Safety analysis of Oseltamivir and Baloxavir Marboxil after market approval: a pharmacovigilance study based on the FDA adverse event reporting system.

BACKGROUND AND OBJECTIVES: Amidst limited influenza treatment options, evaluating the safety of Oseltamivir and Baloxavir Marboxil is crucial, particularly given their comparable efficacy. This study investigates post-market safety profiles, exploring adverse events (AEs) and their drug associations to provide essential clinical references. METHODS: A meticulous analysis of FDA Adverse Event Reporting System (FAERS) data spanning the first quarter of 2004 to the fourth quarter of 2022 was conducted. Using data mining techniques like reporting odds ratio (ROR), proportional reporting ratio, Bayesian Confidence Propagation Neural Network, and Multiple Gamma Poisson Shrinkage, AEs related to Oseltamivir and Baloxavir Marboxil were examined. Venn analysis compared and selected specific AEs associated with each drug. RESULTS: Incorporating 15,104 Oseltamivir cases and 1,594 Baloxavir Marboxil cases, Wain analysis unveiled 21 common AEs across neurological, psychiatric, gastrointestinal, dermatological, respiratory, and infectious domains. Oseltamivir exhibited 221 significantly specific AEs, including appendicolith [ROR (95% CI), 459.53 (340.88 ∼ 619.47)], acne infantile [ROR (95% CI, 368.65 (118.89 ∼ 1143.09)], acute macular neuroretinopathy [ROR (95% CI), 294.92 (97.88 ∼ 888.64)], proctitis [ROR (95% CI), 245.74 (101.47 ∼ 595.31)], and Purpura senile [ROR (95% CI), 154.02 (81.96 ∼ 289.43)]. designated adverse events (DMEs) associated with Oseltamivir included fulminant hepatitis [ROR (95% CI), 12.12 (8.30-17.72), n=27], ventricular fibrillation [ROR (95% CI), 7.68 (6.01-9.83), n=64], toxic epidermal necrolysis [ROR (95% CI), 7.21 (5.74-9.05), n=75]. Baloxavir Marboxil exhibited 34 specific AEs, including Melaena [ROR (95% CI), 21.34 (14.15-32.18), n = 23], cystitis haemorrhagic [ROR (95% CI), 20.22 (7.57-54.00), n = 4], ileus paralytic [ROR (95% CI), 18.57 (5.98-57.71), n = 3], and haemorrhagic diathesis [ROR (95% CI), 16.86 (5.43-52.40)), n = 3]. DMEs associated with Baloxavir Marboxil included rhabdomyolysis [ROR (95% CI), 15.50 (10.53 ∼ 22.80), n = 26]. CONCLUSION: Monitoring fulminant hepatitis during Oseltamivir treatment, especially in patients with liver-related diseases, is crucial. Oseltamivir's potential to induce abnormal behavior, especially in adolescents, necessitates special attention. Baloxavir Marboxil, with lower hepatic toxicity, emerges as a potential alternative for patients with liver diseases. During Baloxavir Marboxil treatment, focused attention on the occurrence of rhabdomyolysis is advised, necessitating timely monitoring of relevant indicators for those with clinical manifestations. The comprehensive data aims to provide valuable insights for clinicians and healthcare practitioners, facilitating an understanding of the safety profiles of these influenza treatments in real-world scenarios.

Effect of Carbamazepine on Darunavir Trough Concentrations: When the Dose Can Make the Difference-A Case Study.

BACKGROUND: Carbamazepine (CBZ) is an antiseizure medication known to induce the expression of cytochrome P4503A metabolic enzymes. Here, we describe a man living with HIV who underwent several changes in the daily dose of CBZ, which resulted in different induction effects on darunavir trough concentrations. METHODS: A 59-year-old man with HIV, successfully undergoing maintenance antiretroviral treatment with darunavir/cobicistat once daily (combined with raltegravir), was prescribed CBZ for recurrent trigeminal neuralgia. Over subsequent months, the patient underwent various changes in the doses (from 200 to 800 mg/d) and trough concentrations (from 3.6 to 18.0 mg/L) of CBZ, guided by clinical response to trigeminal neuralgia. RESULTS: A highly significant inverse association was observed between darunavir trough concentration and both CBZ dose or trough concentration (coefficient of determination >0.75, P < 0.0001). Ultimately, the darunavir dose was increased to 600 mg twice daily with ritonavir and dolutegravir to ensure optimal antiretroviral coverage, anticipating potential further uptitration of CBZ doses. CONCLUSIONS: The impact of CBZ on boosted darunavir exposure seemed to be dose- and concentration-dependent. The management of such drug-drug interactions in daily practice was facilitated through therapeutic drug monitoring. This case underscores the importance of a multidisciplinary approach that incorporates both antiretroviral and nonantiretroviral comedications contributing to the optimal management of polypharmacy in individuals living with HIV.

Dolutegravir and Folic Acid Interaction during Neural System Development in Zebrafish Embryos.

Dolutegravir (DTG) is one of the most prescribed antiretroviral drugs for treating people with HIV infection, including women of child-bearing potential or pregnant. Nonetheless, neuropsychiatric symptoms are frequently reported. Early reports suggested that, probably in relation to folic acid (FA) shortage, DTG may induce neural tube defects in infants born to women taking the drug during pregnancy. Subsequent reports did not definitively confirm these findings. Recent studies in animal models have highlighted the association between DTG exposure in utero and congenital anomalies, and an increased risk of neurologic abnormalities in children exposed during in utero life has been reported. Underlying mechanisms for DTG-related neurologic symptoms and congenital anomalies are not fully understood. We aimed to deepen our knowledge on the neurodevelopmental effects of DTG exposure and further explore the protective role of FA by the use of zebrafish embryos. We treated embryos at 4 and up to 144 h post fertilization (hpf) with a subtherapeutic DTG concentration (1 µM) and observed the disruption of the anterior-posterior axis and several morphological malformations in the developing brain that were both prevented by pre-exposure (2 hpf) and rescued by post-exposure (10 hpf) with FA. By whole-mount in situ hybridization with riboprobes for genes that are crucial during the early phases of neurodevelopment (ntl, pax2a, ngn1, neurod1) and by in vivo visualization of the transgenic Tg(ngn1:EGFP) zebrafish line, we found that DTG induced severe neurodevelopmental defects over time in most regions of the nervous system (notochord, midbrain-hindbrain boundary, eye, forebrain, midbrain, hindbrain, spinal cord) that were mostly but not completely rescued by FA supplementation. Of note, we observed the disruption of ngn1 expression in the dopaminergic regions of the developing forebrain, spinal cord neurons and spinal motor neuron projections, with the depletion of the tyrosine hydroxylase (TH)+ dopaminergic neurons of the dorsal diencephalon and the strong reduction in larvae locomotion. Our study further supports previous evidence that DTG can interfere with FA pathways in the developing brain but also provides new insights regarding the mechanisms involved in the increased risk of DTG-associated fetal neurodevelopmental defects and adverse neurologic outcomes in in utero exposed children, suggesting the impairment of dopaminergic pathways.

Recognition of 8-Oxo-2'-deoxyguanosine in DNA Using the Triphosphate of 2'-Deoxycytidine Connecting the 1,3-Diazaphenoxazine Unit, dCdapTP.

DNA is constantly damaged by various external and internal factors. In particular, oxidative damage occurs in a steady state, and 8-oxo-2'-deoxyguanosine (oxodG) is known as the main oxidative damage. OxodG is a strong genotoxic nucleoside and is thought to be involved in the pathogenesis of cancer and neurological diseases. However, a breakthrough method to detect the position of oxodG in DNA has not yet been developed. Therefore, we attempted to develop a novel method to detect oxodG in DNA using artificial nucleosides. Recently, we have succeeded in the recognition of oxodG in DNA by a single nucleotide elongation reaction using nucleoside derivatives based on a purine skeleton with a 1,3-diazaphenoxazine unit. In this study, we developed a new nucleoside derivative with a pyrimidine skeleton in order to further improve the recognition ability and enzymatic reaction efficiency. We, therefore, designed and synthesized 2'-deoxycytidine-1,3-diazaphenoxazine (Cdap) and its triphosphate derivatives. The results showed that it was incorporated into the primer strand relative to the dG template because of its cytidine skeleton, but it was more effective at the complementary position of the oxodG template. These results indicate that the new nucleoside derivative can be considered as one of the new candidates for the detection of oxodG in DNA.

A targeted fluorescent nanosensor for ratiometric pH sensing at the cell surface.

The correlation between altered extracellular pH and various pathological conditions, including cancer, inflammation and metabolic disorders, is well known. Bulk pH measurements cannot report the extracellular pH value at the cell surface. However, there is a limited number of suitable tools for measuring the extracellular pH of cells with high spatial resolution, and none of them are commonly used in laboratories around the world. In this study, a versatile ratiometric nanosensor for the measurement of extracellular pH was developed. The nanosensor consists of biocompatible polystyrene nanoparticles loaded with the pH-inert reference dye Nile red and is surface functionalized with a pH-responsive fluorescein dye. Equipped with a targeting moiety, the nanosensor can adhere to cell membranes, allowing direct measurement of extracellular pH at the cell surface. The nanosensor exhibits a sensitive ratiometric pH response within the range of 5.5-9.0, with a calculated pKa of 7.47. This range optimally covers the extracellular pH (pHe) of most healthy cells and cells in which the pHe is abnormal, such as cancer cells. In combination with the nanosensors ability to target cell membranes, its high robustness, reversibility and its biocompatibility, the pHe nanosensor proves to be well suited for in-situ measurement of extracellular pH, even over extended time periods. This pH nanosensor has the potential to advance biomedical research by improving our understanding of cellular microenvironments, where extracellular pH plays an important role.

Two-drug regimens for the treatment of HIV in Africa.

Two-drug regimens for the treatment of HIV are increasingly available. The oral regimen of dolutegravir plus lamivudine is recommended as a preferred option in multiple national guidelines but is not currently included in WHO HIV treatment guidelines nor widely used in Africa. Long-acting injectable cabotegravir and rilpivirine is being rolled out in the USA, Europe, and Australia but its use in sub-Saharan Africa is currently restricted to clinical trials. Given the increasing life expectancy, rising prevalence of non-communicable diseases, and resulting polypharmacy among people living with HIV, there are potential advantages to the use of two-drug regimens, particularly in African women, adolescents, and older adults. This Viewpoint reviews existing evidence and highlights the risks, benefits, and key knowledge gaps for the use of two-drug regimens in settings using the public health approach in Africa. We suggest that a two-drug regimen of dolutegravir and lamivudine can be safely used as a switch option for virologically suppressed individuals in settings using the public health approach once chronic hepatitis B has been excluded. Individuals with HIV who are switched to two-drug regimens should receive a full course of hepatitis B vaccinations. More efficacy data is needed to support dolutegravir plus lamivudine combination in the test and treat approach, and long-acting cabotegravir and rilpivirine in the public health system in sub-Saharan Africa.

Construction of a novel near-infrared fluorescent Nile blue@MOF nanoprobe for imaging mitochondrial ATP in living cells.

A near-infrared fluorescent nanoprobe consisting of Nile blue-capped ZIF-90 is first proposed for real-time imaging of mitochondrial ATP. Owing to the strong binding of ATP with Zn2+, the structure of the probe is disrupted, leading to the release of fluorescent NB.

Does commercial indoxacarb pose ecotoxicological consequences? Employing a multi-marker approach in the model species Theba pisana.

Indoxacarb is one of the most extensively used oxadiazine insecticides worldwide, but it may exert detrimental effects on ecosystems, population dynamics, and health. Due to the lack of knowledge on the ecotoxicity of indoxacarb, it is still challenging to assess whether this insecticide poses an ecotoxicological impact on terrestrial environments. Therefore, our study aims to provide novel data on the toxic effects of 28-day dietary exposure to commercial grade indoxacarb at two environmentally relevant concentrations, 0.02 µg/mL and tenfold (0.2 µg/mL) on the model species, Theba pisana. Their effects were studied using a multiple biomarker approach by evaluating physiological, biochemical, and histopathological responses. After 28 days of treatment, indoxacarb at both concentrations significantly reduced the food intake and growth of the treated snails. Also, it caused decreases in lipid peroxidation (LPO)  levels after 7 and 14 days of exposure, whereas an opposite effect occurred after 21 and 28 days. All treated snails were found to exhibit a lower content of glutathione (GSH) after all times of exposure. Moreover, catalase (CAT), glutathione-S-transferase (GST), and glutathione peroxidase (GPx) activities, as well as protein content (PC), were elevated in the treated snails after all time intervals. Post exposure to both realistic indoxacarb concentrations, changes in acetylcholinesterase (AChE) activity between a decrease and an increase were observed. Furthermore, indoxacarb caused histo-architectural changes in the hepatopancreas of T. pisana. Our results demonstrate that, at environmentally relevant concentrations, indoxacarb poses negative consequences for T. pisana, indicating its ecotoxicological impacts.

Alared: Solvatochromic and Fluorogenic Red Amino Acid for Ratiometric Live-Cell Imaging of Bioactive Peptides.

To fill the need for environmentally sensitive fluorescent unnatural amino acids able to operate in the red region of the spectrum, we have designed and synthesized Alared, a red solvatochromic and fluorogenic amino acid derived from the Nile Red chromophore. The new unnatural amino acid can be easily integrated into bioactive peptides using classical solid-phase peptide synthesis. The fluorescence quantum yield and the emission maximum of Alared-labeled peptides vary in a broad range depending on the peptide's environment, making Alared a powerful reporter of biomolecular interactions. Due to its red-shifted absorption and emission spectra, Alared-labeled peptides could be followed in living cells with minimal interference from cellular autofluorescence. Using ratiometric fluorescence microscopy, we were able to track the fate of the Alared-labeled peptide agonists of the apelin G protein-coupled receptor upon receptor activation and internalization. Due to its color-shifting environmentally sensitive emission, Alared allowed for distinguishing the fractions of peptides that are specifically bound to the receptor or unspecifically bound to different cellular membranes.

Discovery of Dolutegravir Derivative against Liver Cancer via Inducing Autophagy and DNA Damage.

We introduced a terminal alkyne into the core structure of dolutegravir, resulting in the synthesis of 34 novel dolutegravir-1,2,3-triazole compounds through click chemistry. These compounds exhibited remarkable inhibitory activities against two hepatocellular carcinoma cell lines, Huh7 and HepG2. Notably, compounds 5e and 5p demonstrated exceptional efficacy, particularly against Huh7 cells, with IC50 values of 2.64 and 5.42 µM. Additionally, both compounds induced apoptosis in Huh7 cells, suppressed tumor cell clone formation, and elevated reactive oxygen species (ROS) levels, further promoting tumor cell apoptosis. Furthermore, compounds 5e and 5p activated the LC3 signaling pathway, inducing autophagy, and triggered the γ-H2AX signaling pathway, resulting in DNA damage in tumor cells. Compound 5e exhibited low toxicity, highlighting its potential as a promising anti-tumor drug.

Sublethal effect and detoxifying metabolism of metaflumizone and indoxacarb on the fall armyworm, Spodoptera frugiperda.

The fall armyworm (FAW), Spodoptera frugiperda (J.E. Smith) (Lepidoptera, Noctuidae), is a highly polyphagous invasive pest that damages various crops. Pesticide control is the most common and effective strategy to control FAW. In this study, we evaluated the toxicity of metaflumizone and indoxacarb against third-instar FAW larvae using the insecticide-incorporated artificial diet method under laboratory conditions. Both metaflumizone and indoxacarb exhibited substantial toxicity against FAW, with LC50 values of 2.43 and 14.66 mg/L at 72 h, respectively. The sublethal effects of metaflumizone and indoxacarb on parental and F1 generation FAW were investigated by exposing third-instar larvae to LC10 and LC30 concentrations of these insecticides. Sublethal exposure to these two insecticides significantly shortened adult longevity, extended pupal developmental times and led to reduced pupal weight, pupation rates, and adult fecundity in the treated parental generation and F1 generation at LC10 or LC30 concentrations, in comparison to the control group. The larval developmental times were shortened in the parental generation but prolonged in the F1 generation, after being treated with sublethal concentrations of metaflumizone. Furthermore, larvae exposed to LC10 or LC30 concentrations of indoxacarb exhibited elevated activity levels of cytochrome P450 monooxygenase and glutathione S-transferase, which coincides with the observed synergistic effect of piperonyl butoxide and diethyl maleate. In conclusion, the high toxicity and negative impact of metaflumizone and indoxacarb on FAW provided significant implications for the rational utilization of insecticides against this pest.

Efficacy and safety of switching to dolutegravir/lamivudine in virologically suppressed people with HIV-1 aged ≥ 50 years: week 48 pooled results from the TANGO and SALSA studies.

BACKGROUND: As the population of people with HIV ages, concerns over managing age-related comorbidities, polypharmacy, immune recovery, and drug-drug interactions while maintaining viral suppression have arisen. We present pooled TANGO and SALSA efficacy and safety results dichotomized by age (< 50 and ≥ 50 years). METHODS: Week 48 data from the open-label phase 3 TANGO and SALSA trials evaluating switch to once-daily dolutegravir/lamivudine (DTG/3TC) fixed-dose combination vs continuing current antiretroviral regimen (CAR) were pooled. Proportions of participants with HIV-1 RNA ≥ 50 and < 50 copies/mL (Snapshot, intention-to-treat exposed) and safety were analyzed by age category. Adjusted mean change from baseline in CD4 + cell count was assessed using mixed-models repeated-measures analysis. RESULTS: Of 1234 participants, 80% of whom were male, 29% were aged ≥ 50 years. Among those aged ≥ 50 years, 1/177 (< 1%) DTG/3TC participant and 3/187 (2%) CAR participants had HIV-1 RNA ≥ 50 copies/mL at 48 weeks; proportions with HIV-1 RNA < 50 copies/mL were high in both treatment groups (≥ 92%), consistent with overall efficacy and similar to observations in participants aged < 50 years (≥ 93%). Regardless of age category, CD4 + cell count increased or was maintained from baseline with DTG/3TC. Change from baseline in CD4 + /CD8 + ratio was similar across age groups and between treatment groups. One CAR participant aged < 50 years had confirmed virologic withdrawal, but no resistance was detected. In the DTG/3TC group, incidence of adverse events (AEs) was similar across age groups. Proportions of AEs leading to withdrawal were low and comparable between age groups. Although drug-related AEs were generally low, across age groups, drug-related AEs were more frequent in participants who switched to DTG/3TC compared with those who continued CAR. While few serious AEs were observed in both treatment groups, more were reported in participants aged ≥ 50 years vs < 50 years. CONCLUSIONS: Among individuals with HIV-1, switching to DTG/3TC maintained high rates of virologic suppression and demonstrated a favorable safety profile, including in those aged ≥ 50 years despite higher prevalence of concomitant medication use and comorbidities. TRIAL REGISTRATION NUMBER: TANGO, NCT03446573 (February 27, 2018); SALSA, NCT04021290 (July 16, 2019).

Use of Two Novel Dyes to Enhance Visualization of Cut Ends of the Vessel in Microvascular Anastomosis-An Experimental Study of 45 Rats.

BACKGROUND: Good visualization is a prerequisite for performing microvascular anastomosis. The most commonly used dye, methylene blue, has several limitations: it is washed off quickly and stains all the vessel layers. The objective of our study is to use 2 new novel dyes for improving visualization. METHODS: After ethical committee approval, 2 Dyes (2% cresyl violet, 1% eosin) were studied in 3 groups, 20 rats in each group and 5 rats in the combined group. End-to-side anastomosis was performed in the classic fashion in 45 rats. After venotomy, the dye was applied to the raw surface of the vessels and subsequently, anastomosis was performed. The improvement in visualization was judged by 3 blinded experts and nonexperts in 4 groups on a scale of 1-10. Scores were statistically analyzed. After 2 weeks, animals were re-explored to check the delayed patency, and segments were harvested for histopathologic analysis. RESULTS: The immediate and delayed patency rates were 100% (45/45) and 97% (33/34), respectively. In statistical analysis, the combined group (P = 0.005)was judged statistically significant because of the contrast in color. All the layers were stained by both dyes, staining lasted until the end of the surgery. Visibility of the cut ends was better in cresyl violet. All histopathologic findings suggested normal changes at the anastomotic site. CONCLUSIONS: This study showed that the use of these 2 dyes was not only feasible but highly efficacious. Even though all the layers were stained by both the dyes, the visibility of the cut ends was better. In both dyes, staining lasted until the end of surgery. To the best of our knowledge, this is the first study that has used these 2 novel dyes to improve visualization in microvascular anastomosis in an experimental setting.

Impact of Genetic Variants in ABCG2 , NR1I2 , and UGT1A1 on the Pharmacokinetics of Dolutegravir in Children.

BACKGROUND: Dolutegravir plasma concentrations and pharmacokinetic (PK) parameters in children display considerable variability. Here, the impact of genetic variants in ABCG2 421C>A (rs2231142), NR1I2 63396 C>T (rs2472677), and UGT1A1 (rs5839491) on dolutegravir PK was examined. METHODS: Children defined by age and administered dolutegravir formulation had AUC 24 at steady state, C max and C 24h determined. Associations between genetic variants and PK parameters were assessed using the dominant inheritance model. RESULTS: The 59 children studied had a median age of 4.6 years, log 10 plasma HIV RNA of 4.79 (copies/mm 3 ), and CD4 + lymphocyte count of 1041 cells/mm 3 ; 51% were female. For ABCG2 , participants with ≥1 minor allele had lower adjusted mean AUC difference (hr*mg/L) controlling for weight at entry, cohort and sex (-15.7, 95% CI: [-32.0 to 0.6], P = 0.06), and log 10 C max adjusted mean difference (-0.15, 95% CI: [-0.25 to -0.05], P = 0.003). Participants with ≥1 minor allele had higher adjusted mean AUC difference (11.9, 95% CI: [-1.1 to 25.0], P = 0.07). For UGT1A1 , poor metabolizers had nonsignificant higher concentrations (adjusted log 10 C max mean difference 11.8; 95% CI: [-12.3 to 36.0], P = 0.34) and lower mean log 10 adjusted oral clearance -0.13 L/h (95% CI: [-0.3 to 0.06], P = 0.16). No association was identified between time-averaged AUC differences by genotype for adverse events, plasma HIV RNA, or CD4 + cell counts. CONCLUSIONS: Dolutegravir AUC 24 for genetic variants in ABCG2 , NR1l2 , and UGT1A1 varied from -25% to +33%. These findings help to explain some of the variable pharmacokinetics identified with dolutegravir in children.

Virological, weight, and drug resistance outcomes among patients initiating a dolutegravir-based first-line antiretroviral therapy regimen in Zimbabwe.

OBJECTIVE: Dolutegravir (DTG)-based antiretroviral therapy (ART) is being scaled up in Africa. However, clinical experience with DTG and patterns of HIV drug resistance (HIVDR) are sparse in Zimbabwe. We assessed virological, weight, and HIVDR outcomes among individuals initiating on a DTG-based ART. DESIGN: We conducted a prospective cohort study among HIV-infected adult (≥18 years old) individuals attending care at Parirenyatwa hospital, Harare, Zimbabwe between October 2021 and April 2023. METHODS: Viral load and weight were assessed at both baseline and follow-up (≥24weeks) visits. HIVDR genotyping was performed by Sanger sequencing among participants with virological failure (viral load ≥1000 copies/ml) at follow-up visit. Factors associated with weight gain were determined using logistic regression analysis on STATA 17.0. RESULTS: One hundred and seventy-two participants were enrolled in the study. The median [interquartile range (IQR) age was 39 (29-48)] years whilst the median (IQR) CD4 + cell count and log 10 viral load at enrolment was 175 (58-328) cells/µl and 5.41 (4.80-5.74), respectively. After a median (IQR) duration of 27 (25-30) weeks on DTG, of the 131 participants with follow-up viral load data available, 129 (98%) had viral load less than 1000 copies/ml and among the 2 (2%) participants with viral load at least 1000 copies/ml, no emergent HIVDR was detected. We observed a significant increase in weight among the participants. The average weight gain was 5.25 kgs ( P  < 0.0001). Baseline CD4 + cell count at least 200 cells/µl was significantly associated with at a smaller weight gain [odds ratio (OR) = 0.26; 95% confidence interval (CI) 0.12-0.58, P  = 0.001]. CONCLUSION: We found high virological suppression and an increased weight among people initiating on DTG in a resource-limited setting. Encouragingly, HIVDR to DTG remains rare.

Nerve Visualization using Phenoxazine-Based Near-Infrared Fluorophores to Guide Prostatectomy.

Fluorescence-guided surgery (FGS) is poised to revolutionize surgical medicine through near-infrared (NIR) fluorophores for tissue- and disease-specific contrast. Clinical open and laparoscopic FGS vision systems operate nearly exclusively at NIR wavelengths. However, tissue-specific NIR contrast agents compatible with clinically available imaging systems are lacking, leaving nerve tissue identification during prostatectomy a persistent challenge. Here, it is shown that combining drug-like molecular design concepts and fluorophore chemistry enabled the production of a library of NIR phenoxazine-based fluorophores for intraoperative nerve-specific imaging. The lead candidate readily delineated prostatic nerves in the canine and iliac plexus in the swine using the clinical da Vinci Surgical System that has been popularized for minimally invasive prostatectomy procedures. These results demonstrate the feasibility of molecular engineering of NIR nerve-binding fluorophores for ready integration into the existing surgical workflow, paving the path for clinical translation to reduce morbidity from nerve injury for prostate cancer patients.

Dolutegravir-induced neural tube defects in mice are folate responsive.

OBJECTIVES: In 2018, the Botswana Tsepamo Study reported a nine-fold increased risk of neural tube defects in infants whose mothers were treated with dolutegravir (DTG) from the time of conception. As maternal folate supplementation and status is a well known modifier of neural tube defect (NTD) risk, we sought to evaluate birth outcomes in mice fed normal and low folic acid diets treated with DTG during pregnancy. DESIGN: DTG was evaluated for developmental toxicity using pregnant mice fed normal or low folic acid diet. METHODS: CD-1 mice were provided diet with normal (3 mg/kg) or low (0.3 mg/kg) folic acid. They were treated with water, a human therapeutic-equivalent dose, or supratherapeutic dose of DTG from mouse embryonic day E6.5 to E12.5. Pregnant dams were sacrificed at term (E18.5) and fetuses were inspected for gross, internal, and skeletal defects. RESULTS: Fetuses with exencephaly, an NTD, were present in both therapeutic human equivalent and supratherapeutic exposures in dams fed low folic acid diet. Cleft palates were also found under both folate conditions. CONCLUSIONS: Recommended dietary folic acid levels during mouse pregnancy ameliorate developmental defects that arise from DTG exposure. Since low folate status in mice exposed to DTG increases the risk for NTDs, it is possible that DTG exposures in people living with HIV with low folate status during pregnancy may explain, at least in part, the elevated NTD risk signal observed in Botswana. Based on these results, future studies should consider folate status as a modifier for DTG-associated NTD risk.

Natural course of AIDS following HIV-2 infection.

In a 21-year-old female, AIDS following infection with HIV-2 was diagnosed alongside an HIV-associated high-grade B cell lymphoma. Treatment of HIV-2 with dolutegravir, emtricitabine, and tenofovir resulted in viral suppression and slow recovery of CD4 cell counts. Treatment of lymphoma caused significant adverse effects but led to complete remission. The patient denied sexual activity and intravenous drug abuse. The patient had been born to an HIV-2-positive mother but appropriate perinatal testing based on national guidelines had remained negative. This case recapitulates the natural course of HIV-2 infection.

Efficient production of an antitumor precursor actinocin and other medicinal molecules from kynurenine pathway in Escherichia coli.

Kynurenine pathway has a potential to convert L-tryptophan into multiple medicinal molecules. This study aims to explore the biosynthetic potential of kynurenine pathway for the efficient production of actinocin, an antitumor precursor selected as a proof-of-concept target molecule. Kynurenine pathway is first constructed in Escherichia coli by testing various combinations of biosynthetic genes from four different organisms. Metabolic engineering strategies are next performed to improve the production by inhibiting a competing pathway, and enhancing intracellular supply of a cofactor S-adenosyl-L-methionine, and ultimately to produce actinocin from glucose. Metabolome analysis further suggests additional gene overexpression targets, which finally leads to the actinocin titer of 719 mg/L. E. coli strain engineered to produce actinocin is further successfully utilized to produce 350 mg/L of kynurenic acid, a neuroprotectant, and 1401 mg/L of 3-hydroxyanthranilic acid, an antioxidant, also from glucose. These competitive production titers demonstrate the biosynthetic potential of kynurenine pathway as a source of multiple medicinal molecules. The approach undertaken in this study can be useful for the sustainable production of molecules derived from kynurenine pathway, which are otherwise chemically synthesized.