Incidences and factors associated with viral suppression or rebound among HIV patients on combination antiretroviral therapy from three counties in Kenya.

BACKGROUND: Limited data are available on the incidence and factors associated with viral rebound following viral suppression among HIV-infected individuals taking antiretroviral therapy (ART) in Kenya. Furthermore, the durability of viral suppression among HIV individuals taking ART is unknown. Information on incidence rates and factors associated with HIV viral load rebound and the durability of viral suppression (undetectable HIV copies in plasma) among HIV-infected individuals taking ART, will help improve the long-term management of HIV-infected individuals and explore approaches to long-term HIV remission or complete cure. OBJECTIVES: The objectives of this study were to investigate the incidence rates of viral rebound following viral suppression, factors associated with viral rebound, and the durability of viral suppression among HIV-infected individuals on ART from Kilifi, Meru, and Nakuru counties in Kenya. METHODS: This was a retrospective study involving 600 HIV-infected individuals taking combination ART (cART) and enrolled in comprehensive care centers (CCCs) at Malindi Sub-county Hospital, Nakuru Level 5 Hospital, and Meru Level 5 Hospital in Kenya. The medical files were inspected and medical history records abstracted for the selected participants. Participant laboratory data including HIV viral loads, types and history of ART, and treatment history of any opportunistic infections were abstracted using an abstraction checklist. Participants were grouped into those who achieved HIV viral suppression, with viral loads lower than the detection limit (LDL) (viral suppression), and those who experienced one or more detectable viral load measurements >40 copies/ml following the initial LDL (viral rebound). Durable viral suppression was defined as all viral load values at LDL over the 2-year period (2017-2019). Univariate and multivariate Poisson regression analyses were performed to assess the rates of viral rebound, as well as to investigate factors associated with it. RESULTS: Out of 549 HIV-positive patients, 324/549 (59%) achieved HIV viral suppression (Meru 159/194 (82%), Nakuru 21/178 (12%), and Malindi 144/177 (81%)). The overall viral rebound rate was 41%, with site-specific viral rebound of 88.2%, 18.6%, and 18.0% in Nakuru, Malindi, and Meru, respectively. There was an overall rate of first viral rebound of 3.9 (95% confidence interval (CI) 6.9-14.4), 0.7 (95% CI 0.5-1.0), and 0.89 (95% CI 0.64-1.24) per 100 person-months in Nakuru, Malindi, and Meru, respectively. Good ART adherence (p = 0.0002), widow status (p = 0.0062), and World Health Organization (WHO) stage I (p = 0.0002) were associated with viral suppression, while poor ART adherence (p < 0.0001), WHO stage II (p = 0.0024), and duration on ART of 36 months (p = 0.0350) were associated with viral rebound. CONCLUSIONS: The rate of viral suppression in patients on cART in the CCCs fell short of the WHO target. However, the study provides proof of evidence of undetectable viral load levels for more than 2 years, a sign that the United Nation's 2030 objective of controlling the risk of HIV transmission could be achieved.

Demonstrating PM2.5 and road-side dust pollution by heavy metals along Thika superhighway in Kenya, sub-Saharan Africa.

This study assessed the level of heavy metal in roadside dust and PM2.5 mass concentrations along Thika superhighway in Kenya. Thika superhighway is one of the busiest roads in Kenya, linking Thika town with Nairobi. Triplicate road dust samples collected from 12 locations were analysed for lead (Pb), chromium (Cr), cadmium (Cd), nickel (Ni), zinc (Zn), and copper (Cu) using atomic absorption spectrophotometry (AAS). PM2.5 samples were collected on pre-weighed Teflon filters using a BGI personal sampler and the filters were then reweighed. The ranges of metal concentrations were 39-101 µg/g for Cu, 95-262 µg/g for Zn, 9-28 µg/g for Cd, 14-24 µg/g for Ni, 13-30 µg/g for Cr, and 20-80 µg/g for Pb. The concentrations of heavy metals were generally highly correlated, indicating a common anthropogenic source of the pollutants. The results showed that the majority of the measured heavy metals were above the background concentration, and in particular, Cd, Pb, and Zn levels indicated moderate to high contamination. Though not directly comparable due to different sampling timeframes (8 h in this study and 24 h for guideline values), PM2.5 for all sites exceeds the daily WHO PM2.5 guidelines of 25 µg/m3. This poses a health risk to people using and working close to Thika superhighway, for example, local residents, traffic police, street vendors, and people operating small businesses. PM2.5 levels were higher for sites closer to Nairobi which could be attributed to increased vehicular traffic towards Nairobi from Thika. This study provides some evidence of the air pollution problem arising from vehicular traffic in developing parts of the world and gives an indication of the potential health impacts. It also highlights the need for source apportionment studies to determine contributions of anthropogenic emissions to air pollution, as well as long-term sampling studies that can be used to fully understand spatiotemporal patterns in air pollution within developing regions.

The use of oral fluralaner for the treatment of feline generalised demodicosis: a case report.

There is little agreement on the most effective and safest treatment for feline demodicosis. Protocols generally consist of long-lasting therapy courses based on rinses, subcutaneous injections, oral drug administration or repeated spot-on formulation and the efficacy of most of these is poorly documented. Many of these products have also been associated with adverse effects and may be difficult to administer in cats, leading to poor owner compliance and treatment failure. This case report describes the successful use of fluralaner in treating a generalised form of demodicosis caused by Demodex cati in an adult cat that was probably triggered by chronic glucocorticoid administration. After a single oral dose of 28 mg/kg fluralaner, negative skin scrapings were obtained within one month and clinical cure within two months. No side effects were observed. Larger studies are needed to evaluate the efficacy of fluralaner in treating feline generalised demodicosis.

Food-specific sublingual immunotherapy is well tolerated and safe in healthy dogs: a blind, randomized, placebo-controlled study.

BACKGROUND: Food allergies are increasing in prevalence but no treatment strategies are currently available to cure dogs with food allergy. Over the past decade, experimental food allergen-specific sublingual immunotherapy (FA-SLIT) has emerged as a potential treatment for food allergies in human medicine. However, FA-SLIT has not been investigated in dogs. Therefore, the objective of this study was to prospectively evaluate the safety, tolerability and dispenser sterility of FA-SLIT in healthy dogs before testing it in food allergic dogs. Eight experimental healthy beagle dogs, never orally exposed to peanut, were randomized in two groups to receive SLIT with peanut or placebo for 4 months. Subjects were monitored daily for local and systemic adverse effects. Blood samples for complete blood count and serum biochemistry, and urine for urinalysis were collected and the dogs' body weight was recorded at day 0, 35 and 119 of the SLIT treatment. Sera for the determination of peanut-specific IgG and IgE were collected at day 0, 35, 49, 70, 91, 105 and 119. Intradermal tests were performed before (day 0) and after (day 119) the experiment. The content of each dispenser used to administer treatment or placebo was tested for sterility after usage. In order to assess the presence or absence of sensitization, dogs were challenged 6 months after the end of the study with 2000 µg of peanut extract daily for 7 to 14 days. RESULTS: All dogs completed the study. The treatment did not provoke either local or systemic side-effects. Peanut-specific IgG significantly increased in treatment group. Even though a significant increase in peanut-specific IgE was also seen, intradermal tests were negative in all dogs before and after the experiment, and the challenge test did not trigger any adverse reactions in the treated dogs, which shows the protocol did not cause sensitization to peanut, but nevertheless primed the immune system as indicated by the humoral immune response. All dispenser solutions were sterile. CONCLUSIONS: Our results demonstrate that the used peanut-SLIT protocol is well tolerated and safe in healthy dogs. Further studies should evaluate tolerability, safety and efficacy in dogs with food allergy.

CD4+ T cell counts in initiation of antiretroviral therapy in HIV infected asymptomatic individuals; controversies and inconsistencies.

The primary goal when devising strategies to define the start of therapy in HIV infected individuals is to avoid HIV disease progression and toxicity from antiretroviral therapy (ART). Intermediate goals includes, avoiding resistance by suppressing HIV replication, reducing transmission, limiting spread and diversity of HIV within the body and protecting the immune system from harm. The question of how early or late to start ART and achieve both primary and intermediate goals has dominated HIV research. The distinction between early and late treatment of HIV infection is currently a matter of CD4+ T cells count, a marker of immune status, rather than on viral load, a marker of virus replication. Discussions about respective benefits of early or delayed therapy, as well as the best CD4+ T cell threshold during the course of HIV infection at which ART is initiated remains inconclusive. Guidelines issued by various agencies, provide different initiation recommendations. This can be confusing for clinicians and policy-makers when determining the best time to initiate therapy. Optimizing ART initiation strategies are clearly complex and must be balanced between individual and broader public health needs. This review assesses available data that contributes to the debate on optimal time to initiate therapy in HIV-infected asymptomatic individuals. We also review reports on CD4+ T cell threshold to guide initiation of ART and finally discuss arguments for and against early or late initiation of ART.

The voting rights of adults with intellectual disabilities: reflections on the arguments, and situation in Kenya and England and Wales.

Article 29 of the Convention on the Rights of Persons with Disabilities guarantees equality of political rights, including the right to vote and stand for election. The affirmation of these rights, first guaranteed by the Universal Declaration of Human Rights, raises an important question given the long-standing association between political rights and beliefs concerning the abilities of citizens to reason and act independently: how and to what degree can people identified as having intellectual disabilities participate in a defining act of the democratic process? Focused specifically on the right to vote, this paper addresses the question by (1) introducing the debates that have surrounded the voting rights of this population; and (2) reporting on recent attempts in Kenya, and in England and Wales, to promote voting by people with intellectual disabilities. It concludes by considering the effectiveness of the different approaches these countries have adopted.

Development of tertiary lymphoid structures in the kidneys of pigs with chronic leptospiral nephritis.

Tertiary lymphoid organs (TLOs) are structures that are morphologically and functionally similar to secondary lymphoid organs. TLOs usually arise in a background of chronic inflammation. Several histological patterns of interstitial nephritis have been documented in porcine leptospirosis. Among them the lympho-follicular pattern is characterized by infiltrates of mononuclear cells organized in lymphoid follicle-like structures. Immunohistological analysis of 5 cases of porcine lympho-follicular nephritis associated with Leptospira Pomona infection demonstrated the presence of inflammatory cell populations, including B cells, T cells, macrophages and follicular dendritic cells (FDCs), which were compartmentalized as in TLOs. Immunohistochemistry for Leptospira Pomona revealed an intimate association between leptospiral antigen and FDCs. Overexpression of MHCII in different populations of both professional and non-professional antigen presenting cells was also demonstrated. FDCs play role during TLOs induction for their ability to retain non-self antigens in the form of immune complexes, thus causing persistent T cell activation, generation of a complex cytokine network and stimulation of humoral immunity. Sustained bacterial antigen presentation in the context of chronic leptospiral nephritis, may also lead to autoimmune mechanisms involved in the generation of TLOs. Whether lymphoid neogenesis and TLOs play a protective role in porcine leptospiral nephritis is still unclear.

Superantigenic activity of toxic shock syndrome toxin-1 is resistant to heating and digestive enzymes.

AIMS: To elucidate the stability of superantigenic activity and pathogenesis of toxic shock syndrome toxin 1 (TSST-1) and staphylococcal enterotoxin A (SEA) against heating and digestive enzymes. METHODS AND RESULTS: Purified TSST-1 and SEA were treated with heating, pepsin and trypsin that are related to food cooking, stomach and intestine conditions. The integrity, superantigenic activity and toxicity of treated TSST-1 and SEA were analysed by Western blotting, spleen cell culture, cytokine assay and toxic shock models. Both TSST-1 and SEA showed strong resistance to heating, pepsin and trypsin digestion. Furthermore, the treated TSST-1 showed significant higher induction of interferon-γ and toxic shock compared with that of SEA. Pepsin- or trypsin-digested TSST-1 fragments still showed significant superantigenic and lethal shock toxicities. CONCLUSIONS: The superantigenic activity of TSST-1 was stable to heating and digestive enzymes. Pepsin- and trypsin-digested TSST-1 fragments still showed superantigenic and lethal shock activities, indicating that digested TSST-1 could cross epithelial cells and induce systemic toxicity. SIGNIFICANCE AND IMPACT OF THE STUDY: This study found, for the first time, that pepsin- or trypsin-digested smaller TSST-1 retained significant superantigenic and lethal shock activities. The different resistance of TSST-1 and SEA participates in the different pathogenic activities during food poisoning and toxic shock syndrome.

The phenomenology and diagnosis of psychiatric illness in people with Prader-Willi syndrome.

BACKGROUND: Psychotic illness is strongly associated with the maternal uniparental disomy (mUPD) genetic subtype of Prader-Willi syndrome (PWS), but not the deletion subtype (delPWS). This study investigates the clinical features of psychiatric illness associated with PWS. We consider possible genetic and other mechanisms that may be responsible for the development of psychotic illness, predominantly in those with mUPD. METHOD: The study sample comprised 119 individuals with genetically confirmed PWS, of whom 46 had a history of psychiatric illness. A detailed clinical and family psychiatric history was obtained from these 46 using the PAS-ADD, OPCRIT, Family History and Life Events Questionnaires. RESULTS: Individuals with mUPD had a higher rate of psychiatric illness than those with delPWS (22/34 v. 24/85, p<0.001). The profile of psychiatric illness in both genetic subtypes resembled an atypical affective disorder with or without psychotic symptoms. Those with delPWS were more likely to have developed a non-psychotic depressive illness (p=0.005) and those with mUPD a bipolar disorder with psychotic symptoms (p=0.00005). Individuals with delPWS and psychotic illness had an increased family history of affective disorder. This was confined exclusively to their mothers. CONCLUSIONS: Psychiatric illness in PWS is predominately affective with atypical features. The prevalence and possibly the severity of illness are greater in those with mUPD. We present a 'two-hit' hypothesis, involving imprinted genes on chromosome 15, for the development of affective psychosis in people with PWS, regardless of genetic subtype.

Effectiveness and safety of hypnotic drugs in the treatment of insomnia in over 70-year old people.

Good sleep is an important index of the quality of life in people and above all in old subjects. Among all the symptoms reported to general practitioner, insomnia is at the 3(rd) place and this is present in particular in the elderly. In elderly people high comorbidity and polytreatment are often present. We have studied 60 elderly people with history of insomnia and concomitant diseases: depression, dementia and behavioral disturbances. All the patients of the present study were visited in our outpatients' department. Three hypnotic drugs were used for the treatment of insomnia: zolpidem, or triazolam, or oxazepam, respectively at doses of 10mg/day, 0.125-0.25mg/day and 15.0mg/day. All the three drugs showed to be effective and safe; no paradoxical effects were observed.

Identification of novel VHL targets that are associated with the development of renal cell carcinoma.

von Hippel-Lindau (VHL) disease is a dominantly inherited family cancer syndrome characterized by the development of retinal and central nervous system haemangioblastomas, renal cell carcinoma (RCC) and phaeochromocytoma. Specific germline VHL mutations may predispose to haemangioblastomas, RCC and phaeochromocytoma to a varying extent. Although dysregulation of the hypoxia-inducible transcription factor-2 and JunB have been linked to the development of RCC and phaeochromocytoma, respectively, the precise basis for genotype-phenotype correlations in VHL disease have not been defined. To gain insights into the pathogenesis of RCC in VHL disease we compared gene expression microarray profiles in a RCC cell line expressing a Type 1 or Type 2B mutant pVHL (RCC-associated) to those of a Type 2A or 2C mutant (not associated with RCC). We identified 19 differentially expressed novel VHL target genes linked to RCC development. Eight targets were studied in detail by quantitative real-time polymerase chain reaction (three downregulated and five upregulated by wild-type VHL) and for six genes the effect of VHL inactivation was mimicked by hypoxia (but hypoxic-induction of smooth muscle alpha-actin 2 was specific for a RCC cell line). The potential role of four RCC-associated VHL target genes was assessed in vitro. NB thymosin beta (TMSNB) and proteinase-activated receptor 2 (PAR2) (both downregulated by wt pVHL) increased cell growth and motility in a RCC cell line, but aldehyde dehydrogenase (ALDH)1 and ALDH7 had no effect. These findings implicate TMSNB and PAR2 candidate oncogenes in the pathogenesis of VHL-associated RCC.

The course and outcome of psychiatric illness in people with Prader-Willi syndrome: implications for management and treatment.

BACKGROUND: This study is part of a larger UK-wide study investigating psychiatric illness in people with Prader-Willi syndrome (PWS), and describes the longitudinal aspect of psychiatric illness, in particular psychotic illness, and examines the use and role of psychotropic medication. METHOD: A total of 119 individuals with genetically confirmed PWS were included in the study. An informant-based questionnaire was administered for each participant to screen for a history of psychopathology. Those who screened positive were visited at their homes to obtain further information. This assessment included a full psychiatric history and mental state examination using the Psychiatric Assessment Schedule for Adults with Developmental Disability and the Operational Criteria Checklist for psychotic and affective illness to collect information regarding phenomenology and course of illness, and a modified life events questionnaire. At the end of the study period, informant-based telephone interviews were again carried out, up to 2.5 years after the initial screening. Information regarding medication usage was collected. RESULTS: The results confirm previous findings that psychiatric illness in people with PWS resembles an affective disorder. Individuals with the maternal uniparental disomy genetic subtype had a more severe course of illness than those with the deletion genetic subtype in terms of a greater risk of recurrence, more episodes, higher incidence and a possibly poorer response to medication with more side-effects. Individuals with a recurrent episode during the follow-up period had a poorer course of illness. Selective serotonin reuptake inhibitor medication is frequently used, and beneficial effects may reflect fundamental pathological processes in PWS. Mood-stabilizing medication was found to be of little benefit and reasons for this are examined. CONCLUSION: The longitudinal course of psychiatric illness and response to medication in people with PWS is fully described. Further research is needed regarding the effect of psychotropic medications, particularly mood-stabilizing medication. These data will enable informed decisions to be made regarding management options and provide information on the possible long-term outcome of illness.

Molecular genetic analysis of FIH-1, FH, and SDHB candidate tumour suppressor genes in renal cell carcinoma.

BACKGROUND: Overexpression of the hypoxia inducible factor 1 (HIF-1) and HIF-2 transcription factors and the consequent upregulation of hypoxia inducible mRNAs is a feature of many human cancers and may be unrelated to tissue hypoxia. Thus, the VHL (von Hippel-Lindau) tumour suppressor gene (TSG) regulates HIF-1 and HIF-2 expression in normoxia by targeting the alpha subunits for ubiquitination and proteolysis. Inactivation of the VHL TSG in VHL tumours and in sporadic clear cell renal cell carcinoma (RCC) results in overexpression of HIF-1 and HIF-2. However, RCC without VHL inactivation may demonstrate HIF upregulation, suggesting that VHL independent pathways for HIF activation also exist. In RCC, three candidate HIF activating genes exist-FIH-1 (factor inhibiting HIF), SDHB, and FH-which may be dependent or independent of VHL inactivation. AIMS: To investigate FIH-1, SDHB, and FH for somatic mutations in sporadic RCC. METHODS: Gene mutation was analysed in primary RCCs (clear cell RCCs, papillary RCCs, and oncocytomas) and RCC cell lines. SDHB mutation analysis was performed by denaturing high performance liquid chromatography followed by direct sequencing of aberrant PCR products. FH and FIH-1 mutation analysis were performed by single stranded conformational polymorphism and direct sequencing of PCR products. RESULTS: No mutations were identified in the three genes investigated. CONCLUSIONS: There was no evidence to suggest that somatic mutations occur in the FH, FIH-1, or SDHB TSGs in sporadic RCCs.