Physiologically Based Pharmacokinetic Modeling To Guide Management of Drug Interactions between Elexacaftor-Tezacaftor-Ivacaftor and Antibiotics for the Treatment of Nontuberculous Mycobacteria.

Nontuberculous mycobacteria (NTM) are the pathogens of concern in people with cystic fibrosis (pwCF) due to their association with deterioration of lung function. Treatment requires the use of a multidrug combination regimen, creating the potential for drug-drug interactions (DDIs) with cystic fibrosis transmembrane conductance regulator (CFTR)-modulating therapies, including elexacaftor, tezacaftor, and ivacaftor (ETI), which are eliminated mainly through cytochrome P450 (CYP) 3A-mediated metabolism. An assessment of the DDI risk for ETI coadministered with NTM treatments, including rifabutin, clofazimine, and clarithromycin, is needed to provide appropriate guidance on dosing. The CYP3A-mediated DDIs between ETI and the NTM therapies rifabutin, clarithromycin, and clofazimine were evaluated using physiologically based pharmacokinetic (PBPK) modeling by incorporating demographic and physiological "system" data with drug physicochemical and in vitro parameters. Models were verified and then applied to predict untested scenarios to guide continuation of ETI during antibiotic treatment, using ivacaftor as the most sensitive CYP3A4 substrate. The predicted area under the concentration-time curve (AUC) ratios of ivacaftor when coadministered with rifabutin, clofazimine, or clarithromycin were 0.31, 2.98, and 9.64, respectively, suggesting moderate and strong interactions. The simulation predicted adjusted dosing regimens of ETI administered concomitantly with NTM treatments, which required delayed resumption of the standard dose of ETI once the NTM treatments were completed. The dosing transitions were determined based on the characteristics of the perpetrator drugs, including the mechanism of CYP3A modulation and their elimination half-lives. This study suggests increased doses of elexacaftor/tezacaftor/ivacaftor 200/100/450 mg in the morning and 100/50/375 mg in the evening when ETI is coadministered with rifabutin and reduced doses of elexacaftor/tezacaftor 200/100 mg every 48 h (q48h) and ivacaftor 150 mg daily or a dose of elexacaftor/tezacaftor/ivacaftor 200/100/150 mg q72h when coadministered with clofazimine or clarithromycin, respectively. Importantly, the PBPK simulations provide evidence in support of the use of treatments for NTM in pwCF receiving concomitant dose-adjusted ETI therapy.

Role of interventional radiology in the management of morbidly adherent placenta.

The incidence of morbidly adherent placenta is rising and is directly proportional to the rate of rise of caesarean deliveries. Despite improvement in antenatal diagnosis, by accuracy of ultrasound and MRI techniques, placenta accreta is still associated with a high maternal morbidity rate. Management of pregnancies with a morbidly adherent placenta is extremely challenging and is becoming an increasingly common problem for maternity units globally. The main challenges include controlling the haemorrhage and dissection of the invaded tissues. Traditionally, these cases were managed by caesarean hysterectomy. There has now been a shift towards conservative management of placenta accreta, involving uterine and placental conservation, with the aid of interventional radiology by means of insertion of occluding balloons into appropriate vessels. We describe three cases of morbidly adherent placentas, managed at our unit where meticulous preoperative planning, multidisciplinary approach and the key role of interventional radiology led to a safe outcome for both the mother and the baby.

Comparative evaluation of the effects of an alum-containing mouthrinse and a saturated saline rinse on the salivary levels of Streptococcus mutans.

BACKGROUND: The literature is replete with studies establishing Streptococcus mutans as a major player in the formation of pit and fissure caries in all dentitions. Salivary bacterial levels in turn are related to the number of colonized surfaces. Therefore, decreasing the salivary levels of S. mutans would have a great benefit in decreasing the incidence of dental diseases. AIMS: Keeping in mind the potential antimicrobial effects of saturated saline and alum solutions, the present study was attempted to compare and evaluate the effects of saturated saline rinse and 0.02 M alum mouthrinse on salivary S. mutans levels in children. MATERIALS AND METHODS: The investigation was a double-blind, stratified comparison of three parallel groups of children who used either saturated saline rinse, 0.02 M alum mouthrinse or distilled water (placebo) rinse twice daily under professional supervision for a 21-day period. A total of three saliva samples were taken from each individual - at baseline, on the 10 th day and on the 21 st day, and colony counts of S. mutans were determined. All data were subjected to statistical analysis using Wilcoxon's Signed Ranks Sum and Mann-Whitney "U" test. RESULTS AND CONCLUSIONS: Children using saturated saline rinse and alum rinse showed statistically significant reductions in salivary S. mutans counts after 10 days and also after 21 days. After 21 days, the saturated saline rinse and alum rinse groups showed statistically significant differences over the placebo rinse group. Again, the alum rinse group showed a statistically significant difference over the saturated saline rinse group.

Diversified genomic contribution among south Indian populations--a study on four endogamous groups of Andhra Pradesh.

BACKGROUND: The present study examines genomic variation among three tribal (Nayakpod, Thoti and Kolam) and a caste (Niyogi Brahmin) population groups of Andhra Pradesh, south India. AIM: The present study examined the genomic diversity of the populations in relation to other population groups of India using 20 autosomal loci. SUBJECTS AND METHODS: A total of 204 blood samples from the population groups described above were collected and analysis was carried out following standard protocols. RESULTS: All markers were found to be polymorphic in these groups except AluCD4 among Thotis. High average heterozygosity values (0.3927 among Thotis to 0.4268 among Brahmins) are comparable with the available autosomal (Alu and restriction site polymorphisms) data for the Nilgiri hill tribes of Tamil Nadu, south India. The gene differentiation value (Gst) was found to be 4.2. The principal coordinate analysis (PCO) based on data from the 20 markers presents a smaller cluster of presently studied populations than that of the Nilgiri hill tribes of Tamil Nadu, south India. CONCLUSION: Although the presently studied populations of Andhra Pradesh have heterozygosity similar to that of Nilgiri hill populations, the former are more closely placed on the PCO plot than the latter, who are more scattered. Also the gene differentiation (Gst) of the former is much lower than that of the latter, indicating considerable regional variation in the inflow of genes from diverse ethnic groups within south India.

A cross-sectional study to assess the stigma associated with tuberculosis among tuberculosis patients in Udupi district, Karnataka.

BACKGROUND: For decades, tuberculosis and other communicable diseases like human immunodeficiency virus/acquired immune deficiency syndrome, leprosy, etc., have been associated with stigma and discrimination by the society; this can interfere with the lifestyle and disease management among these patients. OBJECTIVE: To assess the stigma experienced by tuberculosis patients and to find the factors associated with stigma. METHODS: A cross-sectional study was conducted among 209 sputum-positive and sputum-negative tuberculosis patients. Convenient sampling was used to identify the patients. A predesigned, pretested proforma from Explanatory Model Interview Catalogue developed by World Health Organization was used for data collection. RESULTS: The study revealed that out of 209 respondents, 51.2% of the respondents experienced some form of stigma. Majority of the patients have received only primary education and 71.3% of the respondents were males. Most of the patients were under category 1 of Directly Observed Treatment Short course. Age, education, and smear status of the patient were found to be associated with stigmatization (P<0.05), whereas factors like gender, income, occupation, family history, and marital status were found to be not significantly associated with stigmatization. CONCLUSION: Effective counseling measures are recommended for tuberculosis patients with advancing age and education which can help reduce stigmatization and thereby improve quality of life.

The cause of G2-arrest in Chinese hamster ovary cells treated with anticancer drugs.

The nature of G2-arrest was studied in Chinese hamster ovary cells after exposure to 4'-demethyl-epipodophyllotoxin 9-)4,6-0-2-thenylidene-beta-D-glycopyranoside (VM26), 1,3-bis(2-chloroethyl)-1-nitrosourea, 1,3-cis(2-chloroethyl)-1-nitrosourea, cis-4[[[(2-chloroethyl)-nitrosoamino] carbonyl] amino]- cyclohexane carboxylic acid, or neocarzinostatin. To determine whether this G2-arrest was due to a metabolic block or to damage to the genetic material, we employed the phenomenon of premature chromosome condensation to visualize the chromosomes of the G2-blocked cells by fusing them with mitotic cells. The prematurely condensed chromosomes (PCC) of the treated cells were scored for their position in the cell cycle and the extent of chromosomal damage in the G2-PCC. The data revealed a significant enrichment of the G2-fraction in all the treatments. Most of the G2- PCC from the treated cells were extensively damaged, showing 10 or more breaks and exchanges per cell. These studies clearly indicated that the treated cells accumulated in G2-phase because of their failure to progress into mitosis as a direct or indirect result of the extensive damage to the chromosomes.

Lobster-claw syndrome.

Lobster-Claw syndrome is a rare autosomal dominant, hand-foot malformation with Oro-dental features. This is a rare condition and from the available reports so far, cases being reported are less than 1%. Most reports have focused on the hand-foot deformity of this syndrome. This paper highlights the typical Oro-dental features associated with this syndrome such as retained deciduous teeth, hypodontia and variation in crown size, arch length and arch width.

A study of interaction of a low-dose combination oral contraceptive with anti-tubercular drugs.

Low-dose combination contraceptive (containing norethisterone acetate 1 mg and ethinyl estradiol 30 micrograms) was administered to women receiving concurrent therapy with either Rifampicin or "triple" antitubercular treatment consisting of paraaminosalicylic acid (PAS), isonicotinic acid hydrazide (INH) and streptomycin. Plasma levels of norethisterone (NET) and ethinyl estradiol (EE), PAS and INH were measured and the area under curve (AUC) was calculated for NET and EE. Rifampicin treatment (9 women) caused a statistically significant reduction of the plasma NET levels as well as the AUC of NET. In this group of women, though a trend for reduction in EE levels was observed in individual subjects, it was not statistically significant. Out of 7 regularly menstruating women on Rifampicin therapy, 2 showed a premenstrual rise of plasma progesterone (P) levels (> 4 ng/ml) suggesting an ovulatory cycle and 3 experienced menstrual irregularities. In contrast, plasma levels of NET and EE as well as their AUCs were not altered in 8 women receiving "triple" antitubercular therapy. Only one woman out of 8, had menstrual irregularity and all women had P levels in the anovulatory range. Furthermore, oral contraceptive treatment did not alter the plasma levels of PAS and INH.

Synergistic effects in the solvent extraction of zinc with salicylaldoxime.

The extraction of zinc with salicylaldoxime was studied. The adduct-forming tendency of zinc salicylaldoximate with pyridine, alpha-picoline, beta-picoline, quinohne and isoquinoline was also investigated. This tendency decreases in the order beta-picoline > pyridine > alpha-picoline > isoquinoline > quinoline.

A study on relative contributions of the history, physical examination and investigations in making medical diagnosis.

Here we report an attempt to quantitate the relative contributions of the history, physical examination and investigations in making medical diagnosis. In this prospective study of 100 patients, with new or previously undiagnosed conditions, we listed their differential diagnosis with confidence score; after the history, after physical examination and after the investigations. In two patients no definite final diagnoses could be arrived even after extensive investigation--these two cases were excluded from the study. In seventy seven patients (78.58%) patients, the history led to diagnosis. The physical examination led to diagnosis in eight patients (8.17%); and investigations led to diagnosis in 13 patients (13.27%). The confidence in correct diagnosis increased from 6.36 on a scale of one to ten after the history to 7.57 after physical examination and 9.84 after investigations--implying that history, physical examination and investigation have their own limitation at each stage and an integrative approach is needed in making a medical diagnosis with more emphasis on history.

Effect of exogenous gonadotrophins on restoration of ovarian activities in nicotine treated unilaterally ovariectomized albino rats.

Adult cycling albino rats were hemispayed and administered nicotine for 15 days. FSH/LH or FSH+LH was then administered to these rats. Nicotine inhibited ovarian compensatory hypertrophy significantly and increased cholesterol and lipid levels in the ovary. Administration of FSH alone or in combination with LH restored the ovarian compensatory hypertrophy and decreased the cholesterol and lipid levels significantly, but LH alone was not effective. The results suggest that the inhibition of ovarian growth in nicotine treated rats may be due to lack of availability of pituitary gonadotrophins and these effects can be rectified by the administration of gonadotrophins.

Serum vitamins E, A and lipid peroxidation levels in Kurichias, an Indian tribal population.

Serum vitamins E, A, lipid peroxides, prevalence of dislipidemia, hypertension, obesity and smoking habits were assessed in a volunteer sample of 310 (175 males + 135 females) Kurichias, a tribal population of Kerala, India, who are enjoying longevity relatively free from age associated chronic problems. The mean serum levels of vitamins E and A were higher and lipid peroxides were lower with comparable ages of Indian and Western studies. The prevalence (age standardized to the world population of Segi 95% CI) was obesity 2.87 (1.22-4.53), central obesity 3.71 (2.27-5.15), hypertension 2.70 (1.92-3.48), hypercholesterolemia 0.71 (0.66-0.76), hypertriglyceridemia 2.60 (1.18-4.02) and low high density lipoprotein cholesterol 1.24 (1.07-1.42). Significant negative correlation was observed between vitamins and lipid peroxides. Serum cholesterol and triglycerides showed significant positive correlation with antioxidant vitamins and lipid peroxides. Blood pressure found positive correlation with lipid peroxides and no correlation with vitamins except systolic blood pressure having negative relation with vitamin A. Age showed negative correlation with vitamins and positive correlation with lipid peroxides, whereas lipid peroxides showed positive correlation with obesity only. In multivariate regression analysis serum cholesterol and old age groups were significant predictors of serum antioxidant vitamins and lipid peroxides. The higher levels of antioxidant vitamins, lower levels of lipid peroxides as well as low prevalence of CHD risk factors in Kurichias when compared to other populations suggest that antioxidants or increased intake of foods rich in antioxidants play a key role in their health and longevity.

Number of root canals, their shape, configuration, accessory root canals in radicular pulp morphology. A preliminary study.

Dental Pulp is a soft gelatinous, living cellular tissue of ectomesenchymal origin having various functions, residing within bilayered hard mineralized structures like enamel, dentin and cementum. Hertwigs epithelial root sheath initiates the formation of size, shape and number of radicular pulp. Deciduous pulp cavities differ from permanent teeth present study was conducted to find out number of root canals and their pattern, in deciduous teeth.

Evaluation of the effects of manuka honey on salivary levels of mutans streptococci in children: a pilot study.

BACKGROUND: There has been much debate in the past about whether honey is harmful to the teeth, mostly as part of the debate about raw sugar versus refined sugar and the results have been equivocal. However, what has not been taken into account is that honey varies markedly in the potency of its antibacterial activity. Manuka (Leptospermum scoparium) honey from New Zealand has been found to have substantial levels of non-peroxide antibacterial activity associated with an unidentified phytochemical component, denoted as Unique Manuka Factor (UMF). AIMS: Considering the potential antimicrobial effects of manuka honey, the present study attempted to investigate effects of twice daily use of manuka honey with UMF 19.5 on salivary levels of Mutans streptococci in children. STUDY DESIGN: The investigation was a stratified comparison of two parallel groups of children who either used manuka honey with regular tooth brushing regimen or continued only with regular tooth brushing regimen twice daily under professional supervision for a 21-day period. A total of three salivary samples were taken from each individual at baseline, day 10, and day 21; colony counts of Streptococcus mutans (S. mutans) were determined. All data was subjected to paired T-test and Wilcoxon's signed ranks sum for intra- and intergroup comparisons respectively. RESULTS: Children using manuka honey showed statistically significant reductions in salivary S. mutans after 10 and 21 days. CONCLUSION: Manuka honey with UMF 19.5 may be considered as an effective adjunctive oral hygiene measure for reducing colony counts in children.

The effect of retentive groove, sandblasting and cement type on the retentive strength of stainless steel crowns in primary second molars--an in vitro comparative study.

PURPOSE: This in vitro study was conducted to find out the effect of retentive groove, sand blasting and cement type on the retentive strength of stainless steel crowns in primary second molars. MATERIALS AND METHODS: Thirty-two extracted intact human maxillary and mandibular primary second molars were embedded in aluminum blocks utilizing autopolymerising acrylic resin. After tooth preparation, the 3M stainless steel crown was adjusted to the prepared tooth. Then weldable buccal tubes were welded on the buccal and lingual surfaces of each crown as an attachment for the testing machine. A full factorial design matrix for four factors (retentive groove placement on the tooth, cement type, sandblasting and primary second molar) at two levels each was developed and the study was conducted as dictated by the matrix. The lower and upper limits for each factor were without and with retentive groove placement on the tooth, GIC and RMGIC, without and with sandblasting of crown, maxillary and mandibular second primary molar. For those teeth for which the design matrix dictated groove placement, the retentive groove was placed on the middle third of the buccal surface of the tooth horizontally and for those crowns for which sandblasting of the crowns are to be done, sandblasting was done with aluminium oxide with a particle size of 250 mm. The crowns were luted with either GIC or RMGIC, as dictated by the design matrix. Then the retentive strength of each sample was evaluated by means of an universal testing machine. The obtained data was analyzed using ANOVA for statistical analysis of the data and 't'- tests for pairwise comparison. RESULTS: The mean retentive strength in kg/cm 2 stainless steel crowns luted with RMGIC was 19.361 and the mean retentive strength of stainless steel crowns luted with GIC was 15.964 kg/cm 2 with a mean difference of 3.397 kg/cm 2 and was statistically significant. The mean retentive strength in kg/cm 2 of stainless steel crowns, which was not sandblasted, was 18.880 and which was sandblasted was 16.445 kg/cm 2 with a mean difference of 2.436 kg/cm 2 . These results were again statistically significant. CONCLUSION: It was found that the crowns luted with resin-modified glass ionomer cements (RMGIC's) offered better retentive strength of crowns than glass ionomer cements (GIC) and stainless steel crowns which were cemented without sandblasting showed higher mean retentive strength than with sandblasting of crowns. The presence of groove did not influence the retentive strength of stainless steel crowns.