Causes of loss to follow-up from drug-resistant TB treatment in Khayelitsha, South Africa.

Patients initiated on drug-resistant TB(DR-TB) treatment in 2019 in Khayelitsha, South Africa, with a loss to follow-up outcome were evaluated to better understand reasons for loss to follow-up and to determine if any had returned to care. Of a total of 187 patients, 28 (15%) were lost to follow-up (LTFU), 24 (86%) of whom were traced: 20/24 (83%) were found when they re-presented to facilities and 8/28 (29%) were linked back to DR-TB care. People with DR-TB continue to seek care even after being LTFU; thus better coordination between different components of the healthcare system are required to re-engage with these patients. Interventions to mitigate the socio-economic challenges of people on DR-TB treatment are needed. Many people who were LTFU and symptomatic were willing to re-engage with DR-TB care, which highlights the importance of for compassionate interventions to welcome them back.

Les patients placés sous traitement pour TB pharmacorésistante (DR-TB) en 2019 à Khayelitsha, Afrique du Sud, et ayant été perdus de vue ont été évalués afin de mieux comprendre les raisons de la perte de vue et de déterminer si certains étaient de nouveau suivis. Sur 187 patients, 28 (15%) ont été perdus de vue, dont 24 (86%) ont été retrouvés : 20/24 (83%) ont été retrouvés lorsqu'ils se sont de nouveau présentés en consultation et 8/28 (29%) ont été réinsérés dans le parcours de soins de la DR-TB. Les patients atteints de DR-TB sont toujours en demande de soins, même après avoir été perdus de vue. Ainsi, une meilleure coordination entre les différentes composantes du système de santé est nécessaire afin de rétablir le lien avec ces patients. Des interventions visant à atténuer les problèmes socio-économiques des patients sous traitement pour DR-TB sont nécessaires. De nombreux patients symptomatiques ayant été perdus de vue étaient enclins à reprendre leur traitement de la DR-TB. Il est donc important de mettre en place des programmes compassionnels afin de les réinsérer dans le parcours de soins.

JAK1/3 inhibition preserves epidermal morphology in full-thickness 3D skin models of atopic dermatitis and psoriasis.

BACKGROUND: Janus kinase (JAK) inhibition may be a promising new treatment modality for inflammatory (skin) diseases. However, little is known about direct effects of kinase inhibitors on keratinocyte differentiation and function as well as skin barrier formation. OBJECTIVE: Our aim was to address the direct impact of kinase inhibition of the JAK1/3 pathways by tofacitinib on keratinocyte immune function and barrier formation in atopic dermatitis (AD) and psoriasis. METHODS: 3D skin equivalents of both diseases were developed and concurrently pretreated with tofacitinib. To induce AD, 3D skin equivalents were stimulated with recombinant human IL-4 and IL-13. Psoriasis-like conditions were induced by incubation with IL-17A, IL-22 and tumour necrosis factor α (TNFα). The activation of signal transducer and activator of transcription (STAT)1, STAT3 and STAT6 was assessed by Western blot analysis. Microarray analysis and quantitative real-time PCR were used for gene expression analysis. RESULTS: Tofacitinib pretreatment preserved epidermal morphology and reduced STAT3 and STAT6 phosphorylation of AD-like and STAT3 phosphorylation of psoriasis-like culture conditions in 3D skin models compared to sham-controls. Filaggrin expression was fully maintained in the AD-like models, but only partially in psoriasis-like conditions after pretreatment with tofacitinib. In addition, tofacitinib upregulated DSC1, FLG and KRT1. Using gene expression analysis, downregulation of POSTN and IL24 was observed in AD-like conditions, whereas downregulation of IL20 and IL1B was observed in psoriasis-like conditions. CONCLUSION: JAK1/3 inhibition counteracted cytokine-induced AD- and psoriasis-like epidermal morphology and enhanced keratinocyte differentiation in 3D skin models. This effect was more pronounced in the AD-like models compared to the psoriasis-like 3D skin models.

Virtual reconstruction of the skeletal labyrinth of two lamnid sharks (Elasmobranchii, Lamniformes).

The first virtual reconstruction of the skeletal labyrinth of the porbeagle shark Lamna nasus and the shortfin mako shark Isurus oxyrinchus is presented here using high-resolution micro-computed tomography. The results, in comparison with previously published information, suggest relationships between skeletal labyrinth morphology and locomotion mode in chondrichthyans, but also show that further studies are required to establish such connections. Nevertheless, this study adds to the knowledge of the skeletal labyrinth morphology in two apex elasmobranch species.

Variants of the FTO gene in obese children and their impact on body composition and metabolism before and after lifestyle intervention.

OBJECTIVE: To investigate the impact of variants of the FTO gene (rs1421085, rs17817449, rs9939609) in obese children before and after lifestyle intervention. DESIGN: Longitudinal, clinical intervention study with an increase in physical activity, and nutritional recommendations based on the 'Optimized Mixed Diet for German Children and Adolescents' (Research Institute of Child Nutrition, Germany). STUDY POPULATION: 75 overweight children (40 male, mean BMI 30.4±5.5 kg/m², mean age 12.6±2.6 years). MEASUREMENTS: Genotyping by means of a TaqMan SNP genotyping assay. Lean and fat mass were determined by means of DXA. RESULTS: For the whole study population, the 6-month lifestyle intervention resulted in a significant improvement (before intervention minus time point 6 months; mean±SD) in BMI-SDS (0.10±0.17, p<0.001), HOMA (1.41±3.19, p<0.001) and relative fat-mass-SDS (0.09±0.23, p=0.005). Before and after lifestyle intervention, there was no significant difference between heterozygote (n=52) and homozygote (n=21) carriers of the FTO gene in terms of BMI, body composition, and the metabolic profile (Insulin, HOMA, lipids, liver function tests). CONCLUSION: Variants in the FTO gene are common in obese children but have no impact on body composition and metabolism before and after lifestyle intervention.

The functional muscle-bone unit in obese children - altered bone structure leads to normal strength strain index.

UNLABELLED: Obese children have a twofold increased risk of fracture of the forearm compared to non-obese children. OBJECTIVE: To investigate bone strength and bone structure of the forearm, and the relationship between muscle and bone in obese children. METHODS: The study-group consisted of 84 (40 female) overweight children (mean (SD)) age 11.8 (3.2) years, BMI 29.0 (5.1) kg/m(2)). Bone geometry and strength were measured at the proximal radius of the non-dominant forearm (65% measurement site) by means of pQCT (XCT 2000). Bone mineral density and lean mass of the total body was determined by means of DXA (Lunar, DPXL/PED). Results were compared to reference values by calculating age (SDS(CA)) and height-age (SDS(HA)) dependent standard deviation scores (SDS). RESULTS: Cortical density, -1.11 (1.74) SDS(HA), -0.45 (1.52) SDS(CA); cortical thickness, -1.46 (1.33) SDS(HA), -1.01 (1.46) SDS(CA); cortical area, -0.42 (1.31) SDS(HA), 0.26 (1.58) SDS(CA); total bone area +2.21 (1.47) SDS(HA), 2.91 (1.80) SDS(CA), marrow area +3.12 (2.29) SDS(HA), 3.37 (2.38) SDS(CA); strength strain index +0.10 (1.10) SDS(HA), 0.95 (1.57) SDS(CA). These changes in bone structure were independent from pubertal stage. Measurements revealed correlations between muscle area and SSI (R(2)=0.67, p<0.001), and muscle mass and bone mineral content (DXA; R (2)=0.81, p<0.001). CONCLUSION: Low cortical density, normal cortical area and increased total bone area led to a normal strength strain index adjusted both for height and for age. We assume that this normal bone strength is not appropriate for the higher kinetic energy of impact in case of a fall in overweight children.

Investigation of myostatin serum levels before and after a 6-month lifestyle intervention program in obese children.

OBJECTIVE: To investigate the relationship between myostatin serum levels and muscle mass, fat mass and HOMA before and after a 6-month lifestyle intervention program in obese children and adolescents. DESIGN: A total of 57 overweight children and adolescents (female, n=27; age range, 6.0-16.1 years) were examined between 2007 and 2009. Mean BMI (±SD) was 31.1 (5.7) kg/m(2) corresponding to a mean BMI-SDS LMS of 2.2 (0.4). Muscle and fat mass were determined by means of DXA. Serum myostatin was measured by using a competitive ELISA. RESULTS [MEAN±SD]: After the 6-month intervention program, muscle mass (+2.1±2.7 kg, p<0.0001), and percentage myostatin serum levels (+23.7±26.7%, p<0.0001) were higher than before, whereas decreases in BMI (-0.4 kg/m(2)±1.5, p<0.0001), fat mass (-1.2±3.9 kg, p<0.0001), and HOMA insulin sensitivity index (-0.78±3.28 SD, p=0.0004) were observed. In 86% (n=49, p<0.0001) of all cases, the intervention program resulted in a higher level of myostatin. After lifestyle intervention, patients with the greatest increase of myostatin had a significantly lower increase of muscle mass (p=0.048) but did not differ for fat mass. There was no significant correlation between Myostatin and HOMA insulin sensitivity index before and after lifestyle intervention. CONCLUSION: Both muscle mass and serum myostatin increased concordantly. Patients with the greatest rise of myostatin had a significantly lower increase of muscle mass suggesting a negative feedback loop between myostatin and muscle tissue. In our study, the change of myostatin serum levels was not associated with the amount of fat mass or HOMA insulin sensitivity index.

The consequences upon patient care of moving Brits Hospital: a case study.

BACKGROUND: In 2001, North West Province took the decision to increase bed capacity at Brits Hospital from 66 beds to 267 beds. After careful consideration of costs and an assessment of available land, it was decided to demolish the existing hospital and rebuild the new hospital on the same site. It was planned that during this time that clinical services would be moved to a temporary makeshift hospital and to primary health care clinics. This case study documents the consequences of this decision to move services to the makeshift hospital and how these challenges were dealt with. METHODS: A cross-sectional descriptive study was undertaken. Ten key members of staff at management and service delivery level, in the hospital and the district, were interviewed. Key documents, reports, correspondence, hospital statistics and minutes of meetings related to the move were analysed. RESULTS: The plan had several unforeseen consequences with serious effects on patient care. Maternity services were particularly affected. Maternity beds decreased from 30 beds in the former hospital to 4 beds in the makeshift hospital. As numbers of deliveries did not greatly decrease, this resulted in severe overcrowding, making monitoring and care difficult. Perinatal mortality rates doubled after the move. An increase in maternal deaths was noted. The lack of inpatient ward space resulted in severe overcrowding in Casualty. The lack of X-ray facilities necessitated patients being referred to a facility 72 km away, which often caused a delay of 3 days before management was completed. After-hours X-rays were done in a private facility, adding to unforeseen costs. Although the initial plan was for the makeshift hospital to stabilise and refer most patients, referral routes were not agreed upon or put in writing, and no extra transportation resources were allocated. The pharmacy had insufficient space for storage of medication. In spite of all these issues, relationships and capacity at clinics were strengthened, but not sufficiently to meet the need. DISCUSSION: Hospital revitalisation requires detailed planning so that services are not disrupted. Several case studies have highlighted the planning necessary when services are to be moved temporarily. Makeshift hospitals have been used when renovating or building hospitals. During war or disasters, plans have been made to decant patients from one facility to another. From the Brits case study, it would appear that not enough detailed planning for the move was done initially. This observation includes failure to appreciate the interrelatedness of systems and the practicality of the proposal, and to budget for the move and not just the new structure. CONCLUSION: The current service offered at the makeshift hospital at Brits is not adequate and has resulted in poor patient care. It is the result of a planning process that did not examine the consequences of the move, both logistic and financial, in adequate detail. Committed hospital staff have tried their best to offer good care in difficult circumstances.

Admixture in the Hispanics of the San Luis Valley, Colorado, and its implications for complex trait gene mapping.

Hispanic populations are a valuable resource that can and should facilitate the identification of complex trait genes by means of admixture mapping (AM). In this paper we focus on a particular Hispanic population living in the San Luis Valley (SLV) in Southern Colorado. We used a set of 22 Ancestry Informative Markers (AIMs) to describe the admixture process and dynamics in this population. AIMs are defined as genetic markers that exhibit allele frequency differences between parental populations >or=30%, and are more informative for studying admixed populations than random markers. The ancestral proportions of the SLV Hispanic population are estimated as 62.7 +/- 2.1% European, 34.1 +/- 1.9% Native American and 3.2 +/- 1.5% West African. We also estimated the ancestral proportions of individuals using these AIMs. Population structure was demonstrated by the excess association of unlinked markers, the correlation between estimates of admixture based on unlinked marker sets, and by a highly significant correlation between individual Native American ancestry and skin pigmentation (R2= 0.082, p < 0.001). We discuss the implications of these findings in disease gene mapping efforts.

Ancestral proportions and admixture dynamics in geographically defined African Americans living in South Carolina.

We analyzed admixture in samples of six different African-American populations from South Carolina: Gullah-speaking Sea Islanders in coastal South Carolina, residents of four counties in the "Low Country" (Berkeley, Charleston, Colleton, and Dorchester), and persons living in the city of Columbia, located in central South Carolina. We used a battery of highly informative autosomal, mtDNA, and Y-chromosome markers. Two of the autosomal markers (FY and AT3) are linked and lie 22 cM apart on chromosome 1. The results of this study indicate, in accordance with previous historical, cultural, and anthropological evidence, a very low level of European admixture in the Gullah Sea Islanders (m = 3.5 +/- 0.9%). The proportion of European admixture is higher in the Low Country (m ranging between 9. 9 +/- 1.8% and 14.0 +/- 1.9%), and is highest in Columbia (m = 17.7 +/- 3.1%). A sex-biased European gene flow and a small Native American contribution to the African-American gene pool are also evident in these data. We studied the pattern of pairwise allelic associations between the FY locus and the nine other autosomal markers in our samples. In the combined sample from the Low Country (N = 548), a high level of linkage disequilibrium was observed between the linked markers, FY and AT3. Additionally, significant associations were also detected between FY and 4 of the 8 unlinked markers, suggesting the existence of significant genetic structure in this population. A continuous gene flow model of admixture could explain the observed pattern of genetic structure. A test conditioning on the overall admixture of each individual showed association of ancestry between the two linked markers (FY and AT3), but not between any of the unlinked markers, as theory predicts. Thus, even in the presence of genetic structure due to continuous gene flow or some other factor, it is possible to differentiate associations due to linkage from spurious associations due to genetic structure.

Population structure in admixed populations: effect of admixture dynamics on the pattern of linkage disequilibrium.

Gene flow between genetically distinct populations creates linkage disequilibrium (admixture linkage disequilibrium [ALD]) among all loci (linked and unlinked) that have different allele frequencies in the founding populations. We have explored the distribution of ALD by using computer simulation of two extreme models of admixture: the hybrid-isolation (HI) model, in which admixture occurs in a single generation, and the continuous-gene-flow (CGF) model, in which admixture occurs at a steady rate in every generation. Linkage disequilibrium patterns in African American population samples from Jackson, MS, and from coastal South Carolina resemble patterns observed in the simulated CGF populations, in two respects. First, significant association between two loci (FY and AT3) separated by 22 cM was detected in both samples. The retention of ALD over relatively large (>10 cM) chromosomal segments is characteristic of a CGF pattern of admixture but not of an HI pattern. Second, significant associations were also detected between many pairs of unlinked loci, as observed in the CGF simulation results but not in the simulated HI populations. Such a high rate of association between unlinked markers in these populations could result in false-positive linkage signals in an admixture-mapping study. However, we demonstrate that by conditioning on parental admixture, we can distinguish between true linkage and association resulting from shared ancestry. Therefore, populations with a CGF history of admixture not only are appropriate for admixture mapping but also have greater power for detection of linkage disequilibrium over large chromosomal regions than do populations that have experienced a pattern of admixture more similar to the HI model, if methods are employed that detect and adjust for disequilibrium caused by continuous admixture.

Dexamethasone does not significantly contribute to the response rate of docetaxel and estramustine in androgen independent prostate cancer.

PURPOSE: We evaluated the independent response rate of dexamethasone before docetaxel and estramustine administration as measured by changes in serum prostate specific antigen (PSA) in patients with androgen independent prostate cancer. MATERIALS AND METHODS: A total of 12 patients received 20 mg. dexamethasone orally every 6 hours for 3 doses repeated every 3 weeks before starting cytotoxic therapy with estramustine and docetaxel. After progression on dexamethasone 280 mg. estramustine orally 3 times daily on days 1 to 5 and 70 mg./m.2 docetaxel intravenously for 1 hour on day 2 were given. RESULTS: None of the patients initially treated with dexamethasone monotherapy (median 1 cycle, range 1 to 5) had a PSA decline of 50% or greater. Median PSA increase on monotherapy was 47% (range 0% to 22%). On estramustine and docetaxel therapy PSA decreased 50% or greater in 11 patients (92%, 95% confidence intervals [CI] 60 to 99) and 80% or greater in 7 (58%, 95% CI 29 to 84), and normalized in 5 (42%, 95% CI 16 to 71), with a median duration of response of 153 (range 42 to 371), 132 (range 84 to 287) and 84 (range 21 to 174) days, respectively. Median times to reach 50% and 80% decreases in baseline PSA were 21 (range 21 to 209) and 63 (range 21 to 138) days, respectively. In 9 patients (75%, 95% CI 43 to 93) PSA decreased at least 50% by week 9. Of 4 patients with bidimensionally measurable disease 3 had a partial response. Median time to progression was 263 days (range 91 to 378). CONCLUSIONS: Administration of 20. mg. dexamethasone orally every 6 hours for 3 doses every 3 weeks does not significantly contribute to the PSA response rate of estramustine and docetaxel.

Phase I/II studies of docetaxel (Taxotere) combined with estramustine in men with hormone-refractory prostate cancer.

Evaluation of the combined regimen of estramustine and docetaxel (Taxotere; Rhône-Poulenc Rorer, Collegeville, PA) in men with hormone-refractory prostate cancer is in its early stages. While this combination is promising in terms of efficacy, adverse events associated with estramustine are a concern. Estramustine has been associated with side effects such as nausea, vomiting, edema, and serious vascular events. Reported here are the results of phase I and phase II trials in which 280 mg estramustine was given three times daily on days I to 5 in 21-day treatment cycles with docetaxel at varying doses. Data from patients evaluable thus far support the efficacy of this combination, both in chemotherapeutically naive patients and in those who have had prior therapy. A survival benefit from this combination appears achievable from these early studies. As significant antitumor activity can be achieved with docetaxel alone, future studies need to define the minimal dose of estramustine for this combination.

Phase I trial of docetaxel with estramustine in androgen-independent prostate cancer.

PURPOSE: To evaluate the toxicity, efficacy, and pharmacokinetics of docetaxel when combined with oral estramustine and dexamethasone in a phase I study in patients with progressive metastatic androgen-independent prostate cancer. PATIENTS AND METHODS: Thirty-four men were stratified into minimally pretreated (MPT) and extensively pretreated (EPT) groups. Estramustine 280 mg PO tid was administered 1 hour before or 2 hours after meals on days 1 through 5, with escalated doses of docetaxel from 40 to 80 mg/m2 on day 2. Treatment was repeated every 21 days. RESULTS: Thirty-four patients were assessable for toxicity and 33 for response. In the MPT patients, dose-limiting myelosuppression was reached at 80 mg/m2, with six patients experiencing grade 3/4 granulocytopenia. In EPT patients, escalation above 70 mg/m2 was not attempted. Fourteen MPT (70%) and six EPT (50%) patients had a > or = 50% decline in serum PSA on two consecutive measurements taken at least 2 weeks apart. The overall 50% PSA response rate was 63% (95% confidence interval [CI], 28% to 81%). Of the 18 patients with bidimensionally measurable disease, five (28%; 95% CI, 11% to 54%) achieved a partial response. At the time of entry onto the study, 15 patients required narcotic analgesics for bone pain; after treatment, eight (53%) discontinued their pain medications. The area under the curve for docetaxel increased linearly from 40 to 70 mg/m2. At 80 mg/m2, the measured area under the curve was 8.37 (standard deviation, 0.724), which was significantly higher than the previously reported values. CONCLUSION: The recommended phase II dose of docetaxel combined with estramustine is 70 mg/m2 in MPT patients and 60 mg/m2 in EPT patients. This combination is active in men with androgen-independent prostate cancer.

Inhibition of Na,K-ATPase by cadmium: different mechanisms in different species.

The mechanism of action of Cd on Na,K-ATPase was investigated in two "classical" model systems, the shark rectal gland and rabbit kidney outer medulla. In lyophilized plasma membranes from dogfish rectal gland Cd inhibited Na,K-ATPase activity after 30 min of preincubation with an I50 of 1.3 x 10(-5) M. K-Dependent p-nitrophenylphosphatase (pNPPase) activity was inhibited 50% by Cd at 9.4 x 10(-6) M. Neither Na nor K altered the interaction of the enzyme with Cd. Decreasing the ATP concentration, however, lowered the apparent sensitivity of Na,K-ATPase to Cd. The inhibitory effect was also significantly reduced when the Mg concentration present during the preincubation was increased from 0.5 to 6.0 mM. The apparent Cd sensitivity of the K-dependent pNPPase is lower at 10 mM Mg than at 1 mM Mg. In initial rate experiments 4 x 10(-5) M Cd increased the apparent Km of the enzyme for Mg significantly from 0.88 +/- 0.29 mM to 1.73 +/- 0.3 mM whereas the Vmax (167 +/- 32 mumol/min x mg protein compared to 140 +/- 16 mumol/min x mg protein) remained essentially unchanged. In lyophilized rabbit kidney outer medulla, Cd was found to inhibit Na,K-ATPase activity with an I50 of 1.9 x 10(-5) M. K-Dependent pNPPase was inhibited 50% under identical conditions by Cd at a nominal concentration of 2.1 x 10(-4) M. Increasing K concentrations protected the enzyme from the inhibitory action of Cd as indicated by a 10-fold decrease in sensitivity of pNPPase when the K concentration was increased from 1 to 20 mM. K, 20 mM, delayed also the onset of inhibition by about 15 min at 37 degrees C. These studies suggest that the mode of action of Cd on Na,K-ATPase varies in different species. In rectal gland Cd competes with a Mg site (or sites) critically involved in ATP and pNPP hydrolysis, whereas in rabbit renal medulla Cd interacts with a potassium-binding site. Differences in the protein sequence, protein conformation, and/or in the kind of protein membrane-lipid interaction might contribute to this diversity observed in the inhibitory mechanisms.