±sd adherence to maintenance therapy over months 4-6 was 82.2±16.58% (n=83) in the "maintenance to participants and HCPs" arm and 70.8±27.30% (n=85) in the control arm. The adjusted least squares mean±se was 80.9±3.19% and 69.0±3.19%, respectively (study arm difference: 12.0%, 95% CI 5.2-18.8%; p<0.001). Adherence was also significantly greater in the other CIS arms versus the control arm. The mean percentage of rescue medication free days (months 4-6) was significantly greater in participants receiving data on their rescue use compared with controls. ACT scores improved in all study arms with no significant differences between groups.A CIS can improve adherence to maintenance medication and reduce rescue medication use in patients with uncontrolled asthma.

Carbon footprint impact of the choice of inhalers for asthma and COPD.

In the 1990s, metered dose inhalers (MDIs) containing chlorofluorocarbons were replaced with dry-powder inhalers (DPIs) and MDIs containing hydrofluorocarbons (HFCs). While HFCs are not ozone depleting, they are potent greenhouse gases. Annual carbon footprint (CO2e), per patient were 17 kg for Relvar-Ellipta/Ventolin-Accuhaler; and 439 kg for Seretide-Evohaler/Ventolin-Evohaler. In 2017, 70% of all inhalers sold in England were MDI, versus 13% in Sweden. Applying the Swedish DPI and MDI distribution to England would result in an annual reduction of 550 kt CO2e. The lower carbon footprint of DPIs should be considered alongside other factors when choosing inhalation devices.

Daclatasvir and reduced-dose sofosbuvir: An effective and pangenotypic treatment for hepatitis C in patients with estimated glomerular filtration rate <30 mL/min.

AIM: Sofosbuvir is a key agent for HCV treatment. It is not recommended for patients with chronic kidney disease (CKD) and estimated glomerular filtration rate (eGFR) <30 mL/min. We report real-life experience of treating a cohort of CKD patients with eGFR <30 mL/min using daclatasvir and half-daily dose of sofosbuvir. METHODS: Adults patients who (i) had eGFR<30 mL/min and detectable HCV RNA and (ii) were treated with interferon and ribavirin free, DAA based regimens were included. All patients were treated with daily doses of daclatasvir 60 mg and sofosbuvir 200 mg. The planned duration of treatment was 12 weeks, except for 24 weeks in those with either clinical evidence of cirrhosis or on immunosuppressive drugs. The end-points of the study were: (i) 12 weeks of follow-up after treatment completion, (ii) treatment discontinuation, or (iii) death or loss to follow-up. RESULTS: Thirty-six (88%) among 41 included patients (median [range] age: 48 [19-75] years; 25 [61%] male; genotype 1/3/4 were 17/ 22/2; cirrhosis 5) completed the treatment, two discontinued and three died during treatment. On an intention-to-treat basis, HCV RNA were undetectable at 4 weeks of treatment, treatment completion and after 12 weeks of follow-up in 40/41 (97.6%), 37/41 (90.2%) and 37/41 (90.2%), respectively. None of the patients had a relapse. CONCLUSIONS: Daclatasvir and half-daily dose of sofosbuvir was effective against genotype 1 and 3 HCV infection in patients with eGFR <30 mL/min. This combination could be a pangenotypic treatment option for such patients.

Cardiac structure and function after revascularization versus medical therapy for renal artery stenosis: the ASTRAL heart echocardiographic sub-study.

BACKGROUND: The ASTRAL trial showed no difference in clinical outcomes between medical therapy and revascularization for atherosclerotic renal vascular disease (ARVD). Here we report a sub-study using echocardiography to assess differences in cardiac structure and function at 12 months. METHODS: ASTRAL patients from 7 participating centres underwent echocardiography at baseline and 12 months after randomisation. Changes in left ventricular ejection fraction (LVEF), left ventricular mass (LVM), left atrial diameter (LAD), aortic root diameter (AoRD), E:A, and E deceleration time (EDT) were compared between study arms. Analyses were performed using t-tests and multivariate linear regression. RESULTS: Ninety two patients were included (50 medical versus 42 revascularization). There was no difference between arms in any baseline echocardiographic parameter. Comparisons of longitudinal changes in echocardiographic measurements were: δLVEF medical 0.8 ± 8.7% versus revascularization - 2.8 ± 6.8% (p = 0.05), δLVM - 2.9 ± 33 versus - 1.7 ± 39 g (p = 0.9), δLAD 0.1 ± 0.4 versus 0.01 ± 0.5 cm (p = 0.3), δAoRD 0.002 ± 0.3 versus 0.06 ± 0.3 cm (p = 0.4), δE:A - 0.0005 ± 0.6 versus 0.03 ± 0.7 (p = 0.8), δEDT - 1.1 ± 55.5 versus - 9.0 ± 70.2 ms (p = 0.6). In multivariate models, there were no differences between treatment groups for any parameter at 12 months. Likewise, change in blood pressure did not differ between arms (mean δsystolic blood pressure medical 0 mmHg [range - 56 to + 54], revascularization - 3 mmHg [- 61 to + 59], p = 0.60). CONCLUSIONS: This sub-study did not show any significant differences in cardiac structure and function accompanying renal revascularization in ASTRAL. Limitations include the small sample size, the relative insensitivity of echocardiography, and the fact that a large proportion of ASTRAL patient population had only modest renal artery stenosis as described in the main study.

Correct use and ease of use of a placebo dry powder inhaler in subjects with asthma and chronic obstructive pulmonary disease.

Correct use and ease of use of a placebo dry powder inhaler was evaluated in two single-arm, United States-multicenter, phase-IV studies in adults with asthma ( n = 259) or chronic obstructive pulmonary disease (COPD; n = 278) who were receiving maintenance inhaler therapy. Subjects demonstrating correct placebo inhaler use within three attempts at screening were instructed to take once-daily inhalations from the inhaler for 28 ± 2 days (continuing usual maintenance), followed by randomization to complete one of two versions of an ease-of-use questionnaire and reassessment for correct inhaler use. At study end, 96% asthma/93% COPD subjects rated the placebo inhaler as "easy" or "very easy" to use while demonstrating correct use. Furthermore, 99% asthma/99% COPD subjects indicated it was "easy" or "very easy" to determine number of doses remaining, and 81%/84%, respectively, indicated they would be "likely" or "very likely" to request their current medication in the inhaler, if available. Adverse event (AE) rates were 12% asthma/15% COPD, most frequently headache (3%/3%). Treatment-related AEs were reported in one subject with asthma (cough) and four subjects with COPD (cough, n = 3; back pain, n = 1). At study end, most subjects with asthma or COPD operated the placebo inhaler correctly and found it easy to use.

Fmoc-phenylalanine displays antibacterial activity against Gram-positive bacteria in gel and solution phases.

In the quest for new antimicrobial materials, hydrogels of Fmoc-protected peptides and amino acids have gained momentum due to their ease of synthesis and cost effectiveness; however, their repertoire is currently limited, and the mechanistic details of their function are not well understood. Herein, we report the antibacterial activity of the hydrogel and solution phases of Fmoc-phenylalanine (Fmoc-F) against a variety of Gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA). Fmoc-F, a small molecule hydrogelator, reduces the bacterial load both in vitro and in the skin wound infections of mice. The antibacterial activity of Fmoc-F is predominantly due to its release from the hydrogel. Fmoc-F shows surfactant-like properties with critical micelle concentration nearly equivalent to its minimum bactericidal concentration. Similar to Fmoc-F, some Fmoc-conjugated amino acids (Fmoc-AA) have also shown antibacterial effects that are linearly correlated with their surfactant properties. At low concentrations, where Fmoc-F does not form micelles, it inhibits bacterial growth by entering the cell and reducing the glutathione levels. However, at higher concentrations, Fmoc-F triggers oxidative and osmotic stress and, alters the membrane permeabilization and integrity, which kills Gram-positive bacteria. Herein, we proposed the use of the Fmoc-F hydrogel and its solution for several biomedical applications. This study will open up new avenues to enhance the repertoire of Fmoc-AA to act as antimicrobial agents and improve their structure-activity relationship.

A Randomized Clinical Trial Comparing the ELLIPTA and HandiHaler Dry Powder Inhalers in Patients With COPD: Inhaler-Specific Attributes and Overall Patient Preference.

This randomised, open-label, cross-over, placebo-containing inhaler study assessed patient preference indicators for ELLIPTA and HandiHaler dry powder inhalers in patients with COPD (NCT02786927; GSK identifier: 204983). The primary objective of this study was to assess patient preference between ELLIPTA and HandiHaler based on the number of steps needed to use the inhaler. Eligible patients ≥40 years of age with COPD were randomised 1:1 to receive their current COPD medication plus a placebo-containing ELLIPTA or HandiHaler inhaler once daily for 7 ± 2 days (treatment period 1); this was followed by a 7 ± 2-day placebo treatment with the alternative inhaler. A 5-item questionnaire assessed inhaler-related patient preferences. A total of 212 patients (mean age, 65.1 years) were enrolled at 22 US sites; 73% had a COPD duration ≥5 years. Median (range) exposure was 8 ( 5 , 13 ) days for ELLIPTA and 8 ( 1 , 16) days for HandiHaler. Significantly more patients preferred ELLIPTA to HandiHaler in terms of the number of steps to use and all secondary attributes (size, comfort of the mouthpiece, remaining doses, and ease of use of the two inhalers; all p < 0.001). Similar results were observed irrespective of the order of inhaler use. Eighteen patients (8%) reported at least one AE and two (<1%) patients reported four non-fatal SAEs; none were related to the study treatment. Patient attitude toward a particular inhaler and their experiences in using it can affect adherence to therapy, which can in turn strongly influence effectiveness of inhaled medications. This study uses a robust methodology to assess patient preference.

NMR Spectroscopy-based Metabolomics of Drosophila Model of Huntington's Disease Suggests Altered Cell Energetics.

Huntington's disease (HD) is a neurodegenerative disorder induced by aggregation of the pathological form of Huntingtin protein that has expanded polyglutamine (polyQ) repeats. In the Drosophila model, for instance, expression of transgenes with polyQ repeats induces HD-like pathologies, progressively correlating with the increasing lengths of these repeats. Previous studies on both animal models and clinical samples have revealed metabolite imbalances during HD progression. To further explore the physiological processes linked to metabolite imbalances during HD, we have investigated the 1D 1H NMR spectroscopy-based metabolomics profile of Drosophila HD model. Using multivariate analysis (PCA and PLS-DA) of metabolites obtained from methanolic extracts of fly heads displaying retinal deformations due to polyQ overexpression, we show that the metabolite imbalance during HD is likely to affect cell energetics. Six out of the 35 metabolites analyzed, namely, nicotinamide adenine dinucleotide (NAD), lactate, pyruvate, succinate, sarcosine, and acetoin, displayed segregation with progressive severity of HD. Specifically, HD progression was seen to be associated with reduction in NAD and increase in lactate-to-pyruvate ratio. Furthermore, comparative analysis of fly HD metabolome with those of mouse HD model and HD human patients revealed comparable metabolite imbalances, suggesting altered cellular energy homeostasis. These findings thus raise the possibility of therapeutic interventions for HD via modulation of cellular energetics.

1H nuclear magnetic resonance (NMR)-based serum metabolomics of human gallbladder inflammation.

OBJECTIVE AND DESIGN: We present in this article 1H nuclear magnetic resonance (NMR)-based metabolic approach to screen the serum metabolic alterations in human gallbladder inflammation with chronic cholecystitis (CC). MATERIAL/METHODS: Total of 71 human serum samples was divided into two groups, (n = 41, CC) and (n = 30 control). 1H NMR metabolic profiling was carried out for investigation of metabolic alterations. Multivariate statistical analysis was applied for pattern recognition and identification of metabolites playing crucial role in gallbladder inflammation. Receiver operating curve (ROC) and pathway analysis on NMR data were also carried out to validate the findings. RESULTS: Serum metabolites such as glutamine, low-density lipoprotein (LDL), very low-density lipoprotein (VLDL), alanine, branch chained amino acids (BCAA), histidine and tyrosine were found to be depleted whereas formate, lactate, 1,2-propanediol were found to be elevated in CC. Metabolic pathways associated with metabolite alteration have also been reported. CONCLUSIONS: NMR has been established for disease diagnosis along with identification of metabolic pattern recognition in biofluids. Gallstones cause inflammation of the gallbladder in the form of CC. Inflammation plays a major role in causation of gall bladder cancer and leads the way to malignancy. Metabolic analysis of CC may lead to early diagnosis of disease and its progression to gallbladder cancer.

Safety and effectiveness of response-guided therapy using pegylated interferon and ribavirin for chronic hepatitis C virus infection in patients on maintenance dialysis.

AIM: Treatment of hepatitis C virus (HCV) infection in patients with end-stage renal disease (ESRD) is difficult. Addition of ribavirin to pegylated-interferon (Peg-IFN) may help to improve the treatment response. Further, treatment duration could be shortened using a response-guided treatment (RGT) approach. METHODS: We retrospectively reviewed records of treatment-naïve adult patients with ESRD and chronic HCV infection who had been treated with Peg-IFN and low-dose ribavirin using a RGT approach. Rapid responders (undetectable HCV-RNA at 4 weeks) received treatment for 12 weeks, and slow responders (HCV-RNA detectable at 4 weeks, but undetectable or with >2.0 log10 reduction at week 12) for 24 (genotype 3; GT3) or 48 (genotype 1; GT1) weeks. In those without such reduction (null responders), treatment was discontinued. RESULTS: Of 26 non-cirrhotic patients (GT1 15, GT3 11) treated, four (15%; GT1 3, GT3 1) were null responders. Twenty-two (85%) patients had either rapid (n = 14 (54%); GT1 10, GT3 4) or slow response (n = 8 (31%); GT1 2, GT3 6). Of them, 21 patients had undetectable RNA at the end of treatment; one could not complete the treatment and was lost thereafter. There were no deaths during treatment. Three patients relapsed and three others died in 6 months after stopping treatment. Overall, 15/26 (58%) patients attained SVR24. Fourteen patients underwent transplantation beginning one month after treatment completion, and all were relapse-free after 17 (14-24) months of follow-up. CONCLUSION: RGT using Peg-IFN and ribavirin was effective in ESRD patients on maintenance dialysis. Renal transplant was safely done within one month of completing such treatment.