Genotypic Analysis of Transmitted and Acquired HIV Drug Resistance in People Living with HIV/AIDS in Surabaya, Indonesia, from 2018 to 2019.

BACKGROUND: Despite the availability of various effective antiretroviral (ARV) drugs, human immunodeficiency virus (HIV) infection has come with HIV drug resistance (HIVDR), which compromises its effectiveness in reducing HIV-related morbidity, mortality, and transmission. The emergence of transmitted (TDR) and acquired HIVDR (ADR) among antiretroviral therapy (ART)-naïve and experienced individuals have been reported in several Indonesian regions. Therefore, continuous HIVDR surveillance is needed in Indonesia, especially in Surabaya, which is identified as having the highest prevalence of HIV infection in East Java; thus, this study aimed to identify the emergence of TDR and ADR among people living with HIV/acquired immune deficiency syndrome (AIDS) (PLWHA). METHODS: Fifty-eight PLWHA infected with HIV type 1 (HIV-1), comprising 21 and 37 ART-naïve and experienced individuals were enrolled in this study, respectively. Blood samples collected from study participants were subjected to genotypic analysis, mainly towards the pol gene encoding protease (PR gene) and reverse transcriptase (RT gene) of HIV-1. RESULTS: Seventeen PR and 21 RT genes were successfully amplified and sequenced from 29 samples. HIV-1 subtyping revealed CRF01_AE as the most dominant subtype (24/29; 82.76%), followed by subtype B (3/29; 10.34%). Uncommon subtypes, including subtype D and a recombinant containing subtypes B and G genomic fragments, were also identified. TDR for PR inhibitors was not detected; however, TDR and ADR for RT inhibitors were identified in 11.11% and 41.67% of samples, respectively. Two amino acid insertions at position 69 of the RT gene (69ins), a previously never-reported mutation in Indonesia, were identified in this study. CONCLUSION: Both TDR and ADR have emerged among PLWHA residing in Surabaya, East Java, Indonesia. Uncommon drug-resistance mutations and subtypes were identified in this study. These situations might hamper ART efficacy and treatment success. Continuous surveillance of HIVDR is necessary to monitor both TDR and ADR in Indonesia.

Potential usage of boron modified carbon nanodots as a marker candidate for coronavirus disease (COVID-19) antibody detection.

The global outbreak of COVID-19 in December 2019 has highlighted rapid and accurate diagnostic tools for effective intervention. While the RT-PCR test offers 86 % sensitivity, uncertainties often require supplementary screening. This research investigates how carbon dots (CDs) can be utilized as markers for COVID-19 antibodies, taking advantage of their biocompatibility and low toxicity. CDs were synthesized using citric acid (CA) and APBA with boronic acid, enabling the detection of COVID-19 IgG antibodies with increased absorbance and fluorescence. Comprehensive analyses confirmed the successful synthesis of APBA-CDs, prompting further exploration of their impact on SARS-CoV-2 RNA. Increased absorbance levels were observed in categories K1, K2, and K3, attributed to the introduction of CDs into plasma, indicating effective binding of APBA-CDs to COVID-19 antibodies. In addition, the fluorescence tests consistently showed heightened levels across all categories, emphasizing the effective binding of APBA-CDs with COVID-19 antibodies, particularly in positive plasma samples. As a part of our analysis, we conducted a PCA test to validate the data, which revealed that APBA-CDs are specific to IgG+ antibodies. The results showed a sensitivity rate of 74 % and a specificity rate of 53 %, while, when tested for IgM antibodies, the sensitivity and specificity rates were 63 % and 27 %, respectively. These findings highlight the potential of APBA-CDs as a sensitive and specific marker for COVID-19 antibody detection, offering potential for diagnostic tool development.

Brown Tumour in Chronic Kidney Disease: Revisiting an Old Disease with a New Perspective.

Osteitis fibrosa cystica (OFC) and Brown Tumours are two related but distinct types of bone lesions that result from the overactivity of osteoclasts and are most often associated with chronic kidney disease (CKD). Despite their potential consequences, these conditions are poorly understood because of their rare prevalence and variability in their clinical manifestation. Canonically, OFC and Brown Tumours are caused by secondary hyperparathyroidism in CKD. Recent literature showed that multiple factors, such as hyperactivation of the renin-angiotensin-aldosterone system and chronic inflammation, may also contribute to the occurrence of these diseases through osteoclast activation. Moreover, hotspot KRAS mutations were identified in these lesions, placing them in the spectrum of RAS-MAPK-driven neoplasms, which were until recently thought to be reactive lesions. Some risk factors contributed to the occurrence of OFC and Brown Tumours, such as age, gender, comorbidities, and certain medications. The diagnosis of OFC and Brown Tumours includes clinical symptoms involving chronic bone pain and laboratory findings of hyperparathyroidism. In radiological imaging, the X-ray and Computed tomography (CT) scan could show lytic or multi-lobular cystic alterations. Histologically, both lesions are characterized by clustered osteoclasts in a fibrotic hemorrhagic background. Based on the latest understanding of the mechanism of OFC, this review elaborates on the manifestation, diagnosis, and available therapies that can be leveraged to prevent the occurrence of OFC and Brown Tumours.

Duration of SARS-CoV-2 RNA Shedding Is Significantly Influenced by Disease Severity, Bilateral Pulmonary Infiltrates, Antibiotic Treatment, and Diabetic Status: Consideration for Isolation Period.

Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) ribonucleic acid (RNA) shedding is an important parameter for determining the optimal length of isolation period required for coronavirus disease 2019 (COVID-19) patients. However, the clinical (i.e., patient and disease) characteristics that could influence this parameter have yet to be determined. In this study, we aim to explore the potential associations between several clinical features and the duration of SARS-CoV-2 RNA shedding in patients hospitalized with COVID-19. A retrospective cohort study involving 162 patients hospitalized for COVID-19 in a tertiary referral teaching hospital in Indonesia was performed from June to December 2021. Patients were grouped based on the mean duration of viral shedding and were compared based on several clinical characteristics (e.g., age, sex, comorbidities, COVID-19 symptoms, severity, and therapies). Subsequently, clinical factors potentially associated with the duration of SARS-CoV-2 RNA shedding were further assessed using multivariate logistic regression analysis. As a result, the mean duration of SARS-CoV-2 RNA shedding was found to be 13 ± 8.44 days. In patients with diabetes mellitus (without chronic complications) or hypertension, the duration of viral shedding was significantly prolonged (≥13 days; p = 0.001 and p = 0.029, respectively). Furthermore, patients with dyspnea displayed viral shedding for longer durations (p = 0.011). The multivariate logistic regression analysis reveals that independent risk factors associated with the duration of SARS-CoV-2 RNA shedding include disease severity (adjusted odds ratio [aOR] = 2.94; 95% CI = 1.36-6.44), bilateral lung infiltrates (aOR = 2.79; 95% CI = 1.14-6.84), diabetes mellitus (aOR = 2.17; 95% CI = 1.02-4.63), and antibiotic treatment (aOR = 3.66; 95% CI = 1.74-7.71). In summary, several clinical factors are linked with the duration of SARS-CoV-2 RNA shedding. Disease severity is positively associated with the duration of viral shedding, while bilateral lung infiltrates, diabetes mellitus, and antibiotic treatment are negatively linked with the duration of viral shedding. Overall, our findings suggest the need to consider different isolation period estimations for specific clinical characteristics of patients with COVID-19 that affect the duration of SARS-CoV-2 RNA shedding.

Development of a Hospital-Stakeholder Collaboration Tool Using Mixed Methods to Assess Stakeholder Perspectives for Hospital Service Improvement.

Background: The purpose of this study was to develop the Hospital-Stakeholder Collaboration (HSC) Tool and Hospital Performance Factor (HPF) Tool to explore stakeholder perception and value for hospital service improvement. Methods: This exploratory mixed-method study involved three steps: initial tool development (Step 1), validity testing (Step 2), and module development (Step 3). In Step 1, qualitative data collection through literature reviews, focus group discussions, and interviews with hospital management experts led to the creation of the preliminary tools. Step 2 involved qualitative analysis by α 5-member expert panel, followed by quantitative analysis with 36 respondents for validity (Pearson correlation, α = 0.05) and reliability (Cronbach's Alpha, α = 0.6) tests. Step 3 encompassed the final module development. Results: The HSC tool contains 6 domains and the HPF tool contains 4 perspectives. The 6 HSC domains were: 1) stakeholder identification, 2) interactive dialogue, 3) commitment, 4) planning, 5) implementation, 6) change in action and behavior. The 4 HPF perspectives were: 1) stakeholder perspective, 2) financial perspective, 3) internal business process, and 4) staff and organizational capacity. The values of the HSC tool validity and reliability tests were around 0,0046 and around 0,995, respectively. Additionally, the values of the HPF tool validity and reliability tests were around 0,0062 and around 0,995, respectively. Conclusion: This study offers a practical tool for needs assessment for the improvement of service by analyzing direct feedback from hospital stakeholders and measuring hospital performance factors.

Higher dose corticosteroids in hospitalised COVID-19 patients with hypoxia but not requiring ventilatory support (RECOVERY): a randomised, controlled, open-label, platform trial

BackgroundLow-dose corticosteroids have been shown to reduce mortality for hypoxic COVID-19 patients requiring oxygen or ventilatory support (non-invasive mechanical ventilation, invasive mechanical ventilation or extra-corporeal membrane oxygenation). We evaluated the use of a higher dose of corticosteroids in this patient group. MethodsThis randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]) is assessing multiple possible treatments in patients hospitalised for COVID-19. Eligible and consenting adult patients with clinical evidence of hypoxia (i.e. receiving oxygen or with oxygen saturation <92% on room air) were randomly allocated (1:1) to either usual care with higher dose corticosteroids (dexamethasone 20 mg once daily for 5 days followed by 10 mg once daily for 5 days or until discharge if sooner) or usual standard of care alone (which includes dexamethasone 6 mg once daily for 10 days or until discharge if sooner). The primary outcome was 28-day mortality. On 11 May 2022, the independent Data Monitoring Committee recommended stopping recruitment of patients receiving no oxygen or simple oxygen only to this comparison due to safety concerns. We report the results for these participants only. Recruitment of patients receiving ventilatory support continues. The RECOVERY trial is registered with ISRCTN (50189673) and clinicaltrials.gov (NCT04381936). FindingsBetween 25 May 2021 and 12 May 2022, 1272 COVID-19 patients with hypoxia and receiving no oxygen (1%) or simple oxygen only (99%) were randomly allocated to receive usual care plus higher dose corticosteroids versus usual care alone (of whom 87% received low dose corticosteroids during the follow-up period). Of those randomised, 745 (59%) were in Asia, 512 (40%) in the UK and 15 (1%) in Africa. 248 (19%) had diabetes mellitus. Overall, 121 (18%) of 659 patients allocated to higher dose corticosteroids versus 75 (12%) of 613 patients allocated to usual care died within 28 days (rate ratio [RR] 1{middle dot}56; 95% CI 1{middle dot}18-2{middle dot}06; p=0{middle dot}0020). There was also an excess of pneumonia reported to be due to non-COVID infection (10% vs. 6%; absolute difference 3.7%; 95% CI 0.7-6.6) and an increase in hyperglycaemia requiring increased insulin dose (22% vs. 14%; absolute difference 7.4%; 95% CI 3.2-11.5). InterpretationIn patients hospitalised for COVID-19 with clinical hypoxia but requiring either no oxygen or simple oxygen only, higher dose corticosteroids significantly increased the risk of death compared to usual care, which included low dose corticosteroids. The RECOVERY trial continues to assess the effects of higher dose corticosteroids in patients hospitalised with COVID-19 who require non-invasive ventilation, invasive mechanical ventilation or extra-corporeal membrane oxygenation. FundingUK Research and Innovation (Medical Research Council) and National Institute of Health and Care Research (Grant ref: MC_PC_19056), and Wellcome Trust (Grant Ref: 222406/Z/20/Z).

Screening of anti-HIV activities in ethanol extract and fractions from Ficus fistulosa leaves.

OBJECTIVES: Human immunodeficiency virus (HIV) infection is considered as a major immunosuppressive disease linked to malignancies and other opportunistic infections. Recently, the high prevalence of HIV drug-resistant strains required a high demand for novel antiviral drug development, especially in herbal medicine approaches. The objective of this study was to evaluate the possibility of Ficus fistulosa leaves can inhibit HIV replication in ethanol extract form as well as its fractions using chloroform, ethyl acetate, and butanol solvents. METHODS: F. fistulosa leaves were extracted using ethanol as a solvent and further gradually fractionated in chloroform, ethyl acetate, and butanol solvents. The targeted persistently infected virus (MT4/HIV) cell lines were cocultured with ethanol extract and fractions at different time points. The syncytium formation and cytotoxicity assays were performed to evaluate the potential antiviral activity of F. fistulosa leaves. RESULTS: One of the four tested extract/fractions showed antiviral activity against HIV. The ethanol extract showed weak inhibition with a high level of toxicity (IC50 = 8.96 µg/mL, CC50 ≥50 µg/mL, and SI = 5.58). Meanwhile, chloroform fraction effectively inhibited the MT4/HIV cell proliferation while keeping the toxicity to a minimal level (IC50 = 3.27 µg/mL, CC50 = 29.30 µg/mL, and SI = 8.96). In contrast of ethyl acetate fraction and butanol fraction showed no anti HIV activity with a high level of toxicity (CC50 ≥50 µg/mL) and low SI value (>2.17 µg/mL and >0.97 µg/mL). CONCLUSIONS: Chloroform fraction of F. fistulosa leaves showed effectively as anti-viral activity against MT4/HIV cells.

The clinical impact of bacterial co-infection among moderate, severe and critically ill COVID-19 patients in the second referral hospital in Surabaya.

Background: Data on the prevalence of bacterial co-infections among COVID-19 patients are limited, especially in our country, Indonesia. We aimed to assess the rate of bacterial co-infections in hospitalized COVID-19 patients and report the most common microorganisms involved and the antibiotic use in these patients. Methods: This study is a retrospective cohort study, among COVID-19 adult patients admitted to Universitas Airlangga Hospital Surabaya from 14 March-30 September 2020. The bacterial infection is defined based on clinical assessment, laboratory parameters, and microbiology results. Results: A total of 218 patients with moderate to critical illness and confirmed COVID-19 were included in this study. Bacterial infection was confirmed in 43 patients (19.7%). COVID-19 patients with bacterial infections had longer hospital length of stay (17.6 ± 6.62 vs 13.31±7.12), a higher proportion of respiratory failure, intensive care treatment, and ventilator use. COVID-19 patients with bacterial infection had a worse prognosis than those without bacterial infection (p<0.04). The empirical antibiotic was given to 75.2% of the patients. Gram-negative bacteria were commonly found as causative agents in this study (n = 39; 70.37%). Conclusion: COVID-19 patients with bacterial infection have a longer length of stay and worse outcomes. Healthcare-associated infections during intensive care treatment for COVID-19 patients must be carefully prevented.

The Dominance of CRF01_AE and the Emergence of Drug Resistance Mutations Among Antiretroviral Therapy-Experienced, HIV-1-infected Individuals in Medan, Indonesia.

BACKGROUND: human immunodeficiency virus type 1 (HIV-1) infection is a serious public health threat worldwide. Medan is one example of big cities in Indonesia with a high prevalence of HIV-1 infection; however, quite a limited study had conducted for detecting the circulation of HIV-1 subtypes in Medan. In addition, a serious factor that can implicate the treatment of HIV-1-infected individuals is the emergence of drug resistance mutations. Thus, the information on HIV-1 infection is important to improve the treatment for infected individuals. METHODS: sixty-seven antiretroviral therapy-experienced, HIV-1-infected individuals were recruited for this study. HIV-1 pol genes encoding protease (PR genes) and reverse transcriptase (RT gene), as well as env and gag genes, were amplified from DNA derived from peripheral blood samples. HIV-1 subtyping was conducted to study the dominant HIV-1 subtype circulating in the region. In addition, the emergence of drug resistance mutations was analyzed based on the guidelines published by the International Antiviral Society-United States of America (IAS-USA). RESULTS: the dominant HIV-1 subtype found in Medan was CRF01_AE (77.6%). In addition, another subtype and recombinant viruses such as recombinants between CRF01_AE and subtype B (12.2%), subtype B (4.1%), and CRF02_AG (4.1%) were also found. Drug resistance-associated major mutations were found in 21.6% (8/37) of RT genes and 3.1% (1/32) of PR genes studied. CONCLUSION: our study showed that the dominant subtype found in ART-experienced, HIV-1-infected individuals residing in Medan was CRF01_AE. The emergence of drug resistance mutations in RT and PR genes indicated the importance to monitor the prevalence of drug resistance mutations among HIV-1-infected individuals in Medan.

Age, neutrophil lymphocyte ratio, and radiographic assessment of the quantity of lung edema (RALE) score to predict in-hospital mortality in COVID-19 patients: a retrospective study.

Background: Available data suggest that case fatality rate of COVID-19 patients in Surabaya is higher than global cases. Thus, it is important to identify risk factors to prevent the mortality. This study aimed to assess the factors associated with hospital mortality of COVID-19 patients, and develop a prediction score based on these findings. Methods: We analyzed 111 patients, who were diagnosed with COVID-19 based on reverse-transcriptase polymerase chain reaction. The following patient characteristics were obtained from records: age, gender, type of symptoms, onset of symptoms, neutrophil lymphocyte ratio (NLR), absolute lymphocyte count, chest x-ray abnormalities, lung involvement, type of lesion, radiographic assessment of the quantity of lung edema (RALE) score, and mortality. Data were analyzed using SPSS 25.0. Results Multivariate analysis showed that age >50 years ( p=0.043), NLR score >5.8 ( p=0.016) and RALE score >2 ( p=0.002) can predict the mortality of COVID-19 patients in the hospital. ROC curve analysis of the score ability to predict mortality showed an area under the curve of 0.794. The cut-off point is 4.5, with a sensitivity of 96.7% and specificity of 49.4% to predict the mortality of COVID-19 patient in the hospital. Conclusions Age, NLR score and RALE score were associated with mortality of COVID-19 patients in the hospital and might be used as a predictor for mortality of COVID-19 patients in health care centre where radiologists are available. The prediction score may be useful for frontline physicians to effectively manage patients with a higher score to prevent mortality.

Inactivation of HIV-1 Infection through Integrative Blocking with Amino Phenylboronic Acid Attributed Carbon Dots.

Current antiretroviral HIV therapies continue to have problems related to procedural complications, toxicity, and uncontrolled side effects. In this study, amino phenylboronic acid-modified carbon dots (APBA-CDs) were introduced as a new nanoparticle-based on gp120 targeting that inhibits HIV-1 entry processes. Prolonged by simple pyrolysis for preparing carbon dots, this report further explores attributing amino phenylboronic acid on carbon dots, which prove the formation of graphene-like structures on carbon dots and boronic acid sites, thereby enabling the enhancement of positive optical properties through photoluminescent detection. Aside from performing well in terms of biocompatibility and low cytotoxicity (the CC50 reach up to 11.2 mg/mL), APBA-CDs exhibited superior capabilities in terms of prohibiting HIV-1 entry onto targeted MOLT-4 cells recognized by the delimitations of syncitia formation and higher ATP signal rather than bare carbon dots. The modified carbon dots also promote dual-action on HIV-1 treatment by both intracellularly and extracellularly viral blocking by combining with the Duviral drug, along with compressing p24 antigen signals that are better than APBA-CDs and Duviral itself.

The Emergence of HIV-1 Transmitted Drug Resistance Mutations Among Antiretroviral Therapy-naive Individuals in Buleleng, Bali, Indonesia.

BACKGROUND: the global scale-up of antiretroviral therapy (ART) is the primary factor contributing to the decline in deaths from acquired immune deficiency syndrome (AIDS)-related illnesses. However, the emergence of transmitted drug resistance (TDR) compromises the effects of ART in treatment-naïve individuals, which may hinder treatment success. The present study aimed to identify the presence of TDR among treatment-naive individuals in Buleleng, Bali, which is currently ranked sixth among Indonesian provinces with the highest cumulative human immunodeficiency virus type 1 (HIV-1) infection cases. METHODS: thirty-nine ART-naive individuals in Buleleng Regency General Hospital were enrolled in the present study. Blood samples from participants were subjected to a genotypic analysis. RESULTS: 28 protease (PR) and 30 reverse transcriptase (RT) genes were successfully amplified and sequenced from 37 samples. HIV-1 subtyping revealed CRF01_AE as the dominant circulating recombinant form in the region. No TDR for PR inhibitors was detected; however, TDR for RT inhibitors was identified in five out of 30 samples (16.7%). CONCLUSION: these results indicate the emergence of TDR among ART-naive individuals in Buleleng, Bali. This issue warrants serious consideration because TDR may hamper treatment success and reduce ART efficacy among newly diagnosed individuals. Continuous surveillance with a larger sample size is necessary to monitor TDR among ART-naive individuals.

Sero- and Molecular Epidemiology of HIV-1 in Papua Province, Indonesia.

BACKGROUND: human immunodeficiency virus (HIV) infection and acquired immune deficiency syndrome (AIDS) cause serious health problems and affect the Indonesian economy. Papua province has the highest prevalence of HIV infection in the country; however, epidemiological data are limited. Therefore, in order to reveal the current situation of HIV/AIDS in Papua province, sero- and molecular epidemiological studies of HIV were conducted. METHODS: serological tests were conducted on 157 healthy individuals from the general population residing in Paniai, Papua. In addition, a molecular epidemiological study was then conducted on HIV type 1 (HIV-1) genes derived from infected individuals. Peripheral blood samples from HIV-1-positive individuals and 15 additionally enrolled, previously confirmed HIV-1-positive individuals were subjected to a genotypic analysis. RESULTS: serological tests revealed that 2 out of 157 (1.27%) healthy individuals were HIV-positive. In addition, HIV-1 subtyping revealed that subtype B and CRF01_AE were the major subtype and circulating recombinant form (CRF) of HIV-1 prevalent in the region, while subtype A1 and a recombinant form including viral gene fragments of CRF01_AE and subtype B was also detected. In addition, HIV drug resistance-associated major mutations were detected in the reverse transcriptase gene derived from infected individual on antiretroviral therapy. CONCLUSION: these results provide important information for clearer understanding on the current situation of HIV/AIDS in Papua province in Indonesia.