Reverse transcriptase drug resistance mutations in HIV-1 subtype C infected patients on ART in Karonga District, Malawi

<p>Abstract</p> <p>Background</p> <p>Drug resistance testing before initiation of, or during, antiretroviral therapy (ART) is not routinely performed in resource-limited settings. High levels of viral resistance circulating within the population will have impact on treatment programs by increasing the chances of transmission of resistant strains and treatment failure. Here, we investigate Drug Resistance Mutations (DRMs) from blood samples obtained at regular intervals from patients on ART (Baseline-22 months) in Karonga District, Malawi. One hundred and forty nine reverse transcriptase (RT) consensus sequences were obtained via nested PCR and automated sequencing from blood samples collected at three-month intervals from 75 HIV-1 subtype C infected individuals in the ART programme.</p> <p>Results</p> <p>Fifteen individuals showed DRMs, and in ten individuals DRMs were seen from baseline samples (reported to be ART naïve). Three individuals in whom no DRMs were observed at baseline showed the emergence of DRMs during ART exposure. Four individuals who did show DRMs at baseline showed additional DRMs at subsequent time points, while two individuals showed evidence of DRMs at baseline and either no DRMs, or different DRMs, at later timepoints. Three individuals had immune failure but none appeared to be failing clinically.</p> <p>Conclusion</p> <p>Despite the presence of DRMs to drugs included in the current regimen in some individuals, and immune failure in three, no signs of clinical failure were seen during this study. This cohort will continue to be monitored as part of the Karonga Prevention Study so that the long-term impact of these mutations can be assessed. Documenting proviral population is also important in monitoring the emergence of drug resistance as selective pressure provided by ART compromises the current plasma population, archived viruses can re-emerge</p

Analysis of neonatal clinical trials with twin births

<p>Abstract</p> <p>Background</p> <p>In neonatal trials of pre-term or low-birth-weight infants, twins may represent 10–20% of the study sample. Mixed-effects models and generalized estimating equations are common approaches for handling correlated continuous or binary data. However, the operating characteristics of these methods for mixes of correlated and independent data are not well established.</p> <p>Methods</p> <p>Simulation studies were conducted to compare mixed-effects models and generalized estimating equations to linear regression for continuous outcomes. Similarly, mixed-effects models and generalized estimating equations were compared to ordinary logistic regression for binary outcomes. The parameter of interest is the treatment effect in two-armed clinical trials. Data from the National Institute of Child Health & Human Development Neonatal Research Network are used for illustration.</p> <p>Results</p> <p>For continuous outcomes, while the coverage never fell below 0.93, and the type I error rate never exceeded 0.07 for any method, overall linear mixed-effects models performed well with respect to median bias, mean squared error, coverage, and median width. For binary outcomes, the coverage never fell below 0.90, and the type I error rate never exceeded 0.07 for any method. In these analyses, when randomization of twins was to the same treatment group or done independently, ordinary logistic regression performed best. When randomization of twins was to opposite treatment arms, a rare method of randomization in this setting, ordinary logistic regression still performed adequately. Overall, generalized linear mixed models showed the poorest coverage values.</p> <p>Conclusion</p> <p>For continuous outcomes, using linear mixed-effects models for analysis is preferred. For binary outcomes, in this setting where the amount of related data is small, but non-negligible, ordinary logistic regression is recommended.</p

An Initial In Vitro Investigation into the Potential Therapeutic Use of SupT1 Cells to Prevent AIDS in HIV-Seropositive Individuals

HIV infection usually leads to a progressive decline in number and functionality of CD4+ T lymphocytes, resulting in AIDS development. In this study, I investigated the strategy of using inoculated SupT1 cells to move infection from HIV-1 X4 strains toward the inoculated cells, which should theoretically prevent infection and depletion of normal CD4+ T cells, preventing the development of AIDS-related pathologies. Interestingly, the persistent in vitro replication in SupT1 cells renders the virus less cytopathic and more sensitive to antibody-mediated neutralization, suggesting that replication of the virus in the inoculated SupT1 cells may have a vaccination effect in the long run. In order to mimic the scenario of a therapy in which SupT1 cells are inoculated in an HIV-seropositive patient, I used infected SupT1/PBMC cocultures and a series of control experiments. Infections were done with equal amounts of the wild type HIV-1 LAI virus. The SupT1 CD4+CD8+ T cell population was distinguished from the PBMC CD4+CD8− T cell population by FACS analysis. The results of this study show that the virus-mediated killing of primary CD4+ T cells in the SupT1/PBMC cocultures was significantly delayed, suggesting that the preferential infection of SupT1 cells can induce the virus to spare primary CD4+ T cells from infection and depletion. The preferential infection of SupT1 cells can be explained by the higher viral tropism for the SupT1 cell line. In conclusion, this study demonstrates that it's possible in an in vitro system to use SupT1 cells to prevent HIV infection of primary CD4+ T cells, suggesting that further exploration of the SupT1 cell line as a cell-based therapy against HIV-1 may prove worthwhile

Factors associated with hospital service satisfaction in a sample of Arab subjects with schizophrenia

<p>Abstract</p> <p>Background</p> <p>Assessment of patients' satisfaction with health care services could help to identify the strengths and weaknesses of the system and provide guidance for further development. The study's objectives were to: (i) assess the pattern of satisfaction with hospital care for a sample of people with schizophrenia in Kuwait, using the Verona Service Satisfaction Scale (VSSS-EU); ii) compare the pattern of satisfaction with those of similar studies; and iii) assess the association of VSSS seven domains with a number of variables representing met and unmet needs for care, family caregiver burden, severity of psychopathology, level of psychosocial functioning, socio-demographic characteristics, psychological well-being and objective quality of life.</p> <p>Methods</p> <p>Consecutive outpatients in stable condition and their family caregivers were interviewed with the VSSS-EU and measures of needs for care, caregiver burden, quality of life and psychopathology.</p> <p>Results</p> <p>There were 130 patients (66.1%m, mean age 36.8). While over two-thirds expressed satisfaction with the domains of "overall satisfaction", "professionals' skills", "access", "efficacy", and "relatives' involvement", only about one-third were satisfied with the domains of "information" and "types of intervention". The later two domains were the areas in which European patients had better satisfaction than our patients, while our patients expressed better satisfaction than the Europeans in the domain of "relatives' involvement". In multiple regression analyses, self-esteem, positive and negative affect were the most important correlates of the domains of service satisfaction, while clinical severity, caregiver burden and health unmet needs for care played relatively minor roles.</p> <p>Conclusion</p> <p>The noted differences and similarities with the international data, as well as the predictive power of self-esteem and affective state, support the impression that patients' attitudes towards psychiatric care involve a complex relationship between clinical, personal and socio-cultural characteristics; and that many of the factors that impact on satisfaction with service relate to individual psychological characteristics. The weaknesses in the system, highlighted by the pattern of responses of the participants, indicate possible gaps in the provision of comprehensive psychiatric care in the country and obviate the need for public mental health education and development of services to enhance the quality of care.</p

Sex-Dependent Novelty Response in Neurexin-1α Mutant Mice

Neurexin-1 alpha (NRXN1α) belongs to the family of cell adhesion molecules (CAMs), which are involved in the formation of neuronal networks and synapses. NRXN1α gene mutations have been identified in neuropsychiatric diseases including Schizophrenia (SCZ) and Autism Spectrum Disorder (ASD). In order to get a better understanding of the pleiotropic behavioral manifestations caused by NRXN1α gene mutations, we performed a behavioral study of Nrxn1α heterozygous knock-out (+/−) mice and observed increased responsiveness to novelty and accelerated habituation to novel environments compared to wild type (+/+) litter-mates. However, this effect was mainly observed in male mice, strongly suggesting that gender-specific mechanisms play an important role in Nrxn1α-induced phenotypes

Multimorbidity and comorbidity in the Dutch population - data from general practices

<p>Abstract</p> <p>Background</p> <p>Multimorbidity is increasingly recognized as a major public health challenge of modern societies. However, knowledge about the size of the population suffering from multimorbidity and the type of multimorbidity is scarce. The objective of this study was to present an overview of the prevalence of multimorbidity and comorbidity of chronic diseases in the Dutch population and to explore disease clustering and common comorbidities.</p> <p>Methods</p> <p>We used 7 years data (2002–2008) of a large Dutch representative network of general practices (212,902 patients). Multimorbidity was defined as having two or more out of 29 chronic diseases. The prevalence of multimorbidity was calculated for the total population and by sex and age group. For 10 prevalent diseases among patients of 55 years and older (N = 52,014) logistic regressions analyses were used to study disease clustering and descriptive analyses to explore common comorbid diseases.</p> <p>Results</p> <p>Multimorbidity of chronic diseases was found among 13% of the Dutch population and in 37% of those older than 55 years. Among patients over 55 years with a specific chronic disease more than two-thirds also had one or more other chronic diseases. Most disease pairs occurred more frequently than would be expected if diseases had been independent. Comorbidity was not limited to specific combinations of diseases; about 70% of those with a disease had one or more extra chronic diseases recorded which were not included in the top five of most common diseases.</p> <p>Conclusion</p> <p>Multimorbidity is common at all ages though increasing with age, with over two-thirds of those with chronic diseases and aged 55 years and older being recorded with multimorbidity. Comorbidity encompassed many different combinations of chronic diseases. Given the ageing population, multimorbidity and its consequences should be taken into account in the organization of care in order to avoid fragmented care, in medical research and healthcare policy.</p

Genotyping and drug resistance patterns of M. tuberculosis strains in Pakistan

<p>Abstract</p> <p>Background</p> <p>The incidence of tuberculosis in Pakistan is 181/100,000 population. However, information about transmission and geographical prevalence of <it>Mycobacterium tuberculosis </it>strains and their evolutionary genetics as well as drug resistance remains limited. Our objective was to determine the clonal composition, evolutionary genetics and drug resistance of <it>M. tuberculosis </it>isolates from different regions of the country.</p> <p>Methods</p> <p><it>M. tuberculosis </it>strains isolated (2003–2005) from specimens submitted to the laboratory through collection units nationwide were included. Drug susceptibility was performed and strains were spoligotyped.</p> <p>Results</p> <p>Of 926 <it>M. tuberculosis </it>strains studied, 721(78%) were grouped into 59 "shared types", while 205 (22%) were identified as "Orphan" spoligotypes. Amongst the predominant genotypes 61% were Central Asian strains (CAS ; including CAS1, CAS sub-families and Orphan Pak clusters), 4% East African-Indian (EAI), 3% Beijing, 2% poorly defined TB strains (T), 2% Haarlem and LAM (0.2). Also TbD1 analysis (<it>M. tuberculosis </it>specific deletion 1) confirmed that CAS1 was of "modern" origin while EAI isolates belonged to "ancestral" strain types.</p> <p>Prevalence of CAS1 clade was significantly higher in Punjab (P < 0.01, Pearsons Chi-square test) as compared with Sindh, North West Frontier Province and Balochistan provinces. Forty six percent of isolates were sensitive to five first line antibiotics tested, 45% were Rifampicin resistant, 50% isoniazid resistant. MDR was significantly associated with Beijing strains (P = 0.01, Pearsons Chi-square test) and EAI (P = 0.001, Pearsons Chi-square test), but not with CAS family.</p> <p>Conclusion</p> <p>Our results show variation of prevalent <it>M. tuberculosis </it>strain with greater association of CAS1 with the Punjab province. The fact that the prevalent CAS genotype was not associated with drug resistance is encouraging. It further suggests a more effective treatment and control programme should be successful in reducing the tuberculosis burden in Pakistan.</p