Novel Pyrazole-Chalcone Hybrids: Synthesis and Computational Insights Against Breast Cancer.

More women die of breast cancer than of any other malignancy. The resistance and toxicity of traditional hormone therapy created an urgent need for potential molecules for treating breast cancer effectively. Novel biphenyl-substituted pyrazole chalcones linked to a pyrrolidine ring were designed by using a hybridization approach. The hybrids were assessed against MCF-7 and MDA-MB-231 cells by NRU assay. Among them, 8k, 8d, 8m, 8h, and 8f showed significantly potent IC50 values: 0.17, 5.48, 8.13, 20.51, and 23.61 µM) respectively, on MCF-7 cells compared to the positive control Raloxifene and Tamoxifen. Furthermore, most active compound 8k [3-(3-(4-fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)-1-(2-(2-(pyrrolidin-1-yl)-ethoxy)-phenyl)-chalcone] showed cell death induced through apoptosis, cell cycle arrest at the G2/M phase, and demonstrated decrease of ER-α protein in western blotting study. Docking studies of 8k and 8d established adequate interactions with estrogen receptor-α as required for SERM binding. The active hybrids exhibited good pharmacokinetic properties for oral bioavailability and drug-likeness. Whereas, RMSD, RMSF, and Rg values from Molecular dynamics studies stipulated stability of the complex formed between compound 8k and receptor. All of these findings strongly indicate the antiproliferative potential of pyrazole-chalcone hybrids for the treatment of breast cancer.

Experience on postmortem minimally invasive tissue sampling to ascertain the cause of death determination in South African children: A case for implementing as standard of care.

Determining the death burden for prioritising public health interventions necessitates detailed data on the causal pathways to death. Postmortem minimally invasive tissue sampling (MITS), incorporating histology, molecular and microbial culture diagnostics, enhances cause-of-death attribution, particularly for infectious deaths. MITS proves a valid alternative to full diagnostic autopsies, especially in low- and middle-income countries. In Soweto, South Africa (SA), the Child Health and Mortality Prevention Surveillance (CHAMPS) programme has delineated over 1 000 child and stillbirth deaths since 2017. This SA CHAMPS site supports advocating for the use of postmortem MITS as routine practice, for more granular insights into under-5 mortality causes. This knowledge is crucial for SA's pursuit of Sustainable Development Goal 3.2, targeting reduced neonatal and under-5 mortality rates. This commentary explores the public health advantages and ethicolegal considerations surrounding implementing MITS as standard of care for stillbirths, neonatal and paediatric deaths in SA. Furthermore, based on the data from CHAMPS, we present three pragmatic algorithmic approaches to the wide array of testing options for cost-effectiveness and scalability of postmortem MITS in South African state facilities.

Diagnostic capacity for cutaneous fungal diseases in the African continent.

BACKGROUND: Cutaneous fungal infections are very common, especially in poorer communities and with intercurrent HIV infection. Determining the fungal pathogen in skin-related fungal neglected tropical diseases (NTDs) determines optimal therapy. We undertook a country survey across many African countries to determine the diagnostic capacity for skin fungal diseases. METHODS: A detailed questionnaire was delivered to country contacts to collect data on availability, frequency, and location of testing for key diagnostic procedures and followed up with 2 rounds of validation by video call and by confirmation of individual country data confirmation by email. RESULTS: Of 47 countries with data, seven (15%) and 21 (45%) do not offer skin biopsy in the public or private sector, respectively, but 22 (46%) countries do it regularly, mostly in university hospitals. Direct microscopy is often performed in 20 of 48 (42%) countries in the public sector and not done in 10 (21%). Fungal cultures are often performed in 21 of 48 (44%) countries in the public sector but not done in nine (20%) or 21 (44%) in either public or private facilities. Histopathological examination of tissue is frequently used in 19 of 48 (40%) countries but not in nine (20%) countries in the public sector. The cost of diagnostics to patients was a major limiting factor in usage. CONCLUSION: Major improvements in the availability and use of diagnostic tests for skin, hair, and nail fungal disease are urgently needed across Africa.

Recent progress in targeting KRAS mutant cancers with covalent G12C-specific inhibitors.

KRASG12C has been identified as a potential target in the treatment of solid tumors. One of the most often transformed proteins in human cancers is the small Kirsten rat sarcoma homolog (KRAS) subunit of GTPase, which is typically the oncogene driver. KRASG12C is altered to keep the protein in an active GTP-binding form. KRAS has long been considered an 'undrugable' target, but sustained research efforts focusing on the KRASG12C mutant cysteine have achieved promising results. For example, the US Food and Drug Administration (FDA) has passed emergency approval for sotorasib and adagrasib for the treatment of metastatic lung cancer. Such achievements have sparked several original approaches to KRASG12C. In this review, we focus on the design, development, and history of KRASG12C inhibitors.

Design and Analysis of a Mutant form of the Ice-Binding Protein from Choristoneura fumiferana.

Ice-binding proteins are expressed in the cells of some cold adapted organisms, helping them to survive at extremely low temperatures. One of the problems in studying such proteins is the difficulty of their isolation and purification. For example, eight cysteine residues in the cfAF (antifreeze protein from the eastern spruce budworm Choristoneura fumiferana) form intermolecular bridges during the overexpression of this protein. This impedes the process of the protein purification dramatically. To overcome this issue, in this work, we designed a mutant form of the ice-binding protein cfAFP, which is much easier to isolate that the wild-type protein. The mutant form named mIBP83 did not lose the ability to bind to ice surface. Besides, observation of the processes of freezing and melting of ice in the presence of mIBP83 showed that this protein affects the process of ice melting, increasing its melting temperature, and does not decrease the water freezing temperature.

Sepsis in previously healthy neonates discharged home after delivery in Soweto, South Africa.

BACKGROUND: There is a paucity of data on the aetiology of neonatal sepsis in sub-Saharan Africa. OBJECTIVES: To investigate the incidence, aetiology and outcomes of physician-diagnosed sepsis in hospitalised neonates who had previously been discharged home after delivery in Soweto, South Africa. METHODS: A retrospective review using data abstracted from clinical and laboratory databases identified physician-diagnosed sepsis cases in neonates admitted to the general paediatric wards at Chris Hani Baragwanath Academic Hospital from January 2015 to September 2016. Neonates with physician-diagnosed sepsis were categorised into two groups based on putative pathogens recovered from blood and/or cerebrospinal fluid specimens: (i) culture-confirmed sepsis; and (ii) culture-negative sepsis. RESULTS: Of 1 826 neonatal admissions, 1 025 (56.2%) had physician-diagnosed sepsis: 166 (16.2%) with culture-confirmed sepsis and 859 (83.8%) with culture-negative neonatal sepsis. The commonest pathogens causing culture-confirmed neonatal sepsis were Streptococcus viridans (n=53; 26.5%), S. agalactiae (n=38; 19.0%), and Staphylococcus aureus (n=25; 12.5%). The case fatality rates for culture-confirmed sepsis and culture-negative sepsis were 10.8% (18/166) and 2.6% (22/859), respectively. The odds of death occurring during hospitalisation was 10-fold (95% confidence interval 3.7 - 26.9) higher in neonates with culture-confirmed sepsis compared with culture-negative sepsis. CONCLUSIONS: In our setting, physician-diagnosed sepsis represents a huge disease burden in previously healthy neonates hospitalised from home. Most sepsis cases were attributed to S. viridans, S. agalactiae and S. aureus.

Pathophysiology and Imaging Findings of COVID-19 Infection: An Organ-system Based Review.

BACKGROUND: COVID-19 commonly presents with upper respiratory symptoms; however, studies have shown that SARS-CoV-2 infection affects multiple organ systems. Here, we review the pathophysiology and imaging characteristics of SARS-CoV-2 infection in organ systems throughout the body and explore commonalities. OBJECTIVE: Familiarity with the underlying pathophysiology and imaging characteristics is essential for the radiologist to recognize these findings in patients with COVID-19 infection. Though pulmonary findings are the most prevalent presentation, COVID-19 may have multiple manifestations and recognition of the extrapulmonary manifestations is especially important because of the potential serious and long-term effects of COVID-19 on multiple organ systems.

Subclinical tuberculosis and adverse infant outcomes in pregnant women with HIV.

BACKGROUND: Tuberculosis (TB) in pregnant women with HIV is associated with adverse maternal and infant outcomes. Previous studies have described a substantial prevalence of subclinical TB in this group, but little is known about the impact of subclinical TB on maternal and pediatric outcomes.METHODS: The Tshepiso Study recruited 235 HIV-infected pregnant women with TB (and matched HIV-positive, TB-negative pregnant controls), in Soweto, South Africa, from 2011 to 2014. During enrolment screening, some women initially recruited as controls were subsequently diagnosed with prevalent TB. We therefore assessed the prevalence of subclinical TB, associated participant characteristics and outcomes.RESULTS: Of 162 women initially recruited as TB-negative controls, seven (4.3%) were found to have TB on sputum culture. All seven had negative WHO symptom screens, and six (86%) were smear-negative. Of their seven infants, one was diagnosed with TB, and three (43%) experienced complications compared to zero infants with TB and 11% experiencing complications in the control group of TB-negative mothers (P = 0.045).CONCLUSION: We discovered an appreciable prevalence of subclinical TB in HIV-infected pregnant women in Soweto, which had not been detected by screening algorithms based solely on symptoms. Infants of HIV-infected mothers with subclinical TB appear to have a higher risk of adverse outcomes than those of TB-negative mothers.

Population Genomics of Mycobacterium leprae Reveals a New Genotype in Madagascar and the Comoros.

Human settlement of Madagascar traces back to the beginning of the first millennium with the arrival of Austronesians from Southeast Asia, followed by migrations from Africa and the Middle East. Remains of these different cultural, genetic, and linguistic legacies are still present in Madagascar and other islands of the Indian Ocean. The close relationship between human migration and the introduction and spread of infectious diseases, a well-documented phenomenon, is particularly evident for the causative agent of leprosy, Mycobacterium leprae. In this study, we used whole-genome sequencing (WGS) and molecular dating to characterize the genetic background and retrace the origin of the M. leprae strains circulating in Madagascar (n = 30) and the Comoros (n = 3), two islands where leprosy is still considered a public health problem and monitored as part of a drug resistance surveillance program. Most M. leprae strains (97%) from Madagascar and Comoros belonged to a new genotype as part of branch 1, closely related to single nucleotide polymorphism (SNP) type 1D, named 1D-Malagasy. Other strains belonged to the genotype 1A (3%). We sequenced 39 strains from nine other countries, which, together with previously published genomes, amounted to 242 genomes that were used for molecular dating. Specific SNP markers for the new 1D-Malagasy genotype were used to screen samples from 11 countries and revealed this genotype to be restricted to Madagascar, with the sole exception being a strain from Malawi. The overall analysis thus ruled out a possible introduction of leprosy by the Austronesian settlers and suggests a later origin from East Africa, the Middle East, or South Asia.

Endemic Chromoblastomycosis Caused Predominantly by Fonsecaea nubica, Madagascar1.

Chromoblastomycosis is an implantation fungal infection. Twenty years ago, Madagascar was recognized as the leading focus of this disease. We recruited patients in Madagascar who had chronic subcutaneous lesions suggestive of dermatomycosis during March 2013-June 2017. Chromoblastomycosis was diagnosed in 50 (33.8%) of 148 patients. The highest prevalence was in northeastern (1.47 cases/100,000 persons) and southern (0.8 cases/100,000 persons) Madagascar. Patients with chromoblastomycosis were older (47.9 years) than those without (37.5 years) (p = 0.0005). Chromoblastomycosis was 3 times more likely to consist of leg lesions (p = 0.003). Molecular analysis identified Fonsecaea nubica in 23 cases and Cladophialophora carrionii in 7 cases. Of 27 patients who underwent follow-up testing, none were completely cured. We highlight the persistence of a high level of chromoblastomycosis endemicity, which was even greater at some locations than 20 years ago. We used molecular tools to identify the Fonsecaea sp. strains isolated from patients as F. nubica.

Treatment responses in patients with vitiligo to very potent topical corticosteroids combined with vitaminotherapy in Madagascar.

INTRODUCTION: Vitiligo is a refractory disease in which treatment modalities are not yet established. We aim to assess results obtained 10 years after the initiation of a therapeutic protocol which combines very potent topical corticosteroids (TCS), vitaminotherapy (B12 and C), and suppression of microtraumas in the management of nonsegmental vitiligo in Madagascar. METHODS: It was a prospective and descriptive study over a period of 6 years (2011-2016) in the Department of Dermatology, Joseph Raseta Befelatanana, Antananarivo, Madagascar. The diagnosis of vitiligo was based on clinical data. Patients who agreed to follow the treatment protocol, which combined very potent TCS (two applications/day for 10 days, and then one application/day for the following 10 days), oral vitamin C 500 mg/day for 20 days, and oral vitamin B12 100 mg/day for 20 days, were included in the study. Two successive courses of treatment were made 10 days apart. RESULTS: The details of 308 vitiligo patients were analyzed. The mean age of patients was 33.3 years. There was a female preponderance (sex ratio: 0.6). The duration of treatment in our patients varied from 3 to 18 months. Two hundred and thirty-nine patients had good therapeutic compliance and attended regular follow-up. Excellent repigmentation (more than 76% area repigmented) was noted in 50 patients (65.7%) less than 14 years of age. Lesions evolving in less than 1 year in 31 patients (36.9%) had excellent response to treatment. Localized lesions responded favorably to treatment with excellent repigmentation in 108 patients. CONCLUSION: These results show that therapeutic response is better in young people, lesions less than 1 year of evolution, and for localization of vitiligo in the face and neck.

Chylothorax in a child with rifampicin-resistant tuberculosis.

Chylothorax is rare in children. Only a few cases of tuberculosis (TB)-associated chylothorax have been reported. We present a child on standard four-drug TB treatment who presented with wheezing and a chylothorax. Bronchoscopy showed caseating lymph nodes, and rifampicin-resistant TB was identified from the bronchoalveolar lavage specimen. There was marked clinical and radiological improvement 1 month after starting multidrug-resistant (MDR) TB treatment and steroids. The association of chylothorax and MDR-TB has not been described in children. MDR-TB should be considered in children who fail adherent, empirically started drug-susceptible TB treatment.

An evaluation of the quality of discharge summaries from the general paediatric wards at Chris Hani Baragwanath Academic Hospital, Johannesburg, South Africa.

BACKGROUND: Hospital discharge summaries are deemed to be an essential part of the medical record in South Africa, but formal assessment of their quality is rarely undertaken. At Chris Hani Baragwanath Academic Hospital (CHBAH) in Johannesburg, medical admission notes (bedletters) are difficult to retrieve from the hospital archives and the discharge summary is often the only readily available medical record that documents details of the hospital admission. OBJECTIVES: To determine the proportion of discharge summaries that were appropriately completed for children admitted to the general paediatric wards at CHBAH. METHODS: A retrospective review of discharge summaries completed for children admitted from 1 May to 31 July 2016 was undertaken. The completeness of the following demographic and clinical variables was assessed: patient identifiers, hospital outcome, HIV infection status and anthropometric status. The documentation of correct International Statistical Classification of Diseases and Related Health Problems, 10th revision (ICD-10) codes was assessed in children diagnosed with any form of lower respiratory tract infection (LRTI), which is the commonest diagnosis recorded in hospitalised children at CHBAH. RESULTS: Discharge summaries were available for 1 148 (78.3%) of 1 466 children admitted during the study period. For completed discharge summaries, 80.1 - 93.3% of patient identifiers and 91.4% of patient outcomes were appropriately completed. HIV exposure was documented in 84.7% of summaries. Anthropometric parameters, including weight and length/height at admission and discharge weight, were appropriately completed in 91.4%, 70.9% and 50.0% of summaries, respectively. The ICD-10 code for children with LRTI was appropriately recorded by medical staff in 338 (67.2%) of 503 cases. ICD­10 codes and anthropometric parameters, which are important clinical parameters in the paediatric follow-up consultation, were both correctly recorded for only 21.6% of children who required follow-up clinical consultations at CHBAH. CONCLUSIONS: Compared with similar studies, both the rate of completion and the quality of completed discharge summaries were modest in this tertiary academic teaching hospital. As discharge summaries are crucial medical documents, interventions to improve their completeness rate and quality need to be developed.

Empyema in children hospitalised at Chris Hani Baragwanath Academic Hospital, Johannesburg, South Africa: A retrospective study.

BACKGROUND: There is a paucity of information on empyema in children from low- and middle-income countries since the introduction of the pneumococcal conjugate vaccine. OBJECTIVES: To describe the aetiology and management of empyema in a setting of high HIV and tuberculosis (TB) prevalence. METHODS: A retrospective descriptive study was undertaken between January 2012 and December 2016 in children aged <14 years at a large secondary-tertiary referral hospital in Soweto, South Africa. Cases of empyema were identified through administrative databases. Clinical, laboratory and radiological data were extracted from patient records. RESULTS: We identified 65 cases of protocol-defined empyema, including 22 (33.8%) referred from surrounding hospitals. The median age at presentation was 53.2 months (interquartile range (IQR) 19.5 - 103.6). Thirteen patients (20.0%) were HIV-infected and 6 (9.2%) were HIV-exposed but uninfected. A bacterial pathogen was identified in 36 cases (55.3%). The commonest causative organisms were Staphylococcus aureus (14/65, 21.5%) and Streptococcus pneumoniae (5/65, 7.7%). Treatment for TB, initiated in 28 children (43.1%), was more frequent in HIV-infected children (10/13, 76.9%) (p=0.011); however, microbiological evidence of TB was present in only 5 cases (7.7%). Forty-three children (66.2%) had an intercostal drain (ICD) inserted and 16 (24.6%) a pigtail percutaneous catheter, while a fibrinolytic was only used in 6 (10.2%). Eight children (12.3%) had a thoracotomy and 7 (10.7%) had video-assisted thorascopic drainage, all of whom had a prior ICD inserted, a median of 20 days (IQR 10 - 33) before surgery. Overall, 7 children (10.8%) were mechanically ventilated and 1 (1.5%) died. CONCLUSIONS: Our study showed a dominance of S. aureus as a cause of empyema. A high proportion of HIV-infected children with empyema were initiated on TB treatment, highlighting challenges in managing TB-HIV co-infection. Although fibrinolytics or early surgery are recommended, neither practice was common in this setting.

Outcomes of Kasai hepatoportoenterostomy in children with biliary atresia in Johannesburg, South Africa.

BACKGROUND: Without timely surgical intervention, most children with biliary atresia (BA) are not expected to live beyond 2 years of age. The initial intervention, the Kasai hepatoportoenterostomy (KPE), aims to achieve biliary drainage. Liver transplantation (LT) is performed if jaundice fails to clear or when biliary cirrhosis occurs. In under-resourced South African (SA) academic state hospitals, KPE procedures are the standard of care for the majority of children with BA, but LT is becoming more routinely available. OBJECTIVES: To describe the outcomes of children with BA undergoing KPE, and to identify presenting clinical, laboratory and histological features that were associated with a more favourable outcome. METHODS: All children with BA who underwent KPE between January 2009 and June 2012 at the Johannesburg academic-hospital complex were included. Clinical and laboratory parameters, including paediatric end-stage liver disease (PELD) score at the time of KPE, liver histology fibrosis score, clearance of jaundice at 6 months and 24-month survival were determined. RESULTS: Of 70 children with BA diagnosed during the study period, 43 (61.4%) underwent KPE, but only 12 (27.9%) achieved early resolution of jaundice. By 24 months, 14 (32.6%) of 43 children undergoing KPE were alive with their native liver, and 2 (4.7%) other children underwent LT. PELD score <15 and early resolution of jaundice, but not age at surgery or histological fibrosis score, predicted a favourable outcome. CONCLUSION: Children with BA undergoing KPE in SA state hospitals have a poor prognosis. The PELD score at the time of KPE best predicts 24-month survival.

Excellent response of infantile orbital hemangioma to propranolol.

Infantile hemangiomas are the most common vascular neoplasm that present in infancy, with more than half affecting the head and neck region. Periocularly, hemangiomas may be complicated by visual loss through induction of strabismal, deprivational, or anisometropic astigmatism. We report a case of a 5-year-old girl who presented with orbital hemangioma with potential risk of visual loss who had excellent response to propranolol.

A Case of Fluoroquinolone-Resistant Leprosy Discovered after 9 Years of Misdiagnosis.

We report a case of misdiagnosed leprosy in a 21-year-old Malagasy male, who, improperly treated, developed secondary mycobacterial resistance to fluoroquinolone. The patient contracted the infection 9 years prior to the current consultation, displaying on the right thigh a single papulonodular lesion, which progressively spread to the lower leg, back, and face. Initial administration of ciprofloxacin and prednisolone led to temporary and fluctuating improvement. Subsequent long-term self-medication with ciprofloxacin and corticosteroid did not heal the foul and nonhealing ulcers on the legs and under the right sole. Histopathological findings were compatible with lepromatous leprosy. Skin biopsy was positive for acid-fast bacilli and PCR assay confirmed the presence of a fluoroquinolone-resistant strain of Mycobacterium leprae (gyrA A91V). After 6 months of standard regimen with rifampicin, clofazimine, and dapsone, clinical outcome significantly improved. Clinical characteristics and possible epidemiological implications are discussed.