Impact of ABCB1 genetic polymorphism on carbamazepine dose requirement among Southern Indian persons with epilepsy.

OBJECTIVES: Carbamazepine (CBZ) is one of the oldest, yet first line drugs for treating epilepsy. However, there is a large inter-individual difference in requirement of maintenance dose and one third of persons treated with antiepileptic drugs (AEDs) exhibit drug resistance to therapy. One of the proposed mechanisms for the drug resistance was increased expression of efflux transporter P-glycoprotein. The pharmacogenetic studies of drug transporters (ABCB1) done in combination therapies of AEDs were inconclusive. Hence, we have attempted to study the impact of ABCB1 3435C>T genetic polymorphism and CBZ monotherapy in persons with epilepsy (PWE) from South India, which is a genetically distinct population. With this background, this study was aimed to determine the dose of CBZ in ABCB1 3435C>T genotypes and to determine the distribution of ABCB1 3435C>T genotypes (which codes P-glycoprotein) between responders and non-responders to CBZ therapy. METHODS: A cross sectional study was conducted in 200 persons with epilepsy, who were categorised as responders and non-responders according to ILAE (international league against epilepsy) criteria. Eligible participants were enrolled from the epilepsy clinic of the neurology department and five ml of blood was collected. DNA extraction and genotyping were done by phenol-chloroform method and real time polymerase chain reaction (RT-PCR), respectively. RESULTS: The mean maintenance dose of carbamazepine was statistically significant among different genotypes (p<0.05) of ABCB1 3435C>T (526 vs. 637 mg/day in CC vs. TT genotype). There was no significant association between ABCB1 3435C>T polymorphism (p=0.827) and CBZ resistance in PWE. Duration of disease and age of onset were found to be significant in predicting the response to CBZ therapy. CONCLUSIONS: We report that ABCB1 3435C>T polymorphism is significantly associated with an increase in dose requirement of CBZ in persons with epilepsy from South India.

Psychosis Related to Baclofen Withdrawal or Overdose: A Systematic Review.

OBJECTIVE: To systematically review case reports of psychosis related to withdrawal or overdose of baclofen, which is a gamma-aminobutyric acid (GABA) B agonist. METHODS: PubMed, MEDLINE, CINAHL, and PsychINFO were searched to identify articles related to psychosis secondary to withdrawal or overdose of baclofen using the terms 'baclofen' and ' psychosis'. Comparisons were made between cases in terms of concomitant antipsychotic use, diagnosis of delirium, and evidence of association. Quality of case reports was assessed using the CARE Case Report Guidelines checklist. RESULTS: In total, 34 patients from 28 case reports were reviewed. Twenty-three patients experienced psychosis upon baclofen withdrawal; among them, 18 had resolution of psychosis upon reinitiation of baclofen, whereas antipsychotic monotherapy was less successful (only four of eight patients responded). An additional baclofen withdrawal period led to recurrence of psychotic symptoms in four of seven patients. Eleven patients had psychosis on induction or after overdose of baclofen; among them, four patients had resolution of psychosis upon cessation of baclofen. The mean quality of the case reports was 6.4 of 13. CONCLUSION: Considering its GABAergic agonism, along with evidence of psychosis on induction or withdrawal, baclofen may have some antipsychotic and pro-psychotic properties.

Clinicopathological investigation of nutritional osteodystrophia fibrosa in a flock of young stall-fed goats.

Background: Osteodystrophia fibrosa (ODF) is a metabolic disorder affecting the skeletal system, causing progressive loss of calcified bone mass and its replacement with fibrous tissue, which may be a sequel to primary or secondary hyperparathyroidism. This report intends to document the clinicopathological findings of ODF in a flock of young goats fed primarily on a wheat bran-rich diet. Case description: In a flock of 50 stall-fed goats aged 1 to 2 years, seven were clinically presented with bilateral facial enlargement, leading to dyspnea and difficulty in prehension and mastication. Among the seven clinically affected goats, four died in 2 months. Findings/treatment and outcome: The clinical examination revealed bilateral mandibular enlargement and limb deformities. On radiography, the maxilla and mandible had decreased radiopacity. Fine needle aspiration cytology (FNAC) from the affected bones showed occasional fibroblasts and individual osteoclasts clusters. On necropsy, the enlarged mandible revealed a meaty consistency. Undecalcified histological sections of the mandible showed severe osteopenia, multiple osteoclasts, Howship's lacunae, and extensive fibroplasia. Dietary corrective measures led to the prevention of ODF in the rest of the flock. Conclusion: Excessive wheat bran feeding in stallfed goats might have led to calcium and phosphorus imbalance, resulting in nutritional secondary hyperparathyroidism and subsequent skeletal deformities. FNAC of the affected bones, gross and histological findings provide a clinicopathological diagnosis of ODF.

Molecular subtypes of invasive breast carcinoma of no special type, their correlation with histopathological features, Ki 67 index and tumor budding: A retrospective comparative study.

Context: Tumor budding (TB), poorly differentiated clusters (PDCs), and Ki 67 index are proven adverse prognostic factors in breast carcinoma. Though the relation of Ki 67 index with molecular subtypes of breast carcinoma have been extensively studied, there is very limited information on the role of TB and PDCs. Aims: To grade TB, PDCs, and Ki 67 index and assess histological features and relationship of all these with molecular subtypes of invasive breast carcinoma of no special type. Methods and Material: Retrospective study of 148 cases from 1/1/2019 to 30/12/2019. Division of molecular groups - Luminal A, Luminal B, Her2 neu positive, and triple-negative breast carcinomas (TNBC), and Ki 67 index grades based on St Gallen criteria, intratumoral and peritumoral TB and PDC grades as per the International Tumor Budding Consensus Conference (ITBCC) criteria for colon and correlation between these and other histological features with the molecular subtypes were done. Statistical Analysis: Chi-square test, univariate and multivariate logistic regression models were used. Results: Significant correlation was seen between TB and lymphovascular emboli, Luminal B tumors with high-grade TB and PDCs, Her 2 neu positive and TNBC tumors with low-grade TB, circumscribed tumor margins, tumor necrosis, and Luminal B, Her 2 neu positive and TNBC tumors with larger tumor size and high nuclear grades. Conclusions: TB and PDCs are useful in the prognostication of Luminal A and B tumors when the Ki 67 index values are low/intermediate. Her 2 neu positive and TNBC tumors have a high nuclear grade with necrosis and no association with TB or PDCs.

Acquired bedaquiline resistance in Karakalpakstan, Uzbekistan.

BACKGROUND: The WHO recommends the use of bedaquiline (BDQ) in longer, as well as shorter, multidrug-resistant TB (MDR-TB) treatment regimens. However, resistance to this new drug is now emerging. We aimed to describe the characteristics of patients in Karakalpakstan, Uzbekistan, who were treated for MDR-TB and acquired BDQ resistance during treatment.METHODS: We performed a retrospective study of routinely collected data for patients treated for MDR-TB in Karakalpakstan between January 2015 and December 2020. We included patients on BDQ-containing regimens with baseline susceptibility to BDQ who developed BDQ resistance at any point after treatment initiation. Patients resistant to BDQ at baseline or with no confirmed susceptibility to BDQ at baseline were excluded.RESULTS: Of the 523 patients who received BDQ-containing regimens during the study period, BDQ resistance was detected in 31 patients (5.9%); 20 patients were excluded-16 with no prior confirmation of BDQ susceptibility and 4 who were resistant at baseline. Eleven patients with acquired BDQ resistance were identified. We discuss demographic variables, resistance profiles, treatment-related variables and risk factors for unfavourable outcomes for these patients.CONCLUSION: Our programmatic data demonstrated the acquisition of BDQ resistance during or subsequent to receiving a BDQ-containing regimen in a patient cohort from Uzbekistan. We highlight the need for individualised treatment regimens with optimised clinical and laboratory follow up to prevent resistance acquisition.

Carbon Nitride Quantum Dot-Embedded Poly(vinyl alcohol) Transparent Thin Films for Greenish-Yellow Light-Emitting Diodes.

Recently, freestanding polymer thin films encapsulated with nanostructures have attracted the significant attention of the scientific community due to their promising application in portable optoelectronic devices. In this research contribution, we have fabricated a freestanding polymer thin film of poly(vinyl alcohol) (PVA) encapsulated with carbon nitride quantum dots (CN-QDs) using the casting method, for the first time. The PVA polymer matrix provides mechanical support as well as dispersion of the CN-QDs preventing its solid-state quenching. From UV-visible spectra, it is revealed that optical transparency decreases with an increase in the concentration of CN-QDs within the PVA polymeric thin film. Such kind of decrease in optical transparency is one of the crucial factors for the optical concert of a nanomaterial. Interestingly, we have optimized the synthesis protocol to retain 40% transparency of the thin film by incorporating 10 wt % CN-QDs along with PVA without deteriorating its optical behavior. It is observed that when CN-QDs are embedded in the PVA matrix, emission becomes independent of excitation wavelength and is localized in the 510-530 nm region of the spectrum. Thus, the films exhibit excellent greenish-yellow emission when excited at 420 nm with the Commission Internationale de l'èclairage (CIE) coordinates (0.39, 0.46) and a correlated color temperature (CCT) of 4105 K. These excellent optoelectronic properties make them a promising candidate for practical phosphor applications. In a nutshell, this study demonstrates a promising way to exhibit the luminescence potential of freestanding polymer/CN-QD films in CN-QD-based solid-state lighting systems.

Soil carbon stock and stability under Eucalyptus-based silvopasture and other land-use systems in the Cerrado biodiversity hotspot.

During the past few decades, commercial silvopastoral systems (SPS) with exotic Eucalyptus (hybrid) trees have become popular in the Brazilian Cerrado (savanna). With the increasing awareness about the role of carbon (C) storage in soils as a climate-change mitigation strategy and the relationship between the nature of soil aggregates and the soil's carbon sequestration potential, it is important to understand the influence of such SPS systems on soil organic carbon (SOC) storage. We studied C content in three aggregate size classes in six land-use systems on Oxisols in Minas Gerais, Brazil. The systems were planted forest, native secondary forest, managed pasture, and three 8-year-old SPS, differing in their tree-planting configurations. Eucalyptus hybrid was the tree in SPS and planted forest treatments, and Urochloa decumbens was the grass in SPS and pasture treatments. From each treatment, replicated soil samples were collected from four depth-classes (0-10, 10-30, 30-60, and 60-100 cm), fractionated by wet sieving into the three aggregate-size classes, 2000 to 250 µm, 250 to 53 µm, and <53 µm size classes representing macroaggregates, microaggregates, and silt + clay, respectively, and their C contents determined. Down to 1 m, total SOC stock values ranged from 260 Mg ha-1 under pasture to 167 Mg ha-1 under native forest, with 174 Mg ha-1 for Eucalyptus plantation and about 195 Mg ha-1 for the three SPS. Compared to the degraded native forest, the pasture system had significantly higher SOC in the whole soil and the aggregate size fractions, especially in the lower soil-depth classes. The lower SOC stock of Eucalyptus hybrid SPS compared to open pasture differs from the general trend of SPS having higher stock. Given that the Cerrado biome is a biodiversity hotspot, the use of native nitrogen-fixing trees, of which there are several, is worth investigating. In addition, the conversion from Eucalyptus monocultures to SPS could be considered as a strategy to increase the SOC stock.

Screening of Family Members of Nonalcoholic Fatty Liver Disease Patients can Detect Undiagnosed Nonalcoholic Fatty Liver Disease Among Them: Is There a Genetic Link?

BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) has multifactorial origin. Genetic and environmental factors lead to the biology of this complex disorder. In this study, we screened parents of cases with NAFLD and compared them with parents of cases without NAFLD to see its familial aggregation and the role of patatin-like phospholipase domain containing 3 (PNPLA3). METHOD: It was a cross-sectional study. Parents of probands with NAFLD and without NAFLD were screened with abdominal sonography, anthropometry, blood tests, transient elastography, and PNPLA3 polymorphism. RESULTS: We had enrolled 303 individuals: 51 probands with NAFLD, 50 probands without NAFLD, and their 202 parents. Parents of the NAFLD group had significantly higher metabolic risk factors as compared with parents of the non-NAFLD group. They had a significantly higher rate of fatty liver (P = 0.0001), mean serum aspartate aminotransferase levels (P = 0.011), mean serum alanine aminotransferase levels (P = 0.001),raised fasting and postprandial blood sugar levels, lower mean platelets (P = 0.033) and serum albumin levels (P = 0.005), and higher mean liver stiffness (P = 0.001) on transient elastography.Frequency of PNPLA3 polymorphism within NAFLD group was higher compared to the non-NAFLD group (mutant GG-13.3 vs 3.3%). Similarly, parents of NAFLD group had mutant GG in 15 % versus 5% in parents of non-NAFLD group, (P = 0.105, odds ratio 6), though it was not statistically significant but may be relevant. In this study, offsprings of parents with nonalcoholic steatohepatitis were likely to have GG homozygous allele. A NAFLD16 score based on parent's parameters was calculated to predict the probability of NAFLD occurrence in an overweight obese individual. CONCLUSION: Screening of parents of individuals with NAFLD will help in the identification of undiagnosed NAFLD cases and other metabolic risk factors among them as there is a familial aggregation of NAFLD. One can predict the occurrence of NAFLD in the next generation using the NAFLD16 score.

Optical and thermal properties of edible coatings for application in solar drying.

Solar drying is a sustainable process that may impact the quality of dried food. This is because, pigments contained in food are sensitive to sunlight, and exposure to ultraviolet radiation can affect them. We applied biopolymer-based coatings on strawberry, from hydro-colloidal solutions of Opuntia ficus indica-mucilage, fenugreek, xanthan gum, gum Arabic, and guar gum to evaluate their potential use as UV filters for solar drying of food. Thermal properties and the optical transmittance, absorbance and reflectance of the coatings were measured to assess their influence on food-sunlight interaction. During the drying experiments, the moisture content, total anthocyanins (TA), and total phenolic compounds (TPC) were measured. Optical and thermal properties are influenced by the biopolymer-based coatings. Also, the optical properties are influenced by the coating thickness. The differences in optical and thermal properties influence the drying process. Differences exist in the drying rate for strawberry slices with coating, compared with those without the coatings. In general, the TA and TPC content in the product are better preserved under solar drying than in control experiments done in a drying oven. A partial transmittance of solar UV radiation is recommended to obtain increased TA and TPC contents in the dried product.

Duration of Caffeine for Apnea of Prematurity-A Randomized Controlled Trial.

OBJECTIVES: There is sufficient evidence to support use of caffeine therapy for apnea of prematurity, but practices vary widely when it comes to discontinuing therapy. This study was planned to compare 'recurrence of apnea of prematurity' (RAP); when 2 protocols were used to stop caffeine therapy. METHODS: Neonates delivered at 26-32 wk gestation on caffeine therapy for apnea of prematurity were randomized into 2 groups: Group 1-caffeine stopped at 7 d apnea-free period, and Group 2-continued for a prefixed period till at least 34 wk postmenstrual age (PMA). Proportion of infants in each group with RAP were analyzed. RESULTS: Each group consisted of 60 infants. Proportion of infants in each group with RAP, were not different (15% vs 13%); odds ratio (OR) 0.87; 95% confidence interval (CI) (0.31-2.43). Caffeine could be stopped earlier (33 vs 34 wk PMA); and cumulative duration of therapy was lesser (19.5 vs 33 d) when stopped at 7 d apnea-free period. Other studied outcomes were similar between the two groups. CONCLUSIONS: Mandatorily continuing caffeine therapy up to 34 wk PMA in select preterm groups does not seem to decrease risk of recurrence of apnea. Larger trials that specifically study extremely preterm infants are required to make robust recommendations on when to stop therapy. CLINICAL TRIALS REGISTRY OF INDIA NO: CTRI/2016/12/007559. http://ctri.nic.in/Clinicaltrials/pdf_generate.php?trialid=14195&EncHid=&modid=&compid=%27,%2714195det%27.

Sodium caseinate hinders chymosin-induced aggregation of caseins in concentrated milk: The role of soluble caseins and calcium ions.

Concentrated casein micelle suspensions show an altered balance between the colloidal and soluble phases compared with native skim milk. The objective of this research was to probe the role of such a change on the chymosin-driven destabilization of casein micelles. Skim milk was gently concentrated by osmotic stressing to increase the volume fraction of the micelles while maintaining a constant ionic composition. In situ turbidity measurements demonstrated that the secondary stage of gelation was hindered in the concentrated suspensions. Addition of ionic calcium overcame this inhibition, whereas restoring the original concentration by redilution did not. This work clearly demonstrated that calcium plays a major role in decreasing electrostatic repulsion in casein micelles, but also showed the importance of noncolloidal proteins in altering the gelling functionality of casein micelles in concentrated milk. Additional calcium induces aggregation of these soluble caseins, restoring gelation in concentrates.

Low cost, high efficiency flexible supercapacitor electrodes made from areca nut husk nanocellulose and silver nanoparticle embedded polyaniline.

Energy storage is a key aspect in the smooth functioning of the numerous gadgets that aid easy maneuvering through modern life. Supercapacitors that store energy faradaically have recently emerged as potential inventions for which mechanical flexibility is an absolute requirement for their future applications. Flexible supercapacitors based on nanocellulose extracted from easily available waste materials via low cost methods have recently garnered great attention. In the present work, we discuss the construction of flexible, binder-free supercapacitive electrodes using nanocellulose extracted from locally available areca nut husks and polyaniline embedded with silver nanoparticles. The prepared electrodes were characterized using SEM, TEM, XRD, FTIR, EDX and electrochemical characterization techniques such as CV, galvanostatic charge-discharge, chronoamperometry and EIS. A specific capacitance of 780 F g-1 was obtained for the silver nanoparticle embedded polyaniline-nanocellulose (Ag-PANI-NC) substrate supported electrodes, which is ∼4.2 times greater than that of bare polyaniline-nanocellulose electrodes. We attributed this enhancement to a lowering of the activation energy barrier of correlated electron hopping among localized defect states in the composite matrix by the Ag nanoparticles. An energy density value of 15.64 W h kg-1 and a power density of 244.8 W kg-1 were obtained for the prepared electrodes. It was observed that the Ag-PANI-NC based electrode can retain ∼98% of its specific capacitance upon recovery from mechanical bending to extreme degrees.

Setting up pharmacovigilance based on available endTB Project data for bedaquiline.

SETTING: Active pharmacovigilance (PV) is recommended for TB programmes, notably for multidrug-resistant TB (MDR-TB) patients treated with new drugs. Launched with the support of UNITAID in April 2015, endTB (Expand New Drug markets for TB) facilitated treatment with bedaquiline (BDQ) and/or delamanid of >2600 patients in 17 countries, and contributed to the creation of a central PV unit (PVU).OBJECTIVE: To explain the endTB PVU process by describing the serious adverse events (SAEs) experienced by patients who received BDQ-containing regimens.DESIGN: The overall PV strategy was in line with the 'advanced´ WHO active TB drug safety monitoring and management (aDSM) system. All adverse events (AEs) of clinical significance were followed up; the PVU focused on signal detection from SAEs.RESULTS and CONCLUSION: Between 1 April 2015 and 31 March 2019, the PVU received and assessed 626 SAEs experienced by 417 BDQ patients. A board of MDR-TB/PV experts reviewed unexpected and possibly drug-related SAEs to detect safety signals. The experts communicated on clusters of risks factors, notably polypharmacy and off-label drug use, encouraging a patient-centred approach of care. Organising advanced PV in routine care is possible but demanding. It is reasonable to expect local/national programmes to focus on clinical management, and to limit reporting to aDSM systems to key data, such as the SAEs.

Exacerbations of Severe Asthma While on Anti-IL-5 Biologics.

Anti-interleukin 5 (IL-5) and anti-IL-5 receptor α monoclonal antibodies markedly decrease airway and peripheral blood eosinophil numbers and are thus highly effective in reducing asthma exacerbations. Nonetheless, these biologics do not completely resolve exacerbations. There is very little information on the cellular nature of exacerbations during treatment with biologics. Using illustrative clinical case scenarios, we highlight the importance of carefully characterizing asthmatics at the time of exacerbation and recognizing neutrophilic causes of exacerbations to ensure optimal management. While an eosinophilic exacerbation may improve with more corticosteroids or by switching to another anti-IL-5 monoclonal antibody, a noneosinophilic exacerbation will likely not. An infective exacerbation needs to be recognized, and the pathogen must be identified and treated with the appropriate antimicrobial agent.

Strontium ion reinforced bioceramic scaffold for load bearing bone regeneration.

Bone defects in load bearing areas require bone reconstruction with strong biomaterial having mechanical characteristics like cortical bone. Bioceramics are biomaterials that support bone formation as well as provide adequate mechanical properties. A strontium substitution of the bioceramic is expected to further increase its bioactivity by enhancing osteogenesis and protect the bone from osteoclastic resorption. The study involves development, characterization and in vivo testing of a newly developed strontium substituted hydroxyapatite based bioceramic scaffold (SrHAB) with sufficient biomechanical properties. Optimal concentration of strontium ion required for enhanced osteogenic differentiation was identified by comparing three compositions of SrHAB scaffold; namely Sr10HAB, Sr30HAB and Sr50 HAB for their Alkaline phosphatase activity in vitro. The selected Sr10HAB scaffold demonstrated in vivo bone formation with osteogenic differentiation of stromal derived mesenchymal stem cells (MSC) from human and ovine sources in ectopic and ovine models. Thus, Sr10HAB scaffold has a potential for application in load bearing bone requirements of orthopaedics and dentistry.

The 2020 International Alliance for the Control of Scabies Consensus Criteria for the Diagnosis of Scabies.

BACKGROUND: Scabies is a common parasitic skin condition that causes considerable morbidity globally. Clinical and epidemiological research for scabies has been limited by a lack of standardization of diagnostic methods. OBJECTIVES: To develop consensus criteria for the diagnosis of common scabies that could be implemented in a variety of settings. METHODS: Consensus diagnostic criteria were developed through a Delphi study with international experts. Detailed recommendations were collected from the expert panel to define the criteria features and guide their implementation. These comments were then combined with a comprehensive review of the available literature and the opinion of an expanded group of international experts to develop detailed, evidence-based definitions and diagnostic methods. RESULTS: The 2020 International Alliance for the Control of Scabies (IACS) Consensus Criteria for the Diagnosis of Scabies include three levels of diagnostic certainty and eight subcategories. Confirmed scabies (level A) requires direct visualization of the mite or its products. Clinical scabies (level B) and suspected scabies (level C) rely on clinical assessment of signs and symptoms. Evidence-based, consensus methods for microscopy, visualization and clinical symptoms and signs were developed, along with a media library. CONCLUSIONS: The 2020 IACS Criteria represent a pragmatic yet robust set of diagnostic features and methods. The criteria may be implemented in a range of research, public health and clinical settings by selecting the appropriate diagnostic levels and subcategories. These criteria may provide greater consistency and standardization for scabies diagnosis. Validation studies, development of training materials and development of survey methods are now required. What is already known about this topic? The diagnosis of scabies is limited by the lack of accurate, objective tests. Microscopy of skin scrapings can confirm the diagnosis, but it is insensitive, invasive and often impractical. Diagnosis usually relies on clinical assessment, although visualization using dermoscopy is becoming increasingly common. These diagnostic methods have not been standardized, hampering the interpretation of findings from clinical research and epidemiological surveys, and the development of scabies control strategies. What does this study add? International consensus diagnostic criteria for common scabies were developed through a Delphi study with global experts. The 2020 International Alliance for the Control of Scabies (IACS) Criteria categorize diagnosis at three levels of diagnostic certainty (confirmed, clinical and suspected scabies) and eight subcategories, and can be adapted to a range of research and public health settings. Detailed definitions and figures are included to aid training and implementation. The 2020 IACS Criteria may facilitate the standardization of scabies diagnosis.