A structural study of 4-aminoantipyrine and six of its Schiff base derivatives

Six derivatives of 4-amino-1,5-dimethyl-2-phenyl-2,3-dihydro-1H-pyrazol-3-one (4-aminoantipyrine), C11H13N3O, (I), have been synthesized and structurally characterized to investigate the changes in the observed hydrogen-bonding motifs compared to the original 4-aminoantipyrine. The derivatives were synthesized from the reactions of 4-aminoantipyrine with various aldehyde-, ketone- and ester-containing molecules, producing (Z)-methyl 3-[(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)amino]but-2-enoate, C16H19N3O3, (II), (Z)-ethyl 3-[(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)amino]but-2-enoate, C17H21N3O3, (III), ethyl 2-[(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)amino]cyclohex-1-enecarboxylate, C20H25N3O3, (IV), (Z)-ethyl 3-[(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)amino]-3-phenylacrylate, C22H23N3O3, (V), 2-cyano-N-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)acetamide, C14H14N4O2, (VI), and (E)-methyl 4-{[(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)amino]methyl}benzoate, C20H19N3O3, (VII). The asymmetric units of all these compounds have one molecule on a general position. The hydrogen bonding in (I) forms chains of molecules via intermolecular N-H⋯O hydrogen bonds around a crystallographic sixfold screw axis. In contrast, the formation of enamines for all derived compounds except (VII) favours the formation of a six-membered intramolecular N-H⋯O hydrogen-bonded ring in (II)-(V) and an intermolecular N-H⋯O hydrogen bond in (VI), whereas there is an intramolecular C-H⋯O hydrogen bond in the structure of imine (VII). All the reported compounds, except for (II), feature π-π interactions, while C-H⋯π interactions are observed in (II), C-H⋯O interactions are observed in (I), (III), (V) and (VI), and a C-O⋯π interaction is observed in (II).SP2016http://journals.iucr.org/c/issues/2015/02/00/fn3185

Patterns of disease on admission to children’s wards and changes during a COVID-19 outbreak in KwaZulu-Natal Province, South Africa

Background. Major causes of under-5 child deaths in South Africa (SA) are well recognised, and child mortality rates are falling. The focus of child health is therefore shifting from survival to disease prevention and thriving, but local data on the non-fatal disease burden are limited. Furthermore, COVID-19 has affected children’s health and wellbeing, both directly and indirectly.Objectives. To describe the pattern of disease on admission of children at different levels of care, and assess whether this has been affected by COVID-19.Methods. Retrospective reviews of children’s admission and discharge registers were conducted for all general hospitals in iLembe and uMgungundlovu districts in KwaZulu-Natal Province, SA, from January 2018 to September 2020. The Global Burden of Disease framework was adapted to create a data capture sheet with four broad diagnostic categories and 37 specific cause categories. Monthly admission numbers were recorded per cause category, and basic descriptive analysis was completed in Microsoft Excel.Results. Overall, 36 288 admissions were recorded across 18 hospital wards, 32.0% at district, 49.8% at regional and 18.2% at tertiary level. Communicable diseases, perinatal conditions and nutritional deficiencies (CPNs) accounted for 37.4% of admissions, non-communicable diseases (NCDs) for 43.5% and injuries for 17.1%. The distribution of broad diagnostic categories varied across levels of care, with CPNs being more common at district level and NCDs more common at regional and tertiary levels. Unintentional injuries represented the most common cause category (16.6%), ahead of lower respiratory tract infections (16.1%), neurological conditions (13.6%) and diarrhoeal disease (8.4%). The start of the local COVID-19 outbreak coincided with a 43.1% decline in the mean number of monthly admissions. Admissions due to neonatal conditions and intentional injuries remained constant during the COVID-19 outbreak, while those due to other disease groups (particularly respiratory infections) declined.Conclusions. Our study confirms previous concerns around a high burden of childhood injuries in our context. Continued efforts are needed to prevent and treat traditional neonatal and childhood illnesses. Concurrently, the management of NCDs should be prioritised, and evidence-based strategies are sorely needed to address the high injury burden in SA

Improved outcomes for hepatic trauma in England and Wales over a decade of trauma and hepatobiliary surgery centralisation

Background: Over the last decade trauma services have undergone a reconfiguration in England and Wales. The objective is to describe the epidemiology, management and outcomes for liver trauma over this period and examine factors predicting survival. Methods: Patients sustaining hepatic trauma were identified using the Trauma Audit and Research Network database. Demographics, management and outcomes were assessed between January 2005 and December 2014 and analysed over five, 2-year study periods. Independent predictor variables for the outcome of liver trauma were analysed using multiple logistic regression. Results: 4368 Patients sustained hepatic trauma (with known outcome) between January 2005 and December 2014. Median age was 34 years (interquartile range 23–49). 81% were due to blunt and 19% to penetrating trauma. Road traffic collisions were the main mechanism of injury (58.2%). 241 patients (5.5%) underwent liver-specific surgery. The overall 30-day mortality rate was 16.4%. Improvements were seen in early consultant input, frequency and timing of computed tomography (CT) scanning, use of tranexamic acid and 30-day mortality over the five time periods. Being treated in a unit with an on-site HPB service increased the odds of survival (odds ratio 3.5, 95% confidence intervals 2.7–4.5). Conclusions: Our study has shown that being treated in a unit with an on-site HPB service increased the odds of survival. Further evaluation of the benefits of trauma and HPB surgery centralisation is warranted

Outcomes of laboratory-confirmed SARS-CoV-2 infection during resurgence driven by Omicron lineages BA.4 and BA.5 compared with previous waves in the Western Cape Province, South Africa

OBJECTIVE: We aimed to compare clinical severity of Omicron BA.4/BA.5 infection with BA.1 and earlier variant infections among laboratory-confirmed SARS-CoV-2 cases in the Western Cape, South Africa, using timing of infection to infer the lineage/variant causing infection. METHODS: We included public sector patients aged ≥20 years with laboratory-confirmed COVID-19 between 1-21 May 2022 (BA.4/BA.5 wave) and equivalent prior wave periods. We compared the risk between waves of (i) death and (ii) severe hospitalization/death (all within 21 days of diagnosis) using Cox regression adjusted for demographics, comorbidities, admission pressure, vaccination and prior infection. RESULTS: Among 3,793 patients from the BA.4/BA.5 wave and 190,836 patients from previous waves the risk of severe hospitalization/death was similar in the BA.4/BA.5 and BA.1 waves (adjusted hazard ratio (aHR) 1.12; 95% confidence interval (CI) 0.93; 1.34). Both Omicron waves had lower risk of severe outcomes than previous waves. Prior infection (aHR 0.29, 95% CI 0.24; 0.36) and vaccination (aHR 0.17; 95% CI 0.07; 0.40 for at least 3 doses vs. no vaccine) were protective. CONCLUSION: Disease severity was similar amongst diagnosed COVID-19 cases in the BA.4/BA.5 and BA.1 periods in the context of growing immunity against SARS-CoV-2 due to prior infection and vaccination, both of which were strongly protective

Rapid epidemic expansion of the SARS-CoV-2 Omicron variant in southern Africa

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) epidemic in southern Africa has been characterised by three distinct waves. The first was associated with a mix of SARS-CoV-2 lineages, whilst the second and third waves were driven by the Beta and Delta variants, respectively1-3. In November 2021, genomic surveillance teams in South Africa and Botswana detected a new SARS-CoV-2 variant associated with a rapid resurgence of infections in Gauteng Province, South Africa. Within three days of the first genome being uploaded, it was designated a variant of concern (Omicron) by the World Health Organization and, within three weeks, had been identified in 87 countries. The Omicron variant is exceptional for carrying over 30 mutations in the spike glycoprotein, predicted to influence antibody neutralization and spike function4. Here, we describe the genomic profile and early transmission dynamics of Omicron, highlighting the rapid spread in regions with high levels of population immunity

Risk factors for COVID-19-related in-hospital mortality in a high HIV and tuberculosis prevalence setting in South Africa : a cohort study

BACKGROUND : The interaction between COVID-19, non-communicable diseases, and chronic infectious diseases such as HIV and tuberculosis is unclear, particularly in low-income and middle-income countries in Africa. South Africa has a national HIV prevalence of 19% among people aged 15–49 years and a tuberculosis prevalence of 0·7% in people of all ages. Using a nationally representative hospital surveillance system in South Africa, we aimed to investigate the factors associated with in-hospital mortality among patients with COVID-19. METHODS : In this cohort study, we used data submitted to DATCOV, a national active hospital surveillance system for COVID-19 hospital admissions, for patients admitted to hospital with laboratory-confirmed SARS-CoV-2 infection between March 5, 2020, and March 27, 2021. Age, sex, race or ethnicity, and comorbidities (hypertension, diabetes, chronic cardiac disease, chronic pulmonary disease and asthma, chronic renal disease, malignancy in the past 5 years, HIV, and past and current tuberculosis) were considered as risk factors for COVID-19-related in-hospital mortality. COVID-19 in-hospital mortality, the main outcome, was defined as a death related to COVID-19 that occurred during the hospital stay and excluded deaths that occurred because of other causes or after discharge from hospital; therefore, only patients with a known in-hospital outcome (died or discharged alive) were included. Chained equation multiple imputation was used to account for missing data and random-effects multivariable logistic regression models were used to assess the role of HIV status and underlying comorbidities on COVID-19 in-hospital mortality. FINDINGS : Among the 219 265 individuals admitted to hospital with laboratory-confirmed SARS-CoV-2 infection and known in-hospital outcome data, 51 037 (23·3%) died. Most commonly observed comorbidities among individuals with available data were hypertension in 61 098 (37·4%) of 163 350, diabetes in 43 885 (27·4%) of 159 932, and HIV in 13 793 (9·1%) of 151 779. Tuberculosis was reported in 5282 (3·6%) of 146 381 individuals. Increasing age was the strongest predictor of COVID-19 in-hospital mortality. Other factors associated were HIV infection (adjusted odds ratio 1·34, 95% CI 1·27–1·43), past tuberculosis (1·26, 1·15–1·38), current tuberculosis (1·42, 1·22–1·64), and both past and current tuberculosis (1·48, 1·32–1·67) compared with never tuberculosis, as well as other described risk factors for COVID-19, such as male sex; non-White race; underlying hypertension, diabetes, chronic cardiac disease, chronic renal disease, and malignancy in the past 5 years; and treatment in the public health sector. After adjusting for other factors, people with HIV not on antiretroviral therapy (ART; adjusted odds ratio 1·45, 95% CI 1·22–1·72) were more likely to die in hospital than were people with HIV on ART. Among people with HIV, the prevalence of other comorbidities was 29·2% compared with 30·8% among HIV-uninfected individuals. Increasing number of comorbidities was associated with increased COVID-19 in-hospital mortality risk in both people with HIV and HIV-uninfected individuals. INTERPRETATION : Individuals identified as being at high risk of COVID-19 in-hospital mortality (older individuals and those with chronic comorbidities and people with HIV, particularly those not on ART) would benefit from COVID-19 prevention programmes such as vaccine prioritisation as well as early referral and treatment.DATCOV, as a national surveillance system, is funded by the South African National Institute for Communicable Diseases (NICD) and the South African National Government.http://www.thelancet.com/hivam2022School of Health Systems and Public Health (SHSPH

Clinical features and outcomes of COVID-19 admissions in a population with a high prevalence of HIV and tuberculosis: a multicentre cohort study

Background There is still a paucity of evidence on the outcomes of coronavirus disease 2019 (COVID-19) among people living with human immunodeficiency virus (PWH) and those co-infected with tuberculosis (TB), particularly in areas where these conditions are common. We describe the clinical features, laboratory findings and outcome of hospitalised PWH and human immunodeficiency virus (HIV)-uninfected COVID-19 patients as well as those co-infected with tuberculosis (TB). Methods We conducted a multicentre cohort study across three hospitals in Cape Town, South Africa. All adults requiring hospitalisation with confirmed COVID-19 pneumonia from March to July 2020 were analysed. Results PWH comprised 270 (19%) of 1434 admissions. There were 47 patients with active tuberculosis (3.3%), of whom 29 (62%) were PWH. Three-hundred and seventy-three patients (26%) died. The mortality in PWH (n = 71, 26%) and HIV-uninfected patients (n = 296, 25%) was comparable. In patients with TB, PWH had a higher mortality than HIV-uninfected patients (n = 11, 38% vs n = 3, 20%; p = 0.001). In multivariable survival analysis a higher risk of death was associated with older age (Adjusted Hazard Ratio (AHR) 1.03 95%CI 1.02–1.03, p < 0.001), male sex (AHR1.38 (95%CI 1.12–1.72, p = 0.003) and being “overweight or obese” (AHR 1.30 95%CI 1.03–1.61 p = 0.024). HIV (AHR 1.28 95%CI 0.95–1.72, p 0.11) and active TB (AHR 1.50 95%CI 0.84–2.67, p = 0.17) were not independently associated with increased risk of COVID-19 death. Risk factors for inpatient mortality in PWH included CD4 cell count < 200 cells/mm3, higher admission oxygen requirements, absolute white cell counts, neutrophil/lymphocyte ratios, C-reactive protein, and creatinine levels. Conclusion In a population with high prevalence of HIV and TB, being overweight/obese was associated with increased risk of mortality in COVID-19 hospital admissions, emphasising the need for public health interventions in this patient population

Development and validation of quantitative PCR assays for HIV-associated cryptococcal meningitis in sub-Saharan Africa: a diagnostic accuracy study

Background: HIV-associated cryptococcal meningitis is the second leading cause of AIDS-related deaths, with a 10-week mortality rate of 25–30%. Fungal load assessed by colony-forming unit (CFU) counts is used as a prognostic marker and to monitor response to treatment in research studies. PCR-based assessment of fungal load could be quicker and less labour-intensive. We sought to design, optimise, and validate quantitative PCR (qPCR) assays for the detection, identification, and quantification of Cryptococcus infections in patients with cryptococcal meningitis in sub-Saharan Africa. Methods: We developed and validated species-specific qPCR assays based on DNA amplification of QSP1 (QSP1A specific to Cryptococcus neoformans, QSP1B/C specific to Cryptococcus deneoformans, and QSP1D specific to Cryptococcus gattii species) and a pan-Cryptococcus assay based on a multicopy 28S rRNA gene. This was a longitudinal study that validated the designed assays on cerebrospinal fluid (CSF) of 209 patients with cryptococcal meningitis at baseline (day 0) and during anti-fungal therapy (day 7 and day 14), from the AMBITION-cm trial in Botswana and Malawi (2018–21). Eligible patients were aged 18 years or older and presenting with a first case of cryptococcal meningitis. Findings: When compared with quantitative cryptococcal culture as the reference, the sensitivity of the 28S rRNA was 98·2% (95% CI 95·1–99·5) and of the QSP1 assay was 90·4% (85·2–94·0) in CSF at day 0. Quantification of the fungal load with QSP1 and 28S rRNA qPCR correlated with quantitative cryptococcal culture (R2=0·73 and R2=0·78, respectively). Both Botswana and Malawi had a predominant C neoformans prevalence of 67% (95% CI 55–75) and 68% (57–73), respectively, and lower C gattii rates of 21% (14–31) and 8% (4–14), respectively. We identified ten patients that, after 14 days of treatment, harboured viable but non-culturable yeasts based on QSP1 RNA detection (without any positive CFU in CSF culture). Interpretation: QSP1 and 28S rRNA assays are useful in identifying Cryptococcus species. qPCR results correlate well with baseline quantitative cryptococcal culture and show a similar decline in fungal load during induction therapy. These assays could be a faster alternative to quantitative cryptococcal culture to determine fungal load clearance. The clinical implications of the possible detection of viable but non-culturable cells in CSF during induction therapy remain unclear

Development and validation of quantitative PCR assays for HIV-associated cryptococcal meningitis in sub-Saharan Africa: a diagnostic accuracy study

Background: HIV-associated cryptococcal meningitis is the second leading cause of AIDS-related deaths, with a 10-week mortality rate of 25–30%. Fungal load assessed by colony-forming unit (CFU) counts is used as a prognostic marker and to monitor response to treatment in research studies. PCR-based assessment of fungal load could be quicker and less labour-intensive. We sought to design, optimise, and validate quantitative PCR (qPCR) assays for the detection, identification, and quantification of Cryptococcus infections in patients with cryptococcal meningitis in sub-Saharan Africa. Methods: We developed and validated species-specific qPCR assays based on DNA amplification of QSP1 (QSP1A specific to Cryptococcus neoformans, QSP1B/C specific to Cryptococcus deneoformans, and QSP1D specific to Cryptococcus gattii species) and a pan-Cryptococcus assay based on a multicopy 28S rRNA gene. This was a longitudinal study that validated the designed assays on cerebrospinal fluid (CSF) of 209 patients with cryptococcal meningitis at baseline (day 0) and during anti-fungal therapy (day 7 and day 14), from the AMBITION-cm trial in Botswana and Malawi (2018–21). Eligible patients were aged 18 years or older and presenting with a first case of cryptococcal meningitis. Findings: When compared with quantitative cryptococcal culture as the reference, the sensitivity of the 28S rRNA was 98·2% (95% CI 95·1–99·5) and of the QSP1 assay was 90·4% (85·2–94·0) in CSF at day 0. Quantification of the fungal load with QSP1 and 28S rRNA qPCR correlated with quantitative cryptococcal culture (R2=0·73 and R2=0·78, respectively). Both Botswana and Malawi had a predominant C neoformans prevalence of 67% (95% CI 55–75) and 68% (57–73), respectively, and lower C gattii rates of 21% (14–31) and 8% (4–14), respectively. We identified ten patients that, after 14 days of treatment, harboured viable but non-culturable yeasts based on QSP1 RNA detection (without any positive CFU in CSF culture). Interpretation: QSP1 and 28S rRNA assays are useful in identifying Cryptococcus species. qPCR results correlate well with baseline quantitative cryptococcal culture and show a similar decline in fungal load during induction therapy. These assays could be a faster alternative to quantitative cryptococcal culture to determine fungal load clearance. The clinical implications of the possible detection of viable but non-culturable cells in CSF during induction therapy remain unclear. Funding: European and Developing Countries Clinical Trials Partnership; Swedish International Development Cooperation Agency; Wellcome Trust/UK Medical Research Council/UKAID Joint Global Health Trials; and UK National Institute for Health Research