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NADH-dependent persulfide reductase (Npsr) has been proposed to facilitate dissimilatory sulfur respiration by reducing persulfide or sulfane sulfur-containing substrates to H2S. The presence of this gene in the sulfate and thiosulfate-reducing Archaeoglobus fulgidus DSM 4304 and other hyperthermophilic Archaeoglobales appears anomalous, as A. fulgidus is unable to respire S0 and grow in the presence of elemental sulfur. To assess the role of Npsr in the sulfur metabolism of A. fulgidus DSM 4304, the Npsr from A. fulgidus was characterized. AfNpsr is specific for persulfide and polysulfide as substrates in the oxidative half-reaction, exhibiting kcat/Km on the order of 104 M-1 s-1, which is similar to the kinetic parameters observed for hyperthermophilic CoA persulfide reductases. In contrast to the bacterial Npsr, AfNpsr exhibits low disulfide reductase activity with DTNB; however, similar to the bacterial enzymes, it does not show detectable activity with CoA-disulfide, oxidized glutathione, or cystine. The 3.1 Å X-ray structure of AfNpsr reveals access to the tightly bound catalytic CoA, and the active site Cys 42 is restricted by a flexible loop (residues 60-66) that is not seen in the bacterial homologs from Shewanella loihica PV-4 and Bacillus anthracis. Unlike the bacterial enzymes, AfNpsr exhibits NADH oxidase activity and also shows no detectable activity with NADPH. Models suggest steric and electrostatic repulsions of the NADPH 2′-phosphate account for the strong preference for NADH. The presence of Npsr in the nonsulfur-reducing A. fulgidus suggests that the enzyme may offer some protection against S0 or serve in another metabolic role that has yet to be identified.

BackgroundGuidelines for limited-stage human immunodeficiency virus-associated Kaposi sarcoma (AIDS/KS) recommend antiretroviral therapy (ART) as initial treatment. However, many such individuals show worsening KS and require additional chemotherapy. Methods to identify such patients are lacking.SettingWe studied whether serum levels of biomarkers associated with angiogenesis, systemic inflammation, and immune activation, which are elevated in HIV-infected individuals and implicated in the development of KS, could prospectively identify individuals with limited-stage AIDS-KS who would benefit from chemotherapy administered with ART.MethodsSerum specimens were obtained from participants in a randomized trial evaluating the value of adding oral etoposide chemotherapy to ART in treatment-naïve people with limited-stage AIDS-KS in resource-limited settings. Serum biomarkers of inflammation (C-reactive protein [CRP], interleukin [IL]-6, IL-8, IL-10, granulocyte colony stimulating factor, soluble tumor necrosis factor receptor-2), immune system activation (soluble IL-2 receptor alfa, C-X-C motif chemokine ligand 10/interferon gamma-induced protein 10, C-C motif ligand 2/monocyte chemoattractant protein 1), and angiogenesis (vascular endothelial growth factor, matrix metalloproteinase-2, -9, endoglin, hepatocyte growth factor) were measured at entry to determine whether baseline levels are associated with KS response. On-treatment changes in biomarker levels were determined to assess how etoposide modifies the effects of ART.ResultsPretreatment CRP and IL-10 were higher in those whose KS progressed, and lowest in those who had good clinical responses. Pretreatment CRP, IL-6, and soluble tumor necrosis factor receptor-2 showed significant associations with KS progression at the week-48 primary endpoint. Immediate etoposide led to lower inflammation biomarker levels compared with ART alone. Early KS progression was associated with elevated pretreatment levels of inflammation-associated biomarkers and increasing levels post-treatment.ConclusionsQuantifying serum biomarkers, especially CRP, may help identify persons with AIDS-KS who would benefit from early introduction of chemotherapy in addition to ART.

Plagiarism is a serious type of scholastic misconduct. In Rwanda, no research has been conducted to assess university students' attitudes and knowledge of plagiarism and if they have the skills to avoid plagiarizing. This study was conducted to assess knowledge of and attitudes towards plagiarism, as well as ability to recognize plagiaristic writing, among university students in Rwanda. An online questionnaire containing 10 knowledge questions, 10 attitude statements, and 5 writing cases with excerpts to test identification of plagiarism was administered between February and April 2021. Out of the 330 university students from 40 universities who completed the survey, 75.8% had a high knowledge level (score [greater than or equal to] 80%), but only 11.6% had a high score in recognizing plagiaristic writing (score [greater than or equal to] 80%). There was no statistically significant association between knowledge level and ability to recognize plagiaristic writing (P = 0.109). Lower odds were found in both diploma/certificate and bachelor students of having high knowledge as well as of having high ability to recognize plagiaristic writing than in master's students. Although respondents generally disapproved of plagiarism, approximately half of the respondents indicated that sometimes plagiarism is unavoidable, and self-plagiarism should not be punished in the same way as plagiarism of others' work. Inter-collegial collaboration on effective plagiarism policies and training programs is needed.

Key Clinical Message We report the case of a newborn with aplasia cutis congenita characterized by the absence of skin in the left parietal region, superficial dilatation of the scalp veins, facial dysmorphia, limb anomalies, and severe intrauterine growth retardation. Maternal milk enabled the baby to gain weight, and dermatological treatment was performed for scarring of the vertex. Psychomotor development and stature were spectacular. This case illustrates the clinical variability of this condition and the need for multidisciplinary management.

Usher syndrome is a genetic, clinically heterogeneous condition characterized by sensorineural hearing loss, progressive retinal degeneration, and vestibular dysfunction. There are three phenotypically recognizable types of Usher syndrome. Individuals with Usher syndrome type 1 have no vestibular function and profound sensorineural hearing loss. Individuals with Usher syndrome type 2 have normal vestibular function and mild-to-severe hearing loss with visual impairment that is presented later in life. People with Usher syndrome type III experience hearing and vision loss beginning later in life. In this case report, we are reporting a 7-year-old boy consulted for progressive hearing loss and bilateral vision impairment, and fundus exam revealed mild bilateral retinal vessel attenuation and bone spicule deposits in both eyes. A molecular genetic test done by next-generation sequencing identified a homozygous pathogenic variant in the CDH23 gene (NM_022124.5:c.2255del variant coordinate with amino acid change of p.(Gly752Valfs*13)), confirming the diagnosis of autosomal recessive Usher syndrome type ID (USH1D). The patient had a remarkable improvement with visual and optical aids. Genetic counseling, including reproductive counseling, was provided to the parents. Clinical evaluation, visual hearing tests, and genetic workup confirmed Usher syndrome, which is a rare but dangerous cause of hearing loss and visual impairment that needs to be thoroughly evaluated by a multi-disciplinary team approach.

Malaria remains a significant global health challenge, with nearly half of the world's population at risk of infection. In 2022 alone, malaria claimed approximately 608,000 lives, with 76% of these fatalities occurring in children under the age of five, underscoring the disease's disproportionate impact on vulnerable populations. Africa bears the highest burden, accounting for 94% of global malaria cases. For over 60 years, the development of a malaria vaccine has been a critical objective for scientists and governments, with substantial efforts directed toward this goal. Recent progress has led to the approval of the first malaria vaccines, RTS,S/AS01 (Mosquirix®) and the R21/Matrix-M vaccine. Inspired by the promise of these vaccines, the global malaria community has renewed its focus on malaria eradication, 50 years after flawed earlier eradication efforts in the mid-twentieth century. Since the World Health Organization's endorsement of RTS,S in 2021 and R21 in 2023, several African countries, beginning with Cameroon, have integrated these vaccines into routine immunization programmes. This review examines the role of routine malaria vaccination in Africa as a key strategy toward malaria elimination, explores challenges and solutions for widespread vaccine implementation, and discusses future directions in the ongoing fight to eliminate malaria on the continent. [ABSTRACT FROM AUTHOR]

Pine Island Academy, present in Nocatee Community, Jacksonville, Florida, uses various modes of transport for picking up and dropping off children at school. The parents using private vehicles to pick up and drop off their kids tend to take a long time due to delays and congestion in their routes. Parents who use golf carts (GC) for this activity tend to take a short time to pick up and drop off their kids. Due to this, it is necessary to analyze the use of GC as an alternative mode of transport for children pick up and drop off while reducing delay and congestion. This paper uses VISSIM microscopic simulation for analysis whereby the traffic flow in the morning for drop-off and the afternoon for pickup was observed at different GC traffic compositions regarding the relative delay, queue delay, and travel times. From the analysis, it was observed that the delays and travel times for private vehicles decrease as the GC composition increases in the network. These results show that a GC may be suitable for picking up and dropping off children at school. This factor is further supported by the ANOVA test of significance. Due to the results from this paper, recommendations to the transportation agencies responsible for school management include promoting GC usage, establishing designated GC lanes to ensure smooth traffic flow and minimal interaction with other vehicles, implementing a multi-modal approach that includes GCs, and emphasizing safety training and awareness for GC users. [ABSTRACT FROM AUTHOR]

BackgroundMild-to-moderate AIDS-associated Kaposi sarcoma (KS) often responds to antiretroviral therapy (ART) alone; the role of chemotherapy is unclear. We assessed the impact of immediate vs as-needed oral etoposide (ET) among human immunodeficiency virus (HIV)-infected individuals with mild-to-moderate KS initiating ART.MethodsChemotherapy-naive, HIV type 1-infected adults with mild-to-moderate KS initiating ART in Africa and South America were randomized to ART (tenofovir/emtricitabine/efavirenz) alone (chemotherapy "as-needed" arm) vs ART plus up to 8 cycles of oral ET (immediate arm). Participants with KS progression on ART alone received ET as part of the as-needed strategy. Primary outcome was ordinal as follows: failure, stable, and response at 48 weeks. Secondary outcomes included time to initial KS progression, KS-associated immune reconstitution inflammatory syndrome (KS-IRIS), and KS response.ResultsOf 190 randomized participants (as-needed = 94, immediate = 96), the majority were men (71%) and African (93%). Failure (53.8% vs 56.6%), stable (16.3% vs 10.8%), and response (30% vs 32.5%) did not differ between arms (as-needed vs immediate) among those with week 48 data potential (N = 163, P = .91). Time to KS progression (P = .021), KS-IRIS (P = .003), and KS response (P = .003) favored the immediate arm. Twenty-five participants died (13%). Mortality, adverse events, CD4+ T-cell changes, and HIV RNA suppression were similar at 48 weeks.ConclusionsAmong HIV-infected adults with mild-to-moderate KS, immediate ET provided early, nondurable clinical benefits. By 48 weeks, no clinical benefit was observed compared to use of ET as needed. Mortality was high and tumor response was low.Clinical trials registrationNCT01352117.

BackgroundThe WHO recommended 1200mg/day of fluconazole (FCZ) in the induction phase of cryptococcal meningitis (CM) in HIV prior to 2018 in regions where amphotericin-B (AMB) was unavailable. A 2-stage AMB-controlled, dose-escalation study to determine the maximum tolerated dose and the safety/efficacy of an induction-consolidation strategy of higher doses FCZ (1200mg-2000mg/day), adjusted for weight and renal function (eGFR)in adults with CM was undertaken.MethodsIn Stage-1, three induction doses of FCZ (1200mg/day, 1600mg/day and 2000mg/day) were tested in sequential cohortsand compared with AMB in a 3:1 ratio. A particular dose was not tested in Stage 2 if there were significant predetermined safety or efficacy concerns. In Stage-2, the 1200mg dose was excluded per protocol because of increased mortality, and participants were randomised to 1600mg, 2000mg FCZ or AMB in a 1:1:1 ratio.FindingsOne hundred and sixty eight participants were enrolled with 48, 50, and 48 in the AMB, 1600mg and 2000mg cohorts. The Kaplan Meier proportion for mortality (90% CI) at 10 and 24 weeks for AMB was 17% (10, 29) and 24% (15, 37), compared to 20% (12, 32) and 30% (20, 43) for 1600mg, and 33% (23, 46) and 38% (27, 51) for 2000mg/day FCZ. With the exception of a higher incidence of gastrointestinal side effects in the 2000mg cohort, both induction doses of FCZ were safe and well tolerated. There were no life-threatening changes in electrocardiogram QTc which were similar across all doses of FCZ and AMB. The median (IQR) change in log10 cryptoccal colony forming units (CFU) from week 0 to week 2 was -8(-4.1,-1.9) for AMB; -2.5(-4.0, -1.4) for 1600mg FCZ and -8 (-3.2, -1.0) for 2000mg FCZ. The proportion (90% CI) CSF CM negative at 10 weeks was 81%(71,90) for AMB; 56%(45,69) for 1600mg FCZ and 60%(49,73) for 2000mg FCZ.InterpretationInduction phase weight and renal-adjusted doses of 1600mg and 2000mg/day FCZ for CM were safe and well tolerated except for increased GI side effects in the 2000mg/day dose, and had similar times to achieve CSF sterilization, but took significantly longer than AMB. The WHO recommended 1200mg FCZ was associated with a high mortality. While not statistically significant, mortality was numerically lower in the AMB compared to 1600mg and 2000mg FCZ These data make a case for a phase 3 study of higher doses of FZC.

Le Burundi précolonial fait partie des anciens royaumes de l’Afrique des Grands Lacs. Son organisation sociopolitique a été décrite par de nombreux chercheurs qui ont souligné la stabilité de ses institutions. Notre article identifie les femmes présentes dans les rouages de l’administration précoloniale et montre les modes de gestion de leur place dans la société burundaise actuelle. Nous avons trouvé en effet que les femmes occupaient une place importante dans les rouages du système administratif du Burundi ancien et que, même de nos jours, elles occupent une position influente. Cependant, leur intégration dans les institutions moderne est mal gérée.

Background: The surgical management of rheumatic heart disease (RHD) in Burundi is almost impossible because of the absence of the technical plateau. Aim: To describe the therapeutic and evolutionary aspects of RHD in Burundi. Patients and methods: This is a retrospective and analytical study of patients' records in surgical indication and/or operated for RHD by facilitation of “Maison du Bon Samaritain du Burundi (MBSB)” from February 2015 to February 2017. Results: Among 89 patients consulting for RHD, 45 (50.56%) were operated. The average age of the patients was 25 years. Females predominated with 64.04% of cases. The age of most of patients was between 4 and 40 years with 74 cases (83.14%). All patients had been received at the heart failure stage including 83 (93.25%) at stage III or IV according to the New York Heart Association (NYHA) classification. The ejection fraction was ≤ 50% in 61 patients (68.53%). Pulmonary arterial hypertension was recorded in 79 patients (88.76%). On chest X-ray, cardiomegaly was found in 85 patients (95.50%). Electrical abnormalities were dominated by dilatation of the left atrium in 48 cases (53.93%). Isolated valvular lesions were the most numerous with 67 cases (75.28%). The operative management was mainly valvular replacement (93.47%) with an operative success of 100% six months after the intervention. Conclusion: The diagnosis of RHD was late. Young people were more vulnerable. The postoperative prognosis at six months was good.

: Introduction: ACTG A5288 was a strategy trial conducted in diverse populations from multiple continents of people living with HIV (PLWH) failing second‐line protease inhibitor (PI)‐based antiretroviral therapy (ART) from 10 low‐ and middle‐income countries (LMICs). Participants resistant to lopinavir (LPV) and/or multiple nucleotide reverse transcriptase inhibitors started on third‐line regimens that included raltegravir (RAL), darunavir/ritonavir (DRV/r) and/or etravirine (ETR) according to their resistance profiles. At 48 weeks, 87% of these participants achieved HIV‐1 RNA ≤200 copies/ml. We report here long‐term outcomes over 144 weeks. Methods: Study participants were enrolled from 2013 to 2015, prior to the availability of dolutegravir in LMICs. “Extended Follow‐up” of the study started after the last participant enrolled had reached 48 weeks and included participants still on antiretroviral (ARV) regimens containing RAL, DRV/r and/or ETR at that time. RAL, DRV/r and ETR were provided for an additional 96 weeks (giving total follow‐up of ≥144 weeks), with HIV‐1 RNA measured at 48 and 96 weeks and CD4 count at 96 weeks after entry into Extended Follow‐up. Proportion of participants with HIV‐1 RNA ≤200 copies/ml was estimated every 24 weeks, using imputation if necessary to handle the different measurement schedule in Extended Follow‐up; mean CD4 count changes were estimated using loess regression. Results and Discussion: Of 257 participants (38% females), at study entry, median CD4 count was 179 cells/mm[sup.3], and HIV‐1 RNA was 4.6 log[sub.10] copies/ml. Median follow‐up was 168 weeks (IQR: 156–204); 15 (6%) participants were lost to follow‐up and 9 (4%) died. 27/246 (11%), 26/246 (11%) and 13/92 (14%) of participants who started RAL, DRV/r and ETR, respectively, discontinued these drugs; only three due to adverse events. 87%, 86%, 83% and 80% of the participants had HIV‐1 RNA ≤200 copies/ml at weeks 48, 96, 144 and 168 (95% CI at week 168: 74–85%), respectively. Mean increase from study entry in CD4 count at week 168 was 265 cells/mm[sup.3] (95% CI 247–283). Conclusions: Third‐line regimens comprising of RAL, DRV/r and/or ETR were very well tolerated and had high rates of durable virologic suppression among PLWH in LMICs who were failing on second‐line PI‐based ART prior to the availability of dolutegravir., INTRODUCTION Mathematical modelling suggests that by 2030, up to 4.6 million people living with HIV (PLWH) will require second‐line antiretroviral therapy (ART) globally [1]. Studies in Asia and Africa have [...]

Crashes involving golf carts (GCs) have been on an increasing trend in recent years, particularly in the United States. This study focuses on analyzing GC crashes in the Florida community known as The Villages, one of the largest GC-oriented communities in the nation and worldwide. The objective was to evaluate the injury severity of crashes involving GCs in a retirement community where GCs are a common mode of transportation. The ordinal logistic regression (OLR) and Decision Tree Ensemble (DTE) models were used to analyze the injury severity of 616 GC-related crashes. Models' accuracy parameters were used to check their reliability. The analysis revealed that GC crash severity is influenced by various factors. Factors found to be significant by the OLR model in determining injury severity include ejection of one or more occupants from the GC, the extent of damage to the GC, GC speed prior to the crash, roadway characteristics (including divided roadways, traffic control devices, paved shoulders, and T-intersections), and roll-over incidents. The OLR model demonstrated an overall accuracy of approximately 71% in predicting injury severity. The DTE model performed better, with an overall accuracy of 78%. The OLR model's findings were supported by the DTE model, which identified estimated GC speed, occupant(s) ejection from the GC, estimated GC vehicle damage, intersection type, and type of shoulder as the most important factors influencing GC crash severity. Understanding these factors is vital for transportation agencies to develop effective strategies to reduce the severity of GC crashes, ensuring the safety of GC users. This study provides recommendations to transportation agencies on measures to improve the safety of GCs. [ABSTRACT FROM AUTHOR]

The article deals with international legal issues relating to the immunity of the sitting heads of state in the context of the International Criminal Court’s activities. The main attention is paid to the analysis of customary and conventional norms of international law on the immunity of heads of state, the positions of the International Court of Justice, the UN International Law Commission and the practice of the International Criminal Court (ICC) vis-à-vis the heads of states that are not parties to the Rome Statute of the ICC. The author argues that there are contradictions between the provisions of the Rome Statute of the ICC, the customary international-law norms on the immunity of heads of state and the provisions of other international treaties, in particular the Vienna Convention on the Law of Treaties of 1969, and that the heads of states that are not parties to the Rome Statute of the ICC continue to enjoy immunity until their states take other measures to waiver their immunity

Background: The WHO recommended 1200mg/day of fluconazole (FCZ) in the induction phase of cryptococcal meningitis (CM) in HIV prior to 2018 in regions where amphotericin-B (AMB) was unavailable. A 2-stage AMB-controlled, dose-escalation study to determine the maximum tolerated dose and the safety/efficacy of an induction-consolidation strategy of higher doses FCZ (1200mg-2000mg/day), adjusted for weight and renal function (eGFR)in adults with CM was undertaken. Methods: In Stage-1, three induction doses of FCZ (1200mg/day, 1600mg/day and 2000mg/day) were tested in sequential cohortsand compared with AMB in a 3:1 ratio. A particular dose was not tested in Stage 2 if there were significant predetermined safety or efficacy concerns. In Stage-2, the 1200mg dose was excluded per protocol because of increased mortality, and participants were randomised to 1600mg, 2000mg FCZ or AMB in a 1:1:1 ratio. Findings: One hundred and sixty eight participants were enrolled with 48, 50, and 48 in the AMB, 1600mg and 2000mg cohorts. The Kaplan Meier proportion for mortality (90% CI) at 10 and 24 weeks for AMB was 17% (10, 29) and 24% (15, 37), compared to 20% (12, 32) and 30% (20, 43) for 1600mg, and 33% (23, 46) and 38% (27, 51) for 2000mg/day FCZ. With the exception of a higher incidence of gastrointestinal side effects in the 2000mg cohort, both induction doses of FCZ were safe and well tolerated. There were no life-threatening changes in electrocardiogram QTc which were similar across all doses of FCZ and AMB. The median (IQR) change in log10 cryptoccal colony forming units (CFU) from week 0 to week 2 was -8(-4.1,-1.9) for AMB; -2.5(-4.0, -1.4) for 1600mg FCZ and -8 (-3.2, -1.0) for 2000mg FCZ. The proportion (90% CI) CSF CM negative at 10 weeks was 81%(71,90) for AMB; 56%(45,69) for 1600mg FCZ and 60%(49,73) for 2000mg FCZ. Interpretation: Induction phase weight and renal-adjusted doses of 1600mg and 2000mg/day FCZ for CM were safe and well tolerated except for increased GI side effects in the 2000mg/day dose, and had similar times to achieve CSF sterilization, but took significantly longer than AMB. The WHO recommended 1200mg FCZ was associated with a high mortality. While not statistically significant, mortality was numerically lower in the AMB compared to 1600mg and 2000mg FCZ These data make a case for a phase 3 study of higher doses of FZC. [ABSTRACT FROM AUTHOR]