The HIV Infection: Clarification of Its Legal Classification of Transmission and Measures to Protect Societies from Burdening Caused by Social and Medical Care Services for the Coming Decades

This article addresses issues regarding the transmission of HIV;without the combination antiretroviral treatment (cART), HIV causes a fatal outcome of those infected in most cases. First, legal issues: For years, controversial discussions have dealt with the subject of the legal classification of HIV infection, such as “… criminalization of HIV exposure might limit access to and uptake of HIV prevention services…” Based on the rule of law of a constitutional state, we explain the legal principles that serve to protect the legal rights of its citizens. The state has to protect its citizens from harm by other people. The prosecution and conviction of a specific person for a proven HIV infection are legal. Therefore, general decriminalization of HIV infection would undermine the right of thereby harmed citizens to compensation. Second, HIV prevention strategies: Based on the Test and Treatment Strategy (TASP)1, controlled studies were undertaken to find out which framework conditions could improve their benefit. We outline concepts that can help to curb the still ongoing spread of HIV: By providing early HIV diagnosis and ongoing HIV care services as part of updated education and prevention campaigns. Also, concerted, comprehensive campaigns are required to demonstrate further impacts of HIV infection: Both on the quality of life of infected individuals due to the development of non-communicable diseases and the increasing burden to societies as a whole.

Enemy at the gates： dendritic cells and immunity to mucosal pathogens

Dendritic cells （DC） are diverse and specialized hematopoietic cells serving as an essential bridge between innate and adaptive immunity. DC exist in all lymphoid and nonlymphoid organs and are amongst the first responders to infection at epithelial surfaces including mucosal tissues. DC of the lung, gut, and vaginal mucosa display different phenotypes and functions reflecting each unique tissue and, in contrast to their counterparts in spleen and lymph nodes, are constantly exposed to both harmful and benign factors of their environments. Mucosal DC recognize and respond to pathogens through engagement of pattern recognition receptors, and activated DC migrate to draining lymph nodes to induce adaptive immune responses. The specialized function of DC aids in the induction of immunity and pathogen control at the mucosa. Such specialization includes the potent antiviral interferon response of plasma- cytoid DC to viral nucleic acids, the ability of mucosal DC to capture organisms in the gut lumen, the capacity of DC to cross-present antigen from other infected cells, and the ability of mucosal DC to initiate lgA class switching in B cells. DC plasticity is also critical in the immune response to mucosal pathogens, as DC can respond to the microen- vironment and sense pathogen-induced stress in neighboring epithelial cells. Finally, DC interact with each other through crosstalk to promote antigen presentation and T-cell immunity. Together, these processes condition mucosal DC for the induction of a tailored immune response to pathogens.

The Disregarded HIV Prevention Strategies—Their Potential to Uphold the Pandemic, and the Challenges Facing Societies

The ongoing spread of HIV after sobering news about the goal “End of AIDS” is not encouraging, apart from regional differences. We focus on the consequences of the two essentially failed HIV prevention strategies in certain countries. The first failed because the correct messages concerning preventive behavior did not reach the required levels of target populations to interrupt HIV infection chains. There was a lack of appropriate framework conditions for the target populations to engage in the required scale. The additional biomedical strategy “Treatment as Prevention” didn’t achieve the breakthrough as was hoped. The consequences thereof affect the financial burden on societies, which can take several decades. We draw attention to the unbalanced principles of proportionality to which governments are committed, but which are practiced in favor of those vulnerable people;these people abuse their autonomy and contribute to the further spread of HIV at the expense of financial burdens, social and medical care systems;this behavior is tolerated, although the transmission of HIV is mostly preventable. We point to extreme tendencies, such as the chem-sex settings, whose unswayable participants engage in indirect violence against the societies. Another possible consequence of the still uncontrolled spread of HIV is the potential for HIV to increase its virulence.

Total dysphagia after short course of systemic corticotherapy:Herpes simplex virus esophagitis

A 72 year-old female developed a herpetic esophagitis after 3 d of oral corticotherapy for an acute exacerbation of chronic obstructive pulmonary disease,presenting as odynophagia and total dysphagia.Biospies were taken during a first esophagogastroduodenoscopy(EGD) and the patient was referred to the thoracic surgery service with a presumptive diagnosis of esophageal cancer.A second EGD was planned for dilatation,but by that time the stenosis was completely resolved.The biopsies taken during the first EGD revealed multiple herpetic viral inclusions and ulcerations without any dysplasia or neoplasia.In front of a severe esophageal stenosis,one must still exclude the usual differential diagnosis peptic stenosis and cancer.Visualization of endoscopic lesions can suggest the diagnosis but must be promptly confirmed by biopsy,viral culture or polymerase chain reaction.Although immune systemic effects of corticotherapy are well known and herpetic esophagitis occurs most frequently in immunocompromised individuals,this case emphasizes the importance of clinical awareness concerning short courses of corticotherapy for immunocompetent individuals.This article discusses the reactivation process of herpetic infection in this context and addresses its diagnostic and therapeutic issues.

Current HIV Prevention Policies Are Jeopardizing the “End of AIDS” Project: Realities Counteract Liberal Visions

Here I discuss a series of in adequate decisions made by governments of, e.g., the European Union when designing strategies aimed at preventing the spread of human immunodeficiency virus (HIV). Although there have been minor successes in curbing the spread of HIV, here I focus on the multiple failings that have indirectly fostered the spread of HIV. I propose that a novel, programmatic set of strategies are needed to prevent the spread of HIV, which will be necessary to meet aims of the End of AIDS (acquired immunodeficiency syndrome) project. I also discuss barriers to the End of AIDS project, including financial burdens and noncompliance, in particular of the “at-risk” termed population in resource rich countries, with current prevention strategies. The aim is (i) to foster supporting for the UNAIDS project by customized prevention concepts;and (ii) to raise awareness for the challenges yet to come, should the UNAIDS project fail.

Neonatal and Young Infant Sepsis in a Regional Hospital in Ghana

Background: Neonatal sepsis is a global health problem that mainly affects low- and middle-income countries. We have previously shown that early neonatal mortality is high at the Ho Teaching Hospital (HTH) of Ghana. We sought to determine the prevalence of neonatal sepsis, sepsis-related mortality, and bacterial species patterns in neonatal and young infant sepsis in this hospital. Methods: A hospital-based study was conducted in the hospital’s neonatal intensive care unit (NICU) from March to June 2018. Blood samples from 96 babies clinically diagnosed with or at risk of sepsis were cultured using the BACTEC 9050® machine. Clinical data including gravida, parity and antibiotic medication before delivery of mother and delivery type, gestation, birth weight and antibiotic medication status were collected for analysis. MALDI-TOF MS identified bacterial isolates, and their identities were confirmed via tuf gene sequence typing. The data were analyzed using GraphPad Prism 8.0.2. Results: Blood cultures were positive in 28 of the babies, with 14 and 12 representing early-onset and late-onset neonatal sepsis, respectively, and two cases of unknown sepsis type. Of the bacterial species that caused sepsis in the babies, coagulase-negative staphylococcus (CoNS) was the most prevalent isolate in 22 cases, followed by Klebsiella pneumoniae in two and Staphylococcus aureus, Streptococcus agalactiae, the Acinetobacter species, and Escherichia coli in the rest (one each). Of the CoNS, S. haemolyticus and S. epidermidis were the most prevalent species, found in eight and six cases, respectively. Thirteen neonates died, of whom seven had positive blood cultures, and two were referred. A case fatality rate of 7/26 was estimated. Neonatal mortality caused by Gram-negative bacterial infection was higher than that caused by Gram-positive bacteria. Conclusions: These data suggest a significant burden of sepsis among neonates and young infants and are associated with substantial morbidity and mortality at the HTH. There is a need to investigate risk factors associated with the increased sepsis rate in this hospital to inform measures to reduce the neonatal sepsis rate.

Pathogens causing diarrhoea among Bangladeshi children with malignancy: Results from two pilot studies

BACKGROUND Diarrhoea is a frequent symptom in children with cancer, and occurs due to a composite effect of underlying disease and immunosuppression consequent to therapy, malnutrition, and non-infective aetiologies such as mucositis. In a large proportion of cases, the aetiology of diarrhoea remains unknown but is often attributed to multiple pathogens including parasites.AIM To identify and describe the pathogens causing diarrhoea in Bangladeshi children with cancer.METHODS Two cross-sectional pilot studies were conducted involving paediatric oncology patients with diarrhoea. Stool samples were collected from children who were hospitalised with or without being treated with chemotherapy during the study period, and had diarrhoea at any stage during their admission. In the first study,stool samples were tested by conventional microbiological methods and by polymerase chain reaction for parasites, and by immunoassays for Clostridium difficile. In the second study, conventional microbiology was conducted for bacteria and parasites including an enzyme-linked immunosorbent assay for Cryptosporidium antigen, and in a subset, immunoassays for Clostridium difficile.RESULTS In the first study Giardia lamblia was detected in 68.5% of samples, Entamoeba histolytica in 13%, Cryptosporidium in 5.6%, non-toxigenic C. difficile in 22.4%, and other bacteria in 5.2%. In the second study, E. histolytica was detected in 10% of samples, Cryptosporidium in 4.3%, G. lamblia in 1.4%, C. difficile in 5.1%, and other bacteria in 5.7% of samples.CONCLUSION These pilot data suggest that parasites are important aetiologies of diarrhoea in Bangladeshi children with malignancy. While molecular diagnostic tools detect an array of stool pathogens with greater sensitivity, conventional diagnostic methods are also useful.

Using a Collateral Damage Model to Explain Survival Data in West Nile Virus Infections

Simulation code for a model of the adaptive immune response seen in flavivirus infections is used to explain the immunopathological consequences seen in West Nile Virus virus (WNV) infections. We use a model that specifically handles the differences in how the virus infects resting cells, the G0 state, versus dividing cells, the G1 state, which includes vastly increased MHC-I upregulation for resting cells over dividing cells. The simulation suggests how the infection progresses in a one host model and the results shed insight into the unusual survival curve data obtained for this infection: there is an increase in health even though viral load has increased.

DNA sequences homologous to hepatitis C virus(HCV) in the extrachromosomal circular DNA in peripheral blood mononuclear cells of HCV-negative subjects

Objective: This study aimed to investigate DNA sequences that are substantially homologous to the corresponding RNA sequence sections of the hepatitis C virus (HCV). These DNA sequences are present in the whole DNA extracted from peripheral blood mononuclear cells (PBMCs) of HCV-negative subjects. We presumed that these experimentally proven 5'-noncoding region (5'-NCR) homologous DNA sequences could be contained in the extrachromosomal circular DNA (eccDNA) fraction as part of the whole cellular DNA. Methods: Home-made polymerase chain reaction (PCR) with whole cellular and isolated eccDNA, nucleotide basic local alignment search tool (BLASTn) alignments, and tests for patterns of methylation in selected sequence sections were performed. Results: The PCR tests revealed DNA sequences of up to 320 bp that broadly matched the corresponding sequence sections of known HCV genotypes. In contrast, BLASTn alignment searches of published HCV 5'-NCR sequences with human genome databases revealed only sequence segments of up to 36 bp of the 5'-NCR. The composition of these sequences shows missing base pairs, base pair mismatches as well as complete homology with HCV reference sequences. These short sequence sections are present in numerous copies on both the same and different chromosomes. The selected sequence region within the DNA sequences of the 5'-NCR revealed a broad diversity of individual patterns of methylation. Conclusions: The experimental results confirm our assumption that parts of the HCV 5'-NCR genomic RNA sequences are present at the DNA level in the eccDNA fraction of PBMCs. The tests for methylation patterns therein revealed individual methylomes which could represent an epigenetic feature. The respective sequence section might be subject to genetic regulation.

Control programs for strongyloidiasis in areas of high endemicity: an economic analysis of different approaches

Background:Implementation of control programmes for Strongyloides stercoralis infection is among the targets of the World Health Organization Roadmap to 2030.Aim ofthis work was to evaluate the possible impact in terms of economic resources and health status of two different strategies of preventive chemotherapy(PC)compared to the current situation(strategy A,no PC):administration of ivermectin to school-age children(SAC)and adults(strategy B)versus ivermectin to SAC only(strategy C).Methods:The study was conducted at the IRCCS Sacro Cuore Don Calabria hospital,Negrar di Valpolicella,Verona,Italy,at the University of Florence,Italy,and at the WHO,Geneva,Switzerland,from May 2020 to April 2021.Data for the model were extracted from literature.A mathematical model was developed in Microsoft Excel to assess the impact of strategies B and C in a standard population of 1 million subjects living in a strongyloidiasis endemic area.In a case base seenario,15%prevalence of strongyloidiasis was considered;the 3 strategies were then evaluated at different thresholds of prevalenee,ranging from 5 to 20%.The results were reported as number of infected subjects,deaths,costs,and Incremental-Effectiveness Ratio(ICER).A 1-year and a 10-year horizons were considered.Results:In the case base seenario,cases of infections would reduce dramatically in the first year of implementation of PC with both strategy B and C:from 172500 cases to 77040 following strategy B and 146700 following strategy C.The additional cost per recovered person was United States Dollar(USD)2.83 and USD 1.13 in strategy B and C,respectively,compared to no treatment in the first year.For both strategies,there was a downtrend in costs per recovered person with increasing prevalenee.The number of adverted deaths was larger for strategy B than C,but cost to advert one death was lower for strategy C than B.Conclusions:This analysis permits to estimate the impact of two PC strategies for the control of strongyloidiasis in terms of costs and adverted infections/deaths.This could represent a basis on which each endemic country can evaluate which strategy can be implemented,based on available funds and national health priorities.

Identification of novel small-molecule inhibitors of SARS-CoV-2 by chemical genetics

There are only eight approved small molecule antiviral drugs for treating COVID-19.Among them,four are nucleotide analogues(remdesivir,JT001,molnupiravir,and azvudine),while the other four are protease inhibitors(nirmatrelvir,ensitrelvir,leritrelvir,and simnotrelvir-ritonavir).Antiviral resistance,unfavourable drug‒drug interaction,and toxicity have been reported in previous studies.Thus there is a dearth of new treatment options for SARS-CoV-2.In this work,a three-tier cell-based screening was employed to identify novel compounds with anti-SARS-CoV-2 activity.One compound,designated 172,demonstrated broad-spectrum antiviral activity against multiple human pathogenic coronaviruses and different SARS-CoV-2 variants of concern.Mechanistic studies validated by reverse genetics showed that compound 172 inhibits the 3-chymotrypsin-like protease(3CLpro)by binding to an allosteric site and reduces 3CLpro dimerization.A drug synergistic checkerboard assay demonstrated that compound 172 can achieve drug synergy with nirmatrelvir in vitro.In vivo studies confirmed the antiviral activity of compound 172 in both Golden Syrian Hamsters and K18 humanized ACE2 mice.Overall,this study identified an alternative druggable site on the SARS-CoV-23CLpro,proposed a potential combination therapy with nirmatrelvir to reduce the risk of antiviral resistance and shed light on the development of allosteric protease inhibitors for treating a range of coronavirus diseases.