Noise and thermal performance of a sub-attofarad capacitance sensor for precision measurements, with applications in gravitational wave detectors.

We describe the design principles, fabrication, and characterization of a precision AC resonant capacitance bridge (RCB) sensor, based on a resonant differential planar printed circuit board transformer with a solid (ungapped) MnZn ferrite core, demonstrating a short-term sensitivity at 293 K of 0.225 ± 0.005 aF/√Hz at around 120 kHz resonance frequency and 1 Hz Fourier measurement frequency. At 120 K, the RCB short term noise sensitivity is 0.118 ± 0.005 aF/√Hz. We compare the ungapped configuration to five different RCBs: three with a core gap of 65 µm and two with a core gap of 130 µm. Their average room temperature short term noise sensitivities are 0.30 ± 0.01 and 0.45 ± 0.01 aF/√Hz, while the cryogenic operation of these transformers at 120 K resulted in averaged sensitivities of 0.23 ± 0.01 and 0.36 ± 0.01 aF/√Hz, respectively. Multi-hour room temperature runs, with one core of each of the three gap types, proved the stability of their long-term sensitivities of 0.234 ± 0.005, 0.338 ± 0.009, and 0.435 ± 0.010 aF/√Hz for the ungapped (40-h duration) and the 65 and 130 µm (28-h duration) cores, respectively. At 0.1 mHz, a critical frequency for space gravitational wave detectors, the respective sensitivities are 0.25 ± 0.02, 0.35 ± 0.02, and 0.53 ± 0.07 aF/√Hz. Measurements with the ungapped transformer configuration for temperatures from 325 to 349 K further validate the dependence of the noise model on temperature and permeability. The performance of our RCB with an ungapped core matches the calculated performance value and shows an improvement in signal-to-noise ratio of two or more compared with capacitance bridges developed for similar applications. A further factor of about two noise reductions is achieved by cooling to 120 K.

Pembrolizumab monotherapy versus chemotherapy in platinum-pretreated, recurrent or metastatic nasopharyngeal cancer (KEYNOTE-122): an open-label, randomized, phase III trial.

BACKGROUND: Pembrolizumab previously demonstrated robust antitumor activity and manageable safety in a phase Ib study of patients with heavily pretreated, programmed death ligand 1 (PD-L1)-positive, recurrent or metastatic nasopharyngeal carcinoma (NPC). The phase III KEYNOTE-122 study was conducted to further evaluate pembrolizumab versus chemotherapy in patients with platinum-pretreated, recurrent and/or metastatic NPC. Final analysis results are presented. PATIENTS AND METHODS: KEYNOTE-122 was an open-label, randomized study conducted at 29 sites, globally. Participants with platinum-pretreated recurrent and/or metastatic NPC were randomly assigned (1 : 1) to pembrolizumab or chemotherapy with capecitabine, gemcitabine, or docetaxel. Randomization was stratified by liver metastasis (present versus absent). The primary endpoint was overall survival (OS), analyzed in the intention-to-treat population using the stratified log-rank test (superiority threshold, one-sided P = 0.0187). Safety was assessed in the as-treated population. RESULTS: Between 5 May 2016 and 28 May 2018, 233 participants were randomly assigned to treatment (pembrolizumab, n = 117; chemotherapy, n = 116); Most participants (86.7%) received study treatment in the second-line or later setting. Median time from randomization to data cut-off (30 November 2020) was 45.1 months (interquartile range, 39.0-48.8 months). Median OS was 17.2 months [95% confidence interval (CI) 11.7-22.9 months] with pembrolizumab and 15.3 months (95% CI 10.9-18.1 months) with chemotherapy [hazard ratio, 0.90 (95% CI 0.67-1.19; P = 0.2262)]. Grade 3-5 treatment-related adverse events occurred in 12 of 116 participants (10.3%) with pembrolizumab and 49 of 112 participants (43.8%) with chemotherapy. Three treatment-related deaths occurred: 1 participant (0.9%) with pembrolizumab (pneumonitis) and 2 (1.8%) with chemotherapy (pneumonia, intracranial hemorrhage). CONCLUSION: Pembrolizumab did not significantly improve OS compared with chemotherapy in participants with platinum-pretreated recurrent and/or metastatic NPC but did have manageable safety and a lower incidence of treatment-related adverse events.

Use of anti-inflammatory analgesics in sickle-cell disease.

WHAT IS KNOWN AND OBJECTIVE: Non-steroidal anti-inflammatory drugs (NSAIDs) have been commonly used to treat pain in sickle-cell disease (SCD), but NSAID use is associated with renal, gastrointestinal and cardiovascular toxicities. Our objective was to evaluate the use of aspirin and non-aspirin NSAIDs in SCD. COMMENT: Despite analgesic and anti-inflammatory benefits in SCD, non-aspirin NSAIDs are associated with renal, cardiovascular and gastrointestinal toxicities in this patient population. Aspirin may have less renal and cardiovascular toxicities. The different side effect profile of NSAIDs is related to the COX-1/COX-2 selectivity at their therapeutic doses. Individual risk factors and genetic biomarkers should be considered when selecting appropriate NSAIDs and their dose. WHAT IS NEW AND CONCLUSION: NSAIDs have the potential to be an important component of pain regimens in SCD, but the use of NSAIDs should be individualized based on potential side effects and patient risk factors and the lowest effective dose should be prescribed with proper monitoring in patients with SCD.

Safety and antitumor activity of the anti-PD-1 antibody pembrolizumab in patients with recurrent carcinoma of the anal canal.

Background: Safety and efficacy of pembrolizumab, a humanized programmed death 1 monoclonal antibody, was assessed in KEYNOTE-028, a multicohort, phase Ib trial for patients with programmed death ligand 1 (PD-L1)-positive advanced solid tumors. We report results for the cohort of patients with advanced anal carcinoma. Patients and methods: Patients with PD-L1-positive tumors (≥1%) received intravenous pembrolizumab 10 mg/kg once every 2 weeks for up to 2 years or until confirmed progression or unacceptable toxicity. Response was assessed every 8 weeks for the first 6 months and every 12 weeks thereafter per Response Evaluation Criteria In Solid Tumors, version 1.1. Primary endpoints were safety and overall response rate per investigator review. Secondary endpoints included progression-free survival, overall survival, and response duration. Data cutoff date was 1 July 2015. Results: Of the 43 patients with advanced anal carcinoma evaluable for PD-L1 expression, 32 (74%) had PD-L1-positive tumors as assessed with the 22C3 prototype assay, of whom 25 were enrolled between April and September 2014. Sixteen patients (64%) experienced treatment-related adverse events; the most common ones were diarrhea and fatigue in four patients (16%) each and nausea in three patients (12%). There were no treatment-related deaths or discontinuations as of the data cutoff date. Among the 24 patients with squamous cell carcinoma histology, four had confirmed partial response, for an overall response rate of 17% [95% confidence interval (CI), 5%-37%) and 10 (42%) had confirmed stable disease, for a disease control rate of 58%. One additional patient with non-squamous histology had confirmed stable disease. Conclusion: In this population of patients with PD-L1-positive advanced squamous cell anal carcinoma, pembrolizumab demonstrated a manageable safety profile and encouraging antitumor activity. These data support further study of pembrolizumab for this patient population. ClinicalTrials.gov: NCT02054806.

Quantitative Assessment of Muscle Activity and Joint Load in Braced and Unbraced Osteoarthritis Knee by External Strain Gauge Sensor.

OBJECTIVES: Altered biomechanics leads to the development of degenerative joint disease. The joint pressure and dynamic loading varies during activities of daily living. The study was undertaken to assess the muscle activation pattern of the medial and lateral knee compartments (tibiofemoral joint) during gait in osteoarthritis subjects without and with knee brace undergoing either exercise therapy or balance therapy. The joint load was assessed by the strain gauge transducer and the weight shift pattern is taken as an indicator for the muscle activation pattern. METHODS: In a prospective design study on 57 male subjects diagnosed osteoarthritis knee with Kellagren-Lawrennce scale walked barefooted with and without designed offloader knee brace on a level surface for three minutes. The subjects were allocated in two different study groups i.e. Conventional (exercise therapy) (Control Group, n=31) and Structured Neuromuscular Postural Training (SNPT) group (Balance therapy) (Study Group, n=26). The subjects were sub grouped as pre-elderly (40-60 Years) and elderly (>61 years) group in both. The quantitative assessment of muscle activity and joint loading with and without knee brace was done using designed strain gauge sensor instrument. The pressure changes of strain gauges of muscles around the knee joint viz. vastus medialis (VM), vastus lateralis (VL), semi membranosus/tendinosus (Medial Hamstring) (MH), Biceps Femoris (Lateral Hamstring) (LH), gastro-soleus (GS) and tibialis anterior (TA) muscles during normal gait were observed at baseline and 6 weeks follow up after undergoing exercise therapy or balance therapy treatment as per allocation of study groups. The digital values from MATLAB were recorded and analyzed. RESULTS: At the end of 6 weeks conventional/SNPT (structured neuromuscular postural training) treatments, medial hamstring muscle activity showed significant difference (p<0.001) in pre-elderly subgroup, while significant difference was seen in vastus laterals (VL), medial hamstring (MH) (p<0.005) and lateral hamstring (LH) muscles (p<0.001) in elderly subgroup. Further, the muscle co-contraction has been higher for vastus medialis-medial hamstring (VM-MH) pair compared to vastus lateralis-lateral hamstring (VL-LH) pair without brace at baseline. The application of offloader valgus knee brace significantly increases VL-LH co-contractions in magnitude and decreases in VM-MH co-contractions at 6 weeks follow up. CONCLUSION: Muscle activity increased in medial hamstring both in pre-elderly and elderly subjects. While, Vastus Laterals and lateral hamstring showed increased activities in elderly subjects. Hence, balance training and the application of off loader knee brace will be helpful to redistribute the load on medial tibiofemoral compartment.

Effect of palonosetron (5HT-3 antagonist) and pantoprazole (proton pump inhibitor) against surgical esophagitis induced by forestomach and pylorus ligation in albino rats.

This study was embarked upon to evaluate the effects of pantoprazole and palonosetron on experimental esophagitis in albino wistar rats. Groups of rats, fasted for 36 h, were subjected to pylorus and forestomach ligation, supervened by treatment with normal saline (3 ml/kg, po, sham control), esophagitis control (3 ml/kg, po), pantoprazole (30 mg/kg, po), palonosetron (0.5 mg/kg, po), and their combination. Animals were sacrificed after 12 h and appraised for the volume of gastric juices, total acidity, free acidity, and esophagitis index. Esophageal tissues were further figured out biochemically for markers of oxidative stress and inflammatory mediators. The combination therapy comparably inhibited the esophagitis index (52.86%), gastric volume (66.04%), free acidity (43.76%), and total acidity (42.60%) in comparison with toxic control. The combination therapy also subsidized the biochemical and inflammatory markers to the purview less than toxic control. The morphological changes were scrutinized by scanning electron microscopy and were observed to demonstrate momentous protection by the amalgamation therapy. Combination therapy with pantoprazole and palonosetron flaunted sententious protection against experimental esophagitis.

Introducing dental hygienists in general practice to research - an in-practice evaluation programme in the United Kingdom.

AIM: To introduce dental hygienists (DHs) in the UK to the principles of research through a practice-based product evaluation programme. METHODS: The programme consisted of an initial training and orientation day with presentations on evidence-based practice, research methods and the structure of research papers. The programme and its aims were explained in detail, and participants were briefed on the methods to be used. Participants then recruited seven to ten patients from their practices (offices), carried out a baseline assessment of: plaque, gingival health, calculus and staining at anterior teeth, and gave the patients a questionnaire asking about their teeth and then provided a 3-month supply of a test toothpaste. About 10 weeks later, a follow-up assessment of the same variables was performed and the questionnaire was repeated. A second training day followed during which the DHs provided feedback of their experiences and received training in literature searching and critical appraisal of literature including interpretation of results. RESULTS: Sixty-five DHs attended the first training day; 31 were able to recruit sufficient patients and attend the second training day. The DHs recruited 168 patients who received baseline and follow-up assessments. All the variables improved overall. Feedback from the DHs was very positive, and patients expressed delight with the care they had received. CONCLUSIONS: Qualitative feedback for participating DHs suggests the programme met its aim and could be used in the future as a mechanism for helping DHs who want to increase their understanding of research methodology.

Procedural and follow-up outcomes among patients undergoing successful recanalisation of coronary chronic total occlusions using biolimus drug-eluting stents.

This study aimed at evaluating the outcome of Biolimus eluting stent (BES) implantation in the treatment of chronic total coronary occlusions (CTO). We identified patients who underwent successful angioplasty for a CTO lesion with ≥1 BES between June 2008 and March 2012. All patients were followed up for major adverse cardiac events (MACE), which comprised death, non-fatal myocardial infarction (MI), cerebrovascular accident, target vessel revascularization (TVR), target lesion revascularization (TLR) and stent thrombosis. 125 patients underwent successful CTO angioplasty with ≥1 Biolimus-eluting stents. Mean age was 63.8 ± 12.0 years, and 82.4 % were males. Lesion location was right coronary artery (n = 80, 64 %), left anterior descending artery (n = 35, 28 %) and left circumflex artery (n = 10, 8 %). During follow-up of 579 ± 293 days, all cause mortality was n = 8 (6.4 %) patients, non-fatal MI was n = 3 (2.4 %), TVR was n = 3 (2.4 %) and TLR was n = 1 (0.8 %). Overall MACE was, therefore, n = 15 (12 %). BES is safe and effective in treatment of CTO lesions, with a low rate of major adverse cardiovascular events during follow-up.

Surface modification of poly (l-lactic acid) microspheres for site-specific delivery of ketoprofen for chronic inflammatory disease.

The purpose of this research was to investigate the potential of surface modified Poly (l-lactic acid) (PLA) microspheres as a carrier for site-specific delivery of anti-inflammatory drug, ketoprofen, for the treatment of rheumatoid arthritis. Microspheres were prepared by solvent evaporation method using 20% w/w PLA in methylene chloride and 100 mL of a 2.5% poly vinyl alcohol (PVA) solution. Formulations were optimized for several processing parameters like drug to polymer ratio, stirring rate and volume of preparation medium etc. The surface of PLA microspheres was modified with gelatin to impart fibronectin recognition. The microspheres were characterized by surface morphology, size distribution, encapsulation efficiency, and by in vitro drug release studies. The prepared microspheres were light yellow, discrete, and spherical. Formulation with optimum drug to polymer ratio exhibited smallest vesicle size (43.02), high drug encapsulation efficiency (81.11) and better process yield (83.45). The release of drug was extended up to 24 h with Higuchi pattern of drug release. The in vivo results showed that the gelatin modified formulation reduced paw edema at greater extent than pure drug and PLA microspheres and it could be a promising carrier system for controlled and site-specific delivery of ketoprofen with possible clinical applications.

Effect of Linum usitatissimum (linseed/flaxseed) fixed oil on experimental esophagitis in albino rats.

INTRODUCTION: The present study was undertaken to elucidate the effect of Linum usitatissimum fixed oil on experimental esophagitis in albino rats. METHODS: Group of rats (n = 6), treated with vehicle control (0.9% NaCl, 3 mL/kg, i.p.) or L. usitatissimum fixed oil (1, 2, 3 mL/kg, i.p.) or omeprazole (30 mg/kg, i.p.). Rats were subjected to pylorus and forestomach ligation to induce esophagitis and were compared to a control sham group. Animals were sacrificed after 6 h and evaluated for the gastric pH, gastric volume, total acidity and esophagitis index. Esophageal tissues were further subjected to estimations of sialic acid, collagen, thiobarbituric acid reactive substances, tissue glutathione, catalase and superoxide dismutase. RESULTS: Treatment with fixed oil significantly inhibited the gastric secretion, total acidity and esophagitis index. The oil also altered the levels of sialic acid and collagen towards normal with significant antioxidant activity in esophageal tissues. CONCLUSION: The lipoxygenase inhibitory, histamine antagonistic, antisecretory (anticholinergic) and antioxidant activity of the oil was attributed for its effect in reflux esophagitis.

Paradoxical decrease in HDL-cholesterol and apolipoprotein A1 with simvastatin and atorvastatin in a patient with type 2 diabetes.

Statins are agents widely used to lower LDL-cholesterol (LDL-C) in primary and secondary prevention of coronary heart disease. The five statins available in the UK (simvastatin, pravastatin, fluvastatin, atorvastatin and rosuvastatin) differ in many of their pharmacologic properties. In addition to lowering LDL-C, statins also increase HDL-cholesterol (HDL-C) moderately. There have been rare reports of significant HDL-C decreases in patients commenced on fibrates and when thiazolidinediones are added to fibrates. This is known as a 'paradoxical HDL-C decrease' as both groups of agents usually increase HDL-C. This phenomenon has never been clearly documented following statin therapy. We now describe a patient with type 2 diabetes who showed this paradoxical fall in HDL-C (baseline HDL-C: 1.8 mmol/L; on simvastatin 40 mg HDL-C 0.6 mmol/L; on atorvastatin 20 mg HDL-C 0.9 mmol/L) with a similar decrease in apolipoprotein A1. No similar decrease was observed with pravastatin and rosuvastatin therapy. This phenomenon appeared to be associated with statin treatment and not a statin/fibrate combination. Our patient clearly demonstrated a paradoxical HDL-C fall with simvastatin and atorvastatin, but not pravastatin or rosuvastatin. Simvastatin and atorvastatin share many pharmacokinetic properties such as lipophilicity while pravastatin and rosuvastatin are relatively hydrophilic and are not metabolized by cytochrome P450 3A4. However, these characteristics do not explain the dramatic reductions in HDL-C observed.

Applications of novel drug delivery system for herbal formulations.

Over the past several years, great advances have been made on development of novel drug delivery systems (NDDS) for plant actives and extracts. The variety of novel herbal formulations like polymeric nanoparticles, nanocapsules, liposomes, phytosomes, nanoemulsions, microsphere, transferosomes, and ethosomes has been reported using bioactive and plant extracts. The novel formulations are reported to have remarkable advantages over conventional formulations of plant actives and extracts which include enhancement of solubility, bioavailability, protection from toxicity, enhancement of pharmacological activity, enhancement of stability, improved tissue macrophages distribution, sustained delivery, and protection from physical and chemical degradation. The present review highlights the current status of the development of novel herbal formulations and summarizes their method of preparation, type of active ingredients, size, entrapment efficiency, route of administration, biological activity and applications of novel formulations.

Phytoconstituents as photoprotective novel cosmetic formulations.

Phytoconstituents are gaining popularity as ingredients in cosmetic formulations as they can protect the skin against exogenous and endogenous harmful agents and can help remedy many skin conditions. Exposure of skin to sunlight and other atmospheric conditions causes the production of reactive oxygen species, which can react with DNA, proteins, and fatty acids, causing oxidative damage and impairment of antioxidant system. Such injuries damage regulation pathways of skin and lead to photoaging and skin cancer development. The effects of aging include wrinkles, roughness, appearance of fine lines, lack of elasticity, and de- or hyperpigmentation marks. Herbal extracts act on these areas and produce healing, softening, rejuvenating, and sunscreen effects. We have selected a few photoprotective phytoconstituents, such as curcumin, resveratrol, tea polyphenols, silymarin, quercetin and ascorbic acid, and have discussed the considerations to be undertaken for the development of herbal cosmetic formulations that could reduce the occurrence of skin cancer and delay the process of photoaging. This article is aimed at providing specific and compiled knowledge for the successful preparation of photoprotective herbal cosmetic formulations.

Crocus sativus L.: A comprehensive review.

Crocus sativus L. belonging to the family Iridaceae (syn - kesar) comprises the dried red stigma and is widely cultivated in Iran and other countries such as India and Greece. Saffron contains more than 150 volatile and aroma-yielding compounds mainly terpenes, terpene alcohol, and their esters. The bitter taste and an iodoform or hay-like fragrance are caused by chemicals picrocrocin and safranal. C. sativus possesses a number of medicinally important activities such as antihypertensive, anticonvulsant, antitussive, antigenototoxic and cytotoxic effects, anxiolytic aphrodisiac, antioxidant, antidepressant, antinociceptive , anti-inflammatory, and relaxant activity. It also improves memory and learning skills, and increases blood flow in retina and choroid. The present review explores the historical background, chemical constituents, pharmacological actions, uses, substitutes and adulterants, and toxicity. It also deals with its evaluation, formulations, and chemical tests in detail.