Untreated Infection Research Articles

Mycobacterium avium complex (MAC) infection in severely immunocompromised people living with HIV: Findings from a five-year cohort.

We sought to clarify the current incidence, risk factors and symptoms of disseminated Mycobacterium avium complex (dMAC) infection in admitted people living with HIV in a hospital in the Southeast of Spain. 5-years observational, retrospective and single-centre study. Demographic, clinical and analytical variables, along with microbiological, treatment and follow-up were collected. Five cases of dMAC infection in severely immunocompromised people living with HIV people living were found. dMAC was diagnosed in 22.7% of patients under 100 CD4. All patients presented with fever and clinical manifestations of pneumonia, lymphadenopathy, or gastrointestinal symptoms. Despite low CD4 levels and high viral loads in some cases, primary prophylaxis had not been previously administered. Until 2018, U.S. American guidelines recommended antimycobacterial prophylaxis for patients with low CD4 cell counts, a practice not adopted in Europe. Untreated dMAC infection is associated with high morbidity and mortality rates. dMAC infection represents a prevalent disease in severely immunosuppressed people living with HIV. dMAC requires a high index of suspicion in this population, in order to perform mycobacterial cultures from different samples.

Development and Validation of a Machine Learning Model for Early Detection of Untreated Infection.

Early diagnostic uncertainty for infection causes delays in antibiotic administration in infected patients and unnecessary antibiotic administration in noninfected patients. To develop a machine learning model for the early detection of untreated infection (eDENTIFI), with the presence of infection determined by clinician chart review. Three thousand three hundred fifty-seven adult patients hospitalized between 2006 and 2018 at two health systems in Illinois, United States. We validated in 1632 patients in a third Illinois health system using area under the receiver operating characteristic curve (AUC). Using a longitudinal discrete-time format, we trained a gradient boosted machine model to predict untreated infection in the next 6 hours using routinely available patient demographics, vital signs, and laboratory results. eDENTIFI had an AUC of 0.80 (95% CI, 0.79-0.81) in the validation cohort and outperformed the systemic inflammatory response syndrome criteria with an AUC of 0.64 (95% CI, 0.64-0.65; p < 0.001). The most important features were body mass index, age, temperature, and heart rate. Using a threshold with a 47.6% sensitivity, eDENTIFI detected infection a median 2.0 hours (interquartile range, 0.9-5.2 hr) before antimicrobial administration, with a negative predictive value of 93.6%. Antibiotic administration guided by eDENTIFI could have decreased unnecessary IV antibiotic administration in noninfected patients by 10.8% absolute or 46.4% relative percentage points compared with clinicians. eDENTIFI could both decrease the time to antimicrobial administration in infected patients and unnecessary antibiotic administration in noninfected patients. Further prospective validation is needed.

Differences in HIV-1 reservoir size, landscape characteristics and decay dynamics in acute and chronic treated HIV-1 Clade C infection.

Background Persisting HIV reservoir viruses in resting CD4 T cells and other cellular subsets are the main barrier to cure efforts. Antiretroviral therapy (ART) intensification by early initiation has been shown to enable post-treatment viral control in some cases but the underlying mechanisms are not fully understood. We hypothesized that ART initiated during the hyperacute phase of infection before peak will affect the size, decay dynamics and landscape characteristics of HIV-1 subtype C viral reservoirs. Methods We studied 35 women at high risk of infection from Durban, South Africa identified with hyperacute HIV infection by twice weekly testing for plasma HIV-1 RNA. Study participants included 11 who started ART at a median of 456 (297-1203) days post onset of viremia (DPOV), and 24 who started ART at a median of 1 (1-3) DPOV. We used peripheral blood mononuclear cells (PBMC) to measure total HIV-1 DNA by ddPCR and to sequence reservoir viral genomes by full length individual proviral sequencing (FLIP-seq) from onset of detection of HIV up to 1 year post treatment initiation. Results Whereas ART in hyperacute infection blunted peak viremia compared to untreated individuals (p<0.0001), there was no difference in total HIV-1 DNA measured contemporaneously (p=0.104). There was a steady decline of total HIV DNA in early treated persons over 1 year of ART (p=0.0004), with no significant change observed in the late treated group. Total HIV-1 DNA after one year of treatment was lower in the early treated compared to the late treated group (p=0.02). Generation of 697 single viral genome sequences revealed a difference in the longitudinal proviral genetic landscape over one year between untreated, late treated, and early treated infection: the relative contribution of intact genomes to the total pool of HIV-1 DNA after 1 year was higher in untreated infection (31%) compared to late treated (14%) and early treated infection (0%). Treatment initiated in both late and early infection resulted in a more rapid decay of intact (13% and 51% per month) versus defective (2% and 35% per month) viral genomes. However, intact genomes were still observed one year post chronic treatment initiation in contrast to early treatment where intact genomes were no longer detectable. Moreover, early ART reduced phylogenetic diversity of intact genomes and limited the seeding and persistence of cytotoxic T lymphocyte immune escape variants in the reservoir. Conclusions Overall, our results show that whereas ART initiated in hyperacute HIV-1 subtype C infection did not impact reservoir seeding, it was nevertheless associated with more rapid decay of intact viral genomes, decreased genetic complexity and immune escape in reservoirs, which could accelerate reservoir clearance when combined with other interventional strategies.

8386 The Evolving Face of The Great Masquerader - Panhypopituitarism Associated with Neurosyphilis

Abstract Disclosure: M. Yabe: None. Z. Lin: None. F. Joseph: None. G. Philip: None. R. Silver: None. L. Callejas: None. J. Giunta: None. Untreated syphilis is on the rise in the United States. The CDC reported syphilis cases in newborns have increased 10-fold over a decade in November 2023, signifying the emergence of untreated infections. Pituitary involvement in syphilis is a very rare phenomenon, and endocrinological investigation is often overlooked. This will be the second reported case of neurosyphilis with pituitary involvement in a non-HIV infected patient. A 45-year-old female with no significant past medical history was admitted to the hospital with progressive neurological symptoms of intermittent left-side headache, hearing loss with tinnitus, and gait instability. Postcontrast MRI Brain revealed multifocal leptomeningeal enhancement involving supratentorial and infratentorial regions. Thickening of the enhanced pituitary infundibulum was also noted. Subsequent RPR titer showed 1:16 and lumbar puncture revealed CSF-VDRL titer 1:32, with pleocytosis 83 cells/uL, CSF-glucose 19 mg/dL, and CSF-protein 370 mg/dL. The patient completed Penicillin G 4 million/units intravenous every 4 hours for 14 days, with repeat MRI showing significant interval decrease in previously described extensive supratentorial and infratentorial leptomeningeal enhancement. However, there is no record of her sexual partner receiving treatment. The patient was readmitted one year later after a fall while displaying dysmetria. MRI Brain with contrast revealed a small subacute infarct along the right frontal corona radiata and pituitary gland measuring up to 1.2 cm in craniocaudal dimension compared to 0.4 cm on the prior exam. This prompted evaluation of pituitary hormones: FSH 0.8 IU/L, LH &amp;lt;0.3 IU/L, and ACTH 6.3 pg/mL, with normal serum growth hormone and prolactin levels. Further investigation revealed morning cortisol 2.5 ug/dL, thyrotropin &amp;lt; 0.2 uIU/mL, and free thyroxine 0.63 ng/dL. Radiological evidence is suspicious of inflammatory etiology of the pituitary gland. The patient was discharged with endocrinology follow-up and plan to perform a pituitary gland biopsy as an outpatient for confirmatory result. The association of neurosyphilis and hypophysitis leading to panhypopituitarism in a non-HIV infected patient was first reported in 2015. Since then, there remains limited research regarding their association due to rarity of pituitary involvement in neurosyphilis. With untreated syphilis on the rise and increased availability of MRI, clinicians should expect to encounter more cases of neurosyphilis with pituitary involvement in the future. Early detection of panhypopituitarism in those with positive CSF-VDRL titer could lead to better clinical outcomes. It is paramount that these cases are documented to emphasize pituitary involvement in neurosyphilis and encourage a low threshold to initiate endocrinological testing in the future. Presentation: 6/3/2024

Effect of antenatal Chlamydia trachomatis and Neisseria gonorrhoeae screening on postdelivery prevalence and vertical transmission in Gaborone, Botswana: findings from an exploratory study

ObjectivesChlamydia trachomatis and Neisseria gonorrhoeae are common sexually transmitted infections (STIs). Untreated infection in pregnancy can result in adverse neonatal outcomes, including vertical transmission. Screening for these infections is not...

A-296 Streck Urine Preserve Provides Sample Stability for Cepheid Xpert CT/NG test

Abstract Background Sexually transmitted infections (STIs) are one of the most common communicable diseases worldwide and are associated with significant morbidity and mortality. Data indicates that the four curable STIs - chlamydia, gonorrhea, trichomoniasis, and syphilis - cause over 375 million infections annually. Further, the infection rate for gonorrhea has increased by 63% in the United States and the emergence of resistant gonorrhea is an urgent global public health concern. To prevent transmission of gonorrhea and other curable STIs and minimize the escalation of untreated infections, early and effective prevention and control strategies are paramount. Rapid diagnostic testing and nucleic acid amplification tests (NAATs) have become the gold standard for STI detection. However, limited global access to these technologies often requires that samples be shipped to central laboratories for analysis. Current protocols recommend that neat urine be analyzed within 24 hours of collection if stored at 2 °C to 8 °C or within four days if frozen, as prolonged storage and exposure to freeze-thaws can induce cell lysis and release of nucleases, leading to degradation of DNA and false negative test results. Without sample stabilization, laboratories are left with a small window for accurate analysis. Here, we demonstrate that Streck Urine Preserve (SUP) maintains target and donor DNA concentrations during prolonged storage and that these stabilized samples are compatible with Cepheid’s automated GeneXpert System and associated Xpert CT/NG test. Methods Fresh human urine, with or without SUP, was tested neat or spiked with Neisseria gonorrhoeae (N. gonorrhoeae). Samples were stored at room temperature for up to 18 days before being analyzed on the Cepheid GeneXpert System using the Xpert CT/NG test per manufacturer’s instructions. Differences in average Ct values were compared for the sample processing control, sample adequacy control, and N. gonorrhoeae targets. DNA stability was assessed by comparing the changes between fresh and SUP-treated samples throughout the study period. Results Following prolonged storage, Ct values for neat, untreated urine increased by 3-7 cycles, correlating to a 10- to 100-fold decrease in detectable copies of N. gonorrhoeae and the sample adequacy control compared to urine samples stabilized with SUP. The average Ct value for samples stabilized with SUP did not change by more than 1.5 cycles throughout the study period. Additionally, Ct values for the sample processing control remained constant throughout the testing period, indicating that SUP did not impact sample processing. Conclusions When limited point-of-care testing options require storage and shipping of samples to central laboratories, urine stabilizers are imperative to obtain results representative of the patient sample at the time of collection. SUP effectively stabilized N. gonorrhoeae DNA and donor DNA prior to analysis with the Cepheid Xpert CT/NG test. This contrasts with the marked decrease in DNA copy number in non-stabilized urine over the study duration, which may lead to false negative results for low-positive urine samples. Taken together, SUP provides clinical researchers and assay developers with added flexibility when handling, shipping, and processing urine specimens and supports compatibility with automated NAAT systems and tests.

Neurosymptomatic HIV-1 CSF escape is associated with replication in CNS T cells and inflammation.

During antiretroviral therapy (ART), most people living with HIV-1 have undetectable HIV-1 RNA in their plasma. However, they occasionally present with new or progressive neurologic deficits and detectable HIV-1 RNA in the cerebrospinal fluid (CSF), a condition defined as neurosymptomatic HIV-1 CSF escape (NSE). We explored the source of neuropathogenesis and HIV-1 RNA in the CSF during NSE by characterizing HIV-1 populations and inflammatory biomarkers in CSF from 25 individuals with NSE. HIV-1 populations in the CSF were uniformly drug resistant and adapted to replication in CD4+ T cells, but differed greatly in genetic diversity, with some having low levels of diversity similar to those observed during untreated primary infection and others having high levels like those during untreated chronic infection. Higher diversity in the CSF during NSE was associated with greater CNS inflammation. Finally, optimization of ART regimen was associated with viral suppression and improvement of neurologic symptoms. These results are consistent with CNS inflammation and neurologic injury during NSE being driven by replication of partially drug-resistant virus in CNS CD4+ T cells. This is unlike nonsuppressible viremia in the plasma during ART, which typically lacks clinical consequences and is generated by virus expression without replication.

Eco-friendly drugs induce cellular changes in colistin-resistant bacteria

Abstract Background and objective As a last option, multidrug-resistant Gram-negative infections (caused by Enterobacteriaceae) are treated with the antibiotic colistin, also known as polymyxin E. Colistin-resistant superbugs predispose people to untreatable infections, possibly leading to a high mortality rate. This project aims to study the effect of Acacia nilotica aqueous extract and zinc oxide nanoparticles (ZnO-NPs) on colistin-resistant Klebsiella pneumonia (CRKP). Materials and methods ZnO-NPs were synthesized using the green method and characterized by UV-vis, Fourier transform infrared spectroscopy, and X-ray diffraction. The zone of inhibition (ZI) was measured using the agar-well diffusion method, and the minimum inhibitory concentration (MIC) and minimum bactericidal concentration were estimated to determine the antimicrobial activity of the tested compound. Scanning electron microscopy (SEM) and transmission electronic microscopy (TEM) were used to investigate the alterations in bacterial cells that were treated with the tested drugs. Results The synthesized ZnO-NPs presented good chemical and physical properties, and the plant extract and ZnO-NPs displayed a large ZI. ZnO-NPs had the lowest MIC (0.2 mg·mL−1). SEM and TEM observations revealed various morphological modifications in CRKP cells, including cell shrinkage, cell damage, cytoplasm loss, cell wall thinning, and cell death. Conclusion A. nilotica aqueous extract and ZnO-NPs could be used as alternative natural products to produce antibacterial drugs and to prevent CRKP infection.

Prevalence of bacterial vaginosis, sexually transmitted infections and their association with HPV infections in asymptomatic women attending antenatal care in Ethiopia.

Sexually transmitted infections (STIs) and human papillomavirus (HPV) infections are common among women of reproductive age and can lead to infertility, adverse pregnancy outcomes, neonatal infections and cervical cancer. In countries with limited medical coverage, untreated infections contribute to high morbidity. This study aimed to expand the current knowledge on the prevalence of bacterial vaginosis (BV) and STIs in pregnant Ethiopian women and assess the association of these conditions with HPV infections. Socio-demographic data and vaginal lavage samples were collected from 779 asymptomatic women aged 18 to 45 years (median age, 25.9 years) attending antenatal care in seven centres across Ethiopia. Multiplex polymerase chain reaction was used to test for BV, Chlamydia trachomatis, Trichomonas vaginalis, Neisseria gonorrhoeae, herpes simplex virus types 1 and 2 (HSV-1/2), Mycoplasma, Ureaplasma, Candida species and HPV. Overall, 26.8% (95% confidence interval (CI): 23.7-29.9) of women tested positive for BV or one of the following STIs: C. trachomatis, T. vaginalis, N. gonorrhoeae, Mycoplasma genitalium, HSV-1/2 or Ureaplasma urealyticum. Additionally, 22.1% tested positive for at least one high-risk HPV type. Chlamydia trachomatis and HSV-2 were significantly more common among women who were positive for HPV and high-risk HPV. This study reveals a high prevalence of asymptomatic pregnant women who are positive for BV, STIs or HPV, putting them at risk of adverse pregnancy outcomes, secondary infertility or cervical cancer in a country with limited medical coverage. Screening and treating these women could be crucial in reducing morbidity.

Surgical complications in hepatitis C patients undergoing cholecystectomy

BackgroundHepatitis C (HCV) infection affects more than 2.2 million people in the United States and is associated with liver cirrhosis and gallstone formation. However, cholecystectomy outcomes of patients with and without HCV infection are not well studied. This study aimed to examine the differences in cholecystectomy outcomes among patients with untreated, treated, and no HCV infection history. MethodsA retrospective cohort study was conducted at a single institution that included data of more than 12 years. Patients were excluded if they had a previous chronic hepatitis B or HIV diagnosis. Patients without HCV infection were matched to patients with HCV infection based on age, sex (male or female), and race/ethnicity. ResultsThis study identified 66 patients with untreated HCV infection and 33 patients with treated HCV infection. Furthermore, 324 patients without HCV infection were matched to the cohort HCV infection. The overall postoperative complication rate was 10.9%. There was no statistically significant difference in postoperative complication rates between the groups (P = .71). There was no significant difference in the level of intervention required to treat these complications according to the Clavien-Dindo classification (P = .97), postoperative intensive care unit admission (P = .43), or reoperation rate (P = .45). ConclusionDespite having a longer mean length of stay and increased risk of intraoperative blood product transfusion, both patients with untreated HCV infection and those with treated HCV infection had similar rates of postoperative complications and complication severity compared with controls. Our findings suggest that patients with HCV infection tolerate cholecystectomy at a comparable level to patients without HCV infection. The lack of difference in postoperative complication rates between patients with untreated and treated HCV infection indicates that lack of antiviral treatment should not delay cholecystectomy.

Long-term persistence of mitochondrial dysfunctions after viral infections and antiviral therapies: A review of mechanisms involved.

Mitochondria are vital for most cells' functions. Viruses hijack mitochondria machinery for misappropriation of energy supply or to bypass defense mechanisms. Many of these mitochondrial dysfunctions persist after recovery from treated or untreated viral infections, particularly when mitochondrial DNA is permanently damaged. Quantitative defects and structural rearrangements of mitochondrial DNA accumulate in post-mitotic tissues as recently reported long after SARS-CoV-2 or HIV infection, or following antiviral therapy. These observations are consistent with the "hit-and-run" concept proposed decades ago to explain viro-induced cell transformation and it could apply to delayed post-viral onsets of symptoms and advocate for complementary supportive care. Thus, according to this concept, following exposure to viruses or antiviral agents, mitochondrial damage could evolve into an autonomous clinical condition. It also establishes a pathogenic link between communicable and non-communicable chronic diseases.

Transcriptomic evidence of immune modulation in subjects with chronic Trypanosoma cruzi infection.

Chagas disease is a neglected tropical infection that affects millions of people. This study explores transcriptomic changes in T. cruzi-infected subjects before and after treatment. Using total RNA sequencing, gene transcription was analyzed in peripheral blood mononuclear cells from asymptomatic (n=19) and symptomatic (n=8) T. cruzi-infected individuals, and non-infected controls (n=15). Differential expression was compared across groups, and before/after treatment in infected subgroups. Untreated infection showed 12 upregulated and 206 downregulated genes in all T. cruzi-infected subjects, and 47 upregulated and 215 downregulated genes in the symptomatic group. Few differentially expressed genes were found after treatment and between the different infected groups. Gene set enrichment analysis highlighted immune-related pathways activated during infection, with therapy normalizing immune function. Changes in the kynurenine/tryptophan ratio, increased pre-treatment, suggested chronic immune fatigue, which was restored post-treatment. These differentially expressed genes offer insights for potential biomarkers and pathways associated with disease progression and treatment response.

Epidemiology of Hepatitis C over 28 years of monitoring Canadian blood donors: Insight into a low-risk undiagnosed population

BackgroundHepatitis C is a blood-borne infection with the hepatitis C virus (HCV) that can progress to cirrhosis and liver cancer. About 70% (50–80%) of infections become chronic and exhibit anti-HCV and HCV nucleic acid (NAT) positivity. Direct acting oral pan genotypic antiviral treatment became available in 2014 and was free for most Canadians in 2018. Clinical screening for HCV infection is risk-based. About 1% of Canadians have been infected with HCV, with 0.5% chronically infected (about 25% unaware) disproportionately impacting marginalized groups. Blood donors are in good health, are deferred for risks such as injection drug use and can provide insight into the low-risk undiagnosed population. Here we describe HCV epidemiology in first-time blood donors over 28 years of monitoring.MethodsAll first-time blood donors in all Canadian provinces except Quebec (1993 to 2021) were analyzed. All blood donations were tested for HCV antibodies (anti-HCV) and since late 1999 also HCV NAT. A case-control study was also included. All HCV positive donors (cases) since 2005 and HCV negative donors (1:4 ratio controls) matched for age, sex and location were invited to complete a risk factor interview. Separate logistic regression models for anti-HCV positivity and chronic HCV assessed the association between age cohort, sex, region and neighbourhood material deprivation and ethnocultural concentration. Case: control data were analysed by logistic regression.ResultsThere were 2,334,238 donors from 1993 to 2021 included. Prevalence for anti-HCV was 0.33% (0.30,0.37) in 1993 and 0.07% (0.05,0.09) in 2021 (p < 0.0001). In 2021 0.03% (0.01,0.04) had chronic HCV. Predictors for both anti-HCV positivity and chronic HCV were similar, for chronic HCV were male sex (OR 1.8, 1.6,2.1), birth between 1945 and 1975 (OR 7.1, 5.9,8.5), living in the western provinces (OR 1.4, 1.2,1.7) and living in material deprived (OR 2.7, 2.1,3.5) and more ethnocultural concentrated neighbourhoods (OR 1.8, 1.3,2.5). There were 318 (35.4%) of chronic HCV positive and 1272 (39.6%) of controls who participated in case control interviews. The strongest risks for acquisition were injection drug use (OR 96.9, 22.3,420.3) and birth in a high prevalence country (OR 24.5, 11.2,53.6).ConclusionsBlood donors have 16 times lower HCV prevalence then the general population. Donors largely mirror population trends and highlight the ongoing prevalence of untreated infections in groups without obvious risks for acquisition missed by risk-based patient screening.

Liver Failure and Cirrhosis Prediction- Using Methods for Machine Learning

Liver disease continues to be a major global health concern, accounting for a considerable portion of global mortality. It results in a variety of symptoms such aberrant nerve function, blood in the cough or vomit, renal and liver failure, jaundice, and liver encephalopathy. It is caused by a myriad of variables that influence the liver, including obesity, untreated hepatitis infection, and alcohol misuse. In order to effectively treat liver infections, early detection is essential, and sensor- based medical technology is frequently used in modern medical procedures to identify illnesses. But diagnosing a condition can be expensive and difficult. Thus, the purpose of this paper is to compare the effectiveness of different machine learning algorithms in order to judge how well they function and have what potential to categorize liver diseases.

Hepatitis B Virus Treatment in Children: Common Challenges and Management Options in a Case-Based Format.

The management of hepatitis B virus (HBV) in pediatrics presents many challenges, given the potential sequelae of untreated infection including hepatic fibrosis, cirrhosis, and malignancy, and a lack of clear guidance on the timing of treatment initiation. The goal of this review is to feature common clinical scenarios that occur in the evaluation and treatment of HBV infection in children. Each vignette presents an opportunity to discuss guidelines and evidence-based practices as well as review landmark studies and evolving practices.

Changing Face of Antimicrobial Resistance: A Cross-Sectional Study

Introduction Infections of sterile body fluids are significant contributors to mortality and morbidity. Accurate species-level identification and understanding of the antimicrobial resistance profiles are crucial for selecting appropriate antimicrobials for empirical and targeted therapy. This study aims to examine the distribution of various bacterial species and their evolved antimicrobial resistance profiles isolated from different body fluids. Methods This retrospective study evaluated 301 body fluid samples collected at a tertiary hospital between January 2023 and December 2023. Samples were gram-stained and cultured on an appropriate media. Bacterial identification and susceptibility testing were performed using the BD Phoenix™ system, with disk diffusion method used for antibiotics not available in the system. Results Microbial growth was detected in 151 cases (50.2%), with a comparable prevalence among males and females (53.0% vs. 46.7%). The mean age was 49.81± 24.1 years. Growth rates were slightly higher in hospital-acquired infections (55.7%) than in community-acquired infections (49.2%). Cerebrospinal fluid showed the highest growth rate at 34.3%. Among the isolates, Streptococcus species were the most common (14.6%), while Escherichia coli was the predominant Gram-negative bacterium (13.2%). Sensitivity was highest with tigecycline (100%) and meropenem (92%), whereas resistance was most notable against ampicillin-sulbactam (100%) and azithromycin (95.2%). Multidrug resistance was identified in 106 isolates (70.2%). Conclusion High antibiotic resistance and multidrug-resistant strains underscore the need for rigorous antibiotic stewardship and improved infection control to address untreatable infections.

Cyclization increases bactericidal activity of arginine-rich cationic cell-penetrating peptide for Neisseria gonorrhoeae.

We previously reported that a linear cationic 12-amino acid cell-penetrating peptide (CPP) was bactericidal for Neisseria gonorrhoeae. In this study, our objectives were to determine the effect of cyclization of the linear CPP on its antibacterial activity for N. gonorrhoeae and cytotoxicity for human cells. We compared the bactericidal effect of 4-hour treatment with the linear CPP to that of CPPs cyclized by a thioether or a disulfide bond on human challenge and multi-drug resistant (MDR) strains of N. gonorrhoeae grown in cell culture media with 10% fetal bovine serum (FBS). The effect of lipooligosaccharide (LOS) sialylation on bactericidal activity was analyzed. We determined the ability of the CPPs to treat human cells infected in vitro with N. gonorrhoeae, to reduce the inflammatory response of human monocytic cells to gonococci, to kill strains of three commensal Neisseria species, and to inhibit gonococcal biofilms. The cyclized CPPs killed 100% of gonococci from all strains at 100 µM and >90% at 20 µM and were more potent than the linear form. The thioether-linked but not the disulfide-linked CPP was less cytotoxic for human cervical cells compared to the linear CPP. LOS sialylation had minimal effect on bactericidal activity. In treating infected human cells, the thioether-linked CPP at 20 µM killed >60% of extra- and intracellular bacteria and reduced TNF-α expression by THP-1 cells. The potency of the CPPs for the pathogenic and the commensal Neisseria was similar. The thioether-linked CPP partially eradicated gonococcal biofilms. Future studies will focus on determining efficacy in the female mouse model of gonorrhea.IMPORTANCENeisseria gonorrhoeae remains a major cause of sexually transmitted infections with 82 million cases worldwide in 2020, and 710,151 confirmed cases in the US in 2021, up 25% from 2017. N. gonorrhoeae can infect multiple tissues including the urethra, cervix, rectum, pharynx, and conjunctiva. The most serious sequelae are suffered by infected women as gonococci ascend to the upper reproductive tract and cause pelvic inflammatory disease, chronic pelvic pain, and infertility in 10%-20% of women. Control of gonococcal infection is widely recognized as increasingly challenging due to the lack of any vaccine. N. gonorrhoeae has quickly developed resistance to all but one class of antibiotics and the emergence of multidrug-resistant strains could result in untreatable infections. As such, gonorrhea is classified by the Center for Disease Control (CDC) as an urgent public health threat. The research presented herein on new therapeutics for gonorrhea has identified a cyclic cell-penetrating peptide (CPP) as a potent molecule targeting N. gonorrhoeae.

Rapid synthesis of ferulic acid-derived lignin coated silver nanoparticles with low cytotoxicity and high antibacterial activity

Antibiotic resistance and the rise of untreatable bacterial infections pose severe threats to human health. Silver nanoparticles (AgNPs) have emerged as a promising antibacterial solution due to their broad-spectrum effectiveness. However, their relatively high cytotoxicity has limited their widespread application. In this study, ferulic acid (FA) was used as a reducing agent, while silver oxide served as a silver precursor to rapidly prepare FA-derived lignin (FAL) coated AgNPs (AgNPs@FAL) with a size ranging from 34.8 to 77.1 nm. Density functional theory (DFT) calculations indicated that the coating of FAL endowed AgNPs@FAL with high stability, preventing the oxidation of AgNPs prior to antibacterial applications. Cell experiments further indicated that AgNPs@FAL exhibited lower cell toxicity (∼80 % viability of normal kidney cells cultured at 25 μg/mL AgNPs@FAL) compared to fully exposed commercially available citrate-modified AgNPs (AgNPs@CA). Antibacterial experiments revealed that the minimum inhibitory concentrations (MIC) of AgNPs@FAL against E. coli and S. aureus were 12.5 μg/mL and 25 μg/mL, respectively, surpassing the antibacterial effect of AgNPs@CA, as well as ampicillin and penicillin. Additionally, AgNPs@FAL was capable of disrupting E. coli and S. aureus biofilm formation. This novel AgNPs@FAL formulation presents a promising antibacterial solution, addressing limitations observed in conventional drugs.

Morbidity burden of imported chronic schistosomiasis among West African migrants

Past exposure to schistosomiasis is frequent among migrants from endemic countries, and chronic untreated infection may lead to long-term morbidities. We carried out a prospective population-based cross-sectional study among migrants from endemic Sub-Saharan countries living in Barcelona, Spain. Participants had not been previously diagnosed or treated for schistosomiasis. Clinical signs and symptoms were scrutinised through a systematic revision of electronic medical records and an on-site standardised questionnaire, and blood and urine samples were screened for Schistosoma. We recruited 522 eligible participants, 74.3% males, mean age 42.7 years (SD=11.5, range 18-76), Overall, 46.4% were from Senegal and 23.6% from Gambia. They had lived in the European Union for a median of 16 years (IQR 10-21). The prevalence of a Schistosoma-positive serology was 35.8%. S. haematobium eggs were observed in urine samples in 6 (1.2%) participants. The most prevalent symptoms among Schistosoma-positive participants were chronic abdominal pain (68.8%, OR=1.79; 95%CI 1.2-2.6), eosinophilia (44.9%, OR=2.69; 95%CI 1.8-4.0) and specific symptoms associated with urinary schistosomiasis, like self-reported episodes of haematuria (37.2%; OR=2.47; 95%CI 1.6-3.8), dysuria (47.9%, OR=1.84; 95%CI=1.3-2.7) and current renal insufficiency (13.4%; OR=2.35; 95%CI=1.3-4.3). We found a significant prevalence of gender-specific genital signs and symptoms among females (mainly menstrual disorders) and males (erectile dysfunction and pelvic pain). Individuals typically presented with a multitude of interconnected symptoms, most commonly chronic abdominal pain, which are often disregarded. Despite the lack of urine parasite identification, the high incidence of clinical signs and symptoms strongly correlated with a positive schistosomiasis serology suggests the existence of a heavy clinical burden among long-term West African migrants living for years/decades in the study region. More research is urgently required to determine whether these symptoms are the result of long-term sequelae or a persistent active Schistosoma infection.

Metabolic, Mitochondrial, and Inflammatory Effects of Efavirenz, Emtricitabine, and Tenofovir Disoproxil Fumarate in Asymptomatic Antiretroviral-Naïve People with HIV.

This study aimed to comprehensively assess the metabolic, mitochondrial, and inflammatory effects of first-line efavirenz, emtricitabine, and tenofovir disoproxil fumarate (EFV/FTC/TDF) single-tablet regimen (STR) relative to untreated asymptomatic HIV infection. To this end, we analyzed 29 people with HIV (PWH) treated for at least one year with this regimen vs. 33 antiretroviral-naïve PWH. Excellent therapeutic activity was accompanied by significant alterations in metabolic parameters. The treatment group showed increased plasmatic levels of glucose, total cholesterol and its fractions (LDL and HDL), triglycerides, and hepatic enzymes (GGT, ALP); conversely, bilirubin levels (total and indirect fraction) decreased in the treated cohort. Mitochondrial performance was preserved overall and treatment administration even promoted the recovery of mitochondrial DNA (mtDNA) content depleted by the virus, although this was not accompanied by the recovery in some of their encoded proteins (since cytochrome c oxidase II was significantly decreased). Inflammatory profile (TNFα, IL-6), ameliorated after treatment in accordance with viral reduction and the recovery of TNFα levels correlated to mtDNA cell restoration. Thus, although this regimen causes subclinical metabolic alterations, its antiviral and anti-inflammatory properties may be associated with partial improvement in mitochondrial function.