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Introduction Our objective was to document the incidence of COVID-19 in vaccinated health care professionals and related personnel. Method We conducted an online survey to ascertain the incidence of COVID-19 symptoms, reverse transcriptase polymerase chain reaction (RT-PCR) positivity, effect on normal activity, need for anti-COVID-19 medication, hospitalization, and death among individuals who had completed both doses of COVID vaccination at least 2 weeks earlier. Results A total of 351 unique valid responses were received. Among the 340 people who had been vaccinated in India, 5% (17/340) had COVID-19 symptoms, 4.7% (16) became COVID-19 RT-PCR positive, 12 (3.5%) had sickness preventing normal daily activity, 2.65% (9) required anti-COVID-19 medication, and 1.18% (4) required hospitalization. Among family members living with the survey responders, the corresponding incidence was even lower. There was one death in this group. Discussion Being health care professionals, the responders would be at higher risk of daily exposure to COVID-19. Even in this high risk group, the vaccine efficacy is good. Vulture journalists should stop spreading fake news and misinformation that makes people hesitate taking the vaccine or be afflicted analysis paralysis. Every person who chooses to remain unvaccinated increases the risk for our entire community. We also need to follow universal precautions (wearing mask, physical distancing, handwashing) diligently without letting down our guard.

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BACKGROUND: As Zimbabwe approaches epidemic control of HIV, programs now prioritize viral load over CD4 monitoring, making it difficult to identify persons living with HIV (PLHIV) suffering from advanced disease (AD). We present an analysis of cross-sectional ZIMPHIA data, highlighting PLHIV with AD and concurrent viral load suppression (VLS). METHODS: ZIMPHIA collected blood specimens for HIV testing from 22,501 consenting adults (ages 15 years and older); 3,466 PLHIV had CD4 and VL results. Household HIV testing used the national serial algorithm, and those testing positive then received point-of-care CD4 enumeration with subsequent VL testing. We used logistic regression analysis to explore factors associated with concurrent AD and VLS (<1000 copies/mL). All analyses were weighted to account for complex survey design. RESULTS: Of the 3,466 PLHIV in the survey with CD4 and VL results, 17% were found to have AD (CD4<200cells/mm3). Of all AD patients, 30% had VLS. Concurrent AD and VLS was associated with male sex (aOR 2.45 95%CI 1.61-3.72), older age (35-49 years [aOR 2.46 95%CI 1.03-5.91] and 50+ years [aOR 4.82 95%CI 2.02-11.46] vs 15-24 years), and ART duration (<6 months [aOR 0.46 95%CI 0.29-0.76] and 6-24 months [aOR 2.07 95%CI 1.35-3.17] vs more than 2 years). The relationship between sex and AD is driven by age with significant associations among men aged 25-34, (aOR 3.37 95%CI 1.35-8.41), 35-49 (aOR 5.13 95%CI 2.16-12.18), and 50+ (aOR 12.56 95%CI 4.82-32.72) versus men aged 15-24. CONCLUSIONS: The percentage of PLHIV with AD and VLS illustrates the conundrum of decreased support for CD4 monitoring, as these patients may not receive appropriate clinical services for advanced HIV disease. In high-prevalence settings such as Zimbabwe, CD4 monitoring support warrants further consideration to differentiate care appropriately for the most vulnerable PLHIV. Males may need to be prioritized, given their over-representation in this sub-population.

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BACKGROUND: The 5-year survival rate for metastatic renal cell carcinoma (RCC) is estimated to be <10%. RCC is highly resistant to chemotherapy. Targeted agents are now first choice of therapy for metastatic RCC such as sunitinib and sorafenib. METHODS: This study is a retrospective analysis of 15 patients having metastatic RCC treated with sunitinib. Apart from three patients, all had clear cell histology. Thirteen patients received dosage of 50 mg/d (4 weeks on/2 weeks off cycles). In 14 patients sunitinib was used as 1st line. The primary end point was objective response rate. Secondary end points were progression free survival (PFS) and safety. RESULTS: Until date of reporting, 3 out of 15 patients are currently on sunitinib. The most common Memorial Sloan = Kettering Cancer Centre poor prognostic factor was an interval of <1 year between diagnosis and starting of treatment (80%). The objective response rate was 13.66% (complete response [CR] + partial response [PR] = 0 + 2). Clinical benefit rate (CR + PR + stable disease) was 60% (n = 9). Median PFS in this study was 7.5 months, with a range of 2-22 month. Median overall survival (OS) of patients in this study was 12 months with a range of 3-24 month. An impact of the dose or/and number of cycles on response was seen in this study, with patients having average cycles >3 showing better response rates, PFS and OS. Major toxicities seen were fatigue ( n= 7), diarrhea (n = 3) and skin rash (n = 4) with majority patients experienced Grade 1-2 toxicities. While Grade 3-4 toxicities include fatigue (n = 1), mucositis (n = 1) and nausea (n = 1). CONCLUSIONS: These results confirm efficacy and safety profile of sunitinib in metastatic RCC, particularly as a first line. Sunitinib produced a 60% disease control rate for metastatic RCC in Indian patients, with acceptable rates of toxicity at a dose of 50 mg daily. Response rates were well matched to other studies confirming the efficacy of sunitinib.

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The mechanism of dead-in-bed syndrome (DBS), a rare but devastating condition that mainly affects young type 1 diabetes patients, remains mysterious. A new theory is proposed to explain this syndrome. This theory suggests that repeated episodes of hypoglycaemia-induced adaptation in orexin-A neurons cause (i) defective awakening and (ii) hypotonia of upper airway muscles during sleep. Consequently, due to the combined effect of these factors, long-term exposure of intermittent hypoxia occurs, leading to a combination of factors - such as depression of ventilation, increase in sympathetic tone, fluctuations in intrathoracic pressure and cardiac arrhythmias - these in conjunction with an underlying cardiovascular pathology (genetically inherited or acquired) cause cardio-respiratory failure and thus sudden death during sleep. This mechanism can be generalized to explain other cases of sudden unexplained nocturnal deaths including sudden infant deaths (SIDs).

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Development of therapeutic measures to reduce the risk of potentially fatal episodes of hypoglycaemia and thus to achieve the full benefits of intensive insulin therapy in diabetic patients requires a complete understanding of the multi-factorial mechanisms for repeated hypoglycaemia-induced blunting of the sympatho-adrenal response (BSAR). After critical analysis of the hypotheses, this review paper suggests a heuristic theory. This theory suggests two mechanisms for the BSAR, each involving a critical role for the central brain noradrenergic system. Furthermore, this theory also suggests that the lateral hypothalamus (LH) plays an important role in this phenomenon. Within the framework of this theory, explanations for 1) sexual dimorphism in the adrenomedullary response (AR), 2) dissociation in the blunting of the AR and the sympathetic response (SR) and 3) antecedent exercise-induced blunting of the AR are provided. In addition, habituation of orexin-A neurons is suggested to cause defective awakening. Moreover, potential therapeutics measures have been also suggested that will reduce or prevent severe episodes of hypoglycaemia.

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Serodiagnosis of human immunodeficiency virus (HIV) infection in the United States has traditionally relied on a sequential two-test algorithm: an initial screen with an enzyme immunoassay (EIA) and reflex testing of EIA-reactive specimens with a more specific supplemental test such as Western blotting or immunofluorescence. The supplemental tests are tedious, subjective, and expensive. In addition, there have been major improvements in the performance and accuracy of the EIA tests as well as the introduction of rapid serologic tests (RT) and HIV nucleic acid amplification tests (NAAT). Related to these improvements is the possibility that alternative algorithms using combinations of currently approved HIV tests may function as well as if not better than the current algorithm, with more flexibility, improved accuracy, and lower cost. To this end, we evaluated the performance of 12 currently licensed tests and 1 in-house HIV test (6 EIA, 4 RT, and 3 NAAT) on panels of plasma samples from HIV-infected (n = 621 HIV type 1 [HIV-1] and 34 HIV-2) and uninfected (n = 513) people and of sequential specimens from people early in seroconversion (183 specimens from 15 patients). Test combinations were analyzed in two dual-test (sensitivity-optimized and specificity-optimized) algorithms and in a three-test (tie-breaking) algorithm, and performance was compared to the conventional algorithm. The results indicate that alternative algorithm strategies with currently licensed tests compare favorably with the conventional algorithm in detecting and confirming established HIV infection. Furthermore, there was a lower frequency of discordant or indeterminate results that require follow-up testing, and there was improved detection of early infection.

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BACKGROUND: The HIV incidence data are relevant in depicting the current dynamics and trend of the epidemic. Using a new laboratory method for HIV-1 incidence, we aimed at estimating a 10-year trend in HIV-1 incidence in Addis Ababa, Ethiopia. METHODS: We determined the temporal trends in HIV incidence based on a total of 7744 serum specimens from pregnant women who attended antenatal clinics in Addis Ababa between 1995 and 2003. HIV incidence was determined by IgG-capture HIV-1 BED incidence enzyme immunoassay following a validation using a well-characterized panel of serial serum specimens from subtype C-infected seroconverters. FINDINGS: Of the 1350 HIV+ specimens tested as part of the annual sentinel survey between 1995 and 2003, a total of 1332 (98.7%) were tested by BED HIV-1 incidence assay. The incidence rate of HIV-1 infection declined significantly from 7.7% (95% CI, 3.9-11.5%) in 1995 to 2.0% (95% CI, 0.7-3.3%) in 2003. Although there was a trend, amongst the age group of 15-29 years, in age-specific decline in incidence, it was not statistically significant. No change in HIV incidence rate was observed for the group aged above 30 years. INTERPRETATION: A corresponding decline in the incidence of HIV infection was observed with the decline in the prevalence of HIV infection between 1995 and 2003 in Addis Ababa City. Whether the declines were because of changes in sexual behaviours or other reasons needs to be explored. The BED HIV-1 incidence assay provides a valuable tool in obtaining information on recent HIV-1 infection.

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We evaluated a less-sensitive enzyme immunoassay (3A11-LS) for its possible use for early diagnosis of human immunodeficiency virus type 1 (HIV-1) infection in infants. The results were compared with those from the immunoglobulin G-capture enzyme immunoassay. A total of 239 sera from 77 infants were tested. All 25 sera from the 10 infants born to seronegative mothers were found to be negative by both assays. Forty-one seroreverting infants showed a complete decay of maternal antibodies by 4 months by the 3A11-LS assay. However, the assay detected HIV antibodies in only 9 (36%) of 25 sera collected from infected infants between 4 and 6 months and in 27 (63%) of 43 sera collected after 6 months of age. Further analysis with alternative cutoff values indicated that the 3A11-LS had a sensitivity of 12 to 44% and a specificity of 90 to 100% for infants between 4-6 months of age. This data suggest that a diagnosis of HIV infection in some of the infants could be made after 4 months of age by the 3A11-LS assay, although a negative 3A11-LS test result may not rule out infection and may require a further followup.

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OBJECTIVES: Successful highly active antiretroviral therapy (HAART) is usually associated with a rapid decline in HIV plasma RNA levels and a gradual increase in CD4 T cells. We examined whether changes in cytokine production and profile precede other immunological changes and whether these might occur in temporal association with plasma HIV RNA changes. DESIGN AND METHODS: Eleven HIV-1-infected patients were enrolled into a prospective cohort study; eight patients were naive to antiretroviral therapy. Blood samples were collected pre-therapy (week 0) and at 1, 2, and 3 weeks post-initiation of therapy. RESULTS: All 11 patients enrolled remained on triple HAART for 1 week, eight for 2 weeks, and six for > or = 3 weeks. When compared to week 0, these patients had a > or = 2-log10 decline in HIV plasma RNA levels and/or a decline to < or = 400 copies/ml by week 3 of therapy (p = 0.004). The numbers and percentages of CD4 and CD8 T cells, and the percentage of naive, memory, and activated T cells did not change significantly between weeks 0 and 1 or 0 and 3. Of all the immune parameters examined only: the percentage of CD4 T cells spontaneously producing tumor necrosis factor (TNF)-alpha (median, 2.4 versus 0.5% P = 0.025); the percentage of CD8 T cells spontaneously producing TNF-alpha (median, 0.6 versus 0.2% P = 0.037); and the percentage of CD3 T cells spontaneously producing interleukin-4 (median, 1.8 versus 0.8% P = 0.004) changed significantly between weeks 0 and 3. CONCLUSIONS: In these patients, decreases in the percentage of T cells spontaneously producing TNF-alpha or interleukin-4 preceded changes in CD4 T cells. If confirmed by others, these observations may be useful as early predictors of response to and early failure of HAART.

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The balance between pro- and antiinflammatory cytokines may be important in malaria presentation and outcome. Malaria tends to be more severe in children than in adults, presumably because partial immunity develops with age. However, the full nature of, and age-related differences in, anti-malarial immunity are unknown. We compared: (1) serum and cell-specific cytokines of patients with acute malaria to those of patients with other acute illnesses and to those of healthy adults and (2) the cytokine responses of parasitemic children and parasitemic adults. Flow cytometry was done on the peripheral blood mononuclear cells of 148 hospitalized children, 161 febrile hospitalized adults, and 20 healthy adults in Malawi, Africa, a malaria-endemic country. Serum cytokines were also assessed for 80 of these patients. Thirty-eight participants were parasitemic with Plasmodium falciparum. Serum interleukin (IL)-10 (an antiinflammatory, immunoregulatory, and type 2 cytokine) levels were higher in malaria patients than in other patients (medians 502 pg/mL vs 16 pg/mL, P = 0.002), and the percentages of various lymphocyte populations making IL-6 (a proinflammatory, type 2 cytokine regulating iron distribution) were lower in malaria patients than in other patients (e.g., for spontaneous production by children's CD8(+) T cells: medians 1.4% vs 33.1%, P = 0.004). For adult patients, the percentages of lymphocytes spontaneously making IL-4 (a type 2 cytokine) were significantly lower in those with malaria than in those without malaria (medians 0.9% vs 2.1%, P = 0.005). The percentages of monocytes spontaneously making IL-8 (a chemotactic, proinflammatory chemokine) were higher in parasitemic children than in parasitemic adults (medians 5.8% vs 1.7%, P = 0.003). A number of cellular proinflammatory, type 1 parameters were significantly higher in all children (with or without malaria) than in all adults; these included the percentages of various lymphocyte populations making IL-6, both IL-6 and interferon-gamma, or IL-8. These data support the importance of IL-10 in malaria parasitemia. Given the lack of an IL-4 (type 2) response, IL-10's primary role may be immunoregulatory rather than type 2 in nature. In this study, the immune response to malaria was more proinflammatory in children than in adults. This difference, if corroborated by other studies, could be related to malaria's greater severity in children.

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OBJECTIVES: Information on early HIV-1 infection has come primarily from studies of persons infected with subtype B in North America and Europe; much less is known about other subtypes. The purpose of the present study was to compare the virologic and immunologic parameters following seroconversion among recently-infected persons infected with either of two different HIV-1 subtypes. METHOD: A prospective cohort study was carried out at methadone treatment clinics administered by the Bangkok Metropolitan Administration, Thailand. A total of 130 HIV-1-infected seroconverters (103 with HIV-1 subtype E and 27 with subtype B) were included in the study. The main outcome measures were serial HIV-1 RNA viral load, natural killer cell percentage, CD4 and CD8 lymphocyte counts since seroconversion. RESULTS: The demographic and behavioral characteristics of persons with either subtype were similar. Median RNA viral levels at the earliest time within 3 months of seroconversion were more than three times higher for persons infected with subtype E than subtype B (63 100 versus 18 050 copies/ml, P = 0.001). However, this difference decreased over time such that viral loads were similar at 12, 18, and 24 months following seroconversion. The CD4 and CD8 lymphocyte counts were similar in infections with either subtype during the entire period up to 24 months post-seroconversion. CONCLUSIONS: Higher viral loads associated with subtype E may result from inter-subtype biological differences; however, the epidemiological dynamics of transmission in Bangkok may have also contributed to this phenomenon.

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The development of a serologic algorithm to determine recent HIV seroconversion, using sensitive/less-sensitive testing strategies, has generated widespread interest in applying this approach to estimate HIV-1 incidence in various populations around the world. To evaluate this approach in non-B subtypes, longitudinal specimens (n = 522) collected from 90 incident infections among injecting drug users in Bangkok (subtype B infection, n = 18; subtype E infection, n = 72) were tested by the 3A11-LS assay. Standardized optical density (SOD) was calculated, using median values, and the window period between seroconversion as determined by sensitive and less sensitive tests was estimated by a maximum-likelihood model described previously. Our results show that the mean window period of the 3A11-LS assay was 155 days (95% CI, 128-189 days) for subtype B but was 270 days (95% CI, 187-349 days) for subtype E specimens from Thailand. About 4% of individuals with incident subtype E infections remained below the threshold (SOD of 0.75), even 2 years after seroconversion. Among the patients with clinical AIDS and declining antibodies, none of the 7 individuals with subtype B, but 10 (8.7%) of 115 with subtype E infections, were misclassified as recent infections. Lowering the cutoff to an SOD of 0.45 for subtype E specimens resulted in a mean window period of 185 days (95% CI, 154-211 days), with all individuals seroconverting, and reduced the number of subtype E-infected patients with AIDS who were misclassified as having recent infection to 2.6%. Our results demonstrate that the 3A11-LS assay has different performance characteristics in detecting recent infections among individuals infected with subtypes B or E. Determining appropriate cutoffs and mean window periods for other HIV-1 subtypes will be necessary before this approach can be reliably implemented in settings where non-B subtypes are common.

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Pregnant women infected with HIV-1 were enrolled in a prospective mother-to-infant transmission study from 1992 through 1994 in Bangkok. In participating hospitals, voluntary HIV testing was routinely offered at the beginning of antenatal care and again in the middle of the third trimester of pregnancy. Women who seroconverted to HIV during pregnancy were compared with women who had tested positive on their first antenatal test. Maternal HIV RNA levels were determined during pregnancy, at delivery, and postpartum using RNA polymerase chain reaction (PCR), and infection status in infants was determined by DNA PCR. No infants were breast-fed, but prophylactic antiretroviral therapy was not yet used in Thailand to prevent transmission from mother to infant. Among enrolled women, 16 who seroconverted during pregnancy and 279 who were HIV-1-seropositive at their first antenatal test gave birth. Median plasma RNA levels at delivery were similar for the two groups (17,505 and 20,845 copies/ml, respectively; p =.8). Two (13.3%) of 15 infants born to women who seroconverted and 66 (24.8%) of 266 infants born to previously HIV-seropositive women were infected with HIV (p =.5). There was no increased risk for mother-to-infant HIV transmission and no significant difference in viral load at delivery between HIV-infected women who seroconverted to HIV during pregnancy and those who were HIV-seropositive when first tested.

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We evaluated 16 antibody assays for their performance in discriminating recent from established HIV-1 infection. These approaches were based on antigen specificity, quantity, conformation dependence, and avidity/affinity of HIV-specific antibodies. A panel of 41 sera from subjects who had seroconverted in the previous 2-6 months (n = 20) and from subjects with established infection (>1 year, n = 21) were run in each assay. Compared with anti-Gag and anti-Pol responses, quantitative anti-Env antibody levels were initially lower and ultimately higher, resulting in the greatest spread and least overlap between incident and established infection. Quantitative measurement included end-point titer in Western blot, end-point titer or response at a given dilution in solid-phase enzyme immunoassays (EIAs) with recombinant proteins or synthetic peptides, and IgG capture assays that reflect the relative proportion of IgG that is anti-HIV antibody. Focusing on the anti-env response, we measured specific responses to the V3 region of gp120, to the CD4-binding site of gp120, to a peptide corresponding to the immunodominant region of gp41, and to conformation-dependent epitopes of gp120. We also measured antibody affinity for gp41 peptide and the relative avidity for gp120 or gp41 peptide by thermal or urea-elution assays. These assays also discriminated recent from established infection but were not necessarily superior to the quantitative anti-Env assays. Appropriate approaches, based on distinct principles or combination of principles, can be used to develop simple assays for identifying individuals recently infected with HIV-1.

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The presence of human immunodeficiency virus (HIV)-specific antibodies was examined in plasma and cervicovaginal (mucosal) samples of 24 HIV-exposed uninfected (EU) female sexual partners of HIV-infected men, and compared with findings in 18 HIV-infected and 15 low-risk HIV-uninfected women. Only HIV-infected women had detectable HIV-specific immunoglobulin G (IgG) (18 of 18) or HIV-IgA (6 of 18) in cervicovaginal samples by enzyme immunoassay (EIA). However, 3 of 24 EU women had positive Western blot (WB) for HIV-IgG in cervicovaginal secretions, while 2 of 24 EU women and 1 of 15 low-risk controls had indeterminate IgG-WB. EU women with positive or indeterminate IgG-WB in the cervicovaginal samples were similar in risk to the remaining EU women. None of the HIV-uninfected women had mucosal HIV-IgA. The findings suggest that some sexually or parenterally exposed HIV-uninfected women might develop low-level mucosal IgG responses. However, it appears unlikely that HIV-specific cervicovaginal antibodies play a major role in protection from HIV infection in this EU population.

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The contribution of chronic immune stimulation on the progression of lentivirus-induced disease was evaluated in the SIVmac251 macaque model of AIDS. Following SIV inoculation, seroconversion and control of the acute viral replication phase, repeated immune stimulations with tetanus toxoid (TT), keyhole limpet hemocyanin (KLH) and allogeneic peripheral blood mononuclear cells (PBMC) were initiated in four monkeys. These animals showed a significant shortening of survival when compared with eight non-immune-stimulated control animals inoculated with the same route, dose and stock of SIVmac251 (median survival 9.5 months versus 17 months, P = 0.010). In addition, when the comparison was extended to another 22 control animals of different origin but inoculated by the same route with similar doses and stocks of SIVmac251, the difference in survival was still significant (9.5 versus 18 months, P = 0.003). This accelerated progression of symptomatic disease was not accompanied with significant increases in plasma viral loads, but suboptimal antibody responses to the immunizing antigens were noted, correlating with the length of survival. These findings may have implications for HIV-infected humans suffering from chronic infectious diseases.

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A group of three rhesus macaques were inoculated with SIV isolated from a human (SIVhu) accidentally exposed and infected with SIVsm. Extensive sequence analyses of SIVhu obtained from the human and macaques following infection indicated the presence of truncated nef. Not only did nef fail to repair itself in vivo postinfection (p.i.), but instead, further mutations added additional stop codons with increasing time p.i. Infection of these animals was associated with minimal acute viral replication, followed by undetectable plasma viral loads and only intermittent PCR detection up to 5 years p.i. The three SIVhu infected and three control monkeys were then challenged with the heterologous highly pathogenic SHIV89.6p. All three controls became infected and showed rapid declines in peripheral CD4(+) lymphocytes, disease, and death at 10 and 32 weeks p.i., respectively. In contrast, all three animals previously infected with SIVhu are healthy and exhibit stable CD4(+) lymphocyte levels and undetectable plasma viral loads at >20 months post-SHIV89. 6p challenge. Only transient, low levels of SHIV replication were noted in these animals. Whereas responses to SIVgag/pol were noted, no evidence for SIV/SHIV envelope cross-reactivity was detected by antibody or CTL analyses, suggesting that the protective immune mechanisms to the heterologous challenge isolate were most likely not directed to envelope but rather to other viral determinants.

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Here, we show that the IFN-beta enhanceosome activates transcription by directing the ordered recruitment of chromatin modifying and general transcription factors to the IFN-beta promoter. The enhanceosome is assembled in the nucleosome-free enhancer region of the IFN-beta gene, leading to the modification and remodeling of a strategically positioned nucleosome that masks the TATA box and the start site of transcription. Initially, the GCN5 complex is recruited, which acetylates the nucleosome, and this is followed by recruitment of the CBP-PolII holoenzyme complex. Nucleosome acetylation in turn facilitates SWI/SNF recruitment by CBP, resulting in chromatin remodeling. This program of recruitment culminates in the binding of TFIID to the promoter and the activation of transcription.

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