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Ample quantitative studies have shown that parents raising children with neurodevelopmental disabilities are prone to experience more stress and challenges in their parenthood. Notwithstanding the strength of this line of research, qualitative studies are crucial to grasp the complex reality of these parenting experiences. This qualitative study adopted the Self-Determination Theory to analyze parents' described experiences, appraising both challenges and opportunities in parents' psychological need for autonomy, relatedness, and competence. A multi-group comparative design is adopted to examine similarities and differences in the perspectives of 160 parents raising an adolescent with autism spectrum disorder, cerebral palsy, Down syndrome, or without a disability (M age child = 13.09 years, 67.5% boys). Parents' perspectives were examined through speech samples probing parents to talk spontaneously about their child, their relationship with the child, and their parental experiences. Forty samples in each group were randomly chosen from a larger dataset and were analyzed using deductive thematic analysis. Parents of children with a disability described more need-frustrating but also more autonomy-satisfying experiences compared to parents of children without a disability. Parents of children with autism spectrum disorder reported the most challenges concerning their relatedness with their child and their own parental competence. Parents raising a child with cerebral palsy expressed the most worries about their child's future and continuity of care. Parents of a child with Down syndrome described the most need-satisfying experiences in their family life. This study offers a more balanced view on the realm of parenting a child with a neurodevelopmental disability.

In order to enhance the anti-HIV-1 potency and selectivity of the previously reported compound 3 (EC 50  = 27 nM, SI = 1361), a series of novel biphenyl-diarylpyrimidine derivatives were developed by employing structure-based drug design strategy. Among these derivatives, compound M44 demonstrated the most potent inhibitory activity against wild-type (WT) HIV-1 as well as five drug-resistant mutants (EC 50  = 5-148 nM), which were 5-173 times more potent than that of 3 (EC 50  = 27-9810 nM). Furthermore, this analogue exhibited approximately 11-fold lower cytotoxicity (CC 50  = 54 μM) than that of etravirine and rilpivirine. Concurrently, it possessed an improved selectivity index (SI) of 10995. Additionally, compound M44 was characterized by favorable metabolic stability in human plasma and human liver microsomes. No acute toxicity or organ damage was observed at a dose of 2 g/kg. Overall, M44 represents a highly promising lead compound that warrants further optimization efforts to identify potential anti-HIV-1 drug candidates., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier Masson SAS. All rights reserved.)

The pivotal involvement of reverse transcriptase activity in the pathogenesis of the progressive HIV virus has stimulated gradual advancements in drug discovery initiatives spanning three decades. Consequently, nonnucleoside reverse transcriptase inhibitors (NNRTIs) have emerged as a preeminent category of therapeutic agents for HIV management. Academic institutions and pharmaceutical companies have developed numerous NNRTIs, an essential component of antiretroviral therapy. Six NNRTIs have received Food and Drug Administration approval and are widely used in clinical practice, significantly improving the quality of HIV patients. However, the rapid emergence of drug resistance has limited the effectiveness of these medications, underscoring the necessity for perpetual research and development of novel therapeutic alternatives. To supplement the existing literatures on NNRTIs, a comprehensive review has been compiled to synthesize this extensive dataset into a comprehensible format for the medicinal chemistry community. In this review, a thorough investigation and meticulous analysis were conducted on the progressions achieved in NNRTIs within the past 8 years (2016-2023), and the experiences and insights gained in the development of inhibitors with varying chemical structures were also summarized. The provision of a crucial point of reference for the development of wide-ranging anti-HIV medications is anticipated., (© 2024 Wiley Periodicals LLC.)

To promote the development of the new generation of HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs), a series of novel 2,4,5-trisubstituted pyrimidine derivatives targeting the "tolerant region I″ and "tolerant region II" of NNRTI binding pocket (NNIBP) were designed through multi-site binding strategy. Among them, 13a was demonstrated with an improved potency against wild-type (WT) and a panel of mutant HIV-1 strains with EC 50 values ranging from 0.0062 to 0.25 μM, being superior to that of efavirenz (EFV, EC 50  = 0.0080-0.37 μM). In addition, 13a was proved to have low cytotoxicity (CC 50  = 160.7 μM) and high SI values (SI = 25254). Further HIV-1 RT inhibition assay demonstrated that 13a is a classical NNRTI with an IC 50 value of 0.41 μM. Molecular docking and molecular dynamics simulations results illustrated its binding mode with HIV-1 RT. Overall, these enchanting results illuminated the potential of 13a as a promising lead for the development of the new generation HIV-1 NNRTIs drugs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025. Published by Elsevier Masson SAS.)

Background: Many respiratory pathogens have been identified in people living with HIV-1 and pulmonary infection, but their impact on clinical outcomes remains largely unclear., Methods: Metagenomic sequencing and traditional laboratory diagnostics were applied to identify bacterial, viral, and fungal respiratory pathogens. Clinical outcomes were assessed by (i) mortality or ICU transfer during hospitalization, and (ii) 30-day re-hospitalization and 180-day mortality after hospital discharge., Results: Microbiological analyses of bacterial, viral and fungal pathogens in 237 in-patients with HIV-1 and pulmonary infections revealed Pneumocystis jirovecii (58 %) as the most prevalent respiratory pathogen, followed by Cytomegalovirus (39 %), Mycobacterium tuberculosis (22 %), Talaromyces marneffei (17 %), and Epstein-Barr virus (16 %). Fifty-six patients (24 %) were coinfected with bacterial, viral and fungal pathogens, referred to as bacterial+fungal+viral coinfections. Risk factors for bacterial+fungal+viral coinfections (RR=8.41, 95 %CI: 4.2-14.3), severe pneumonia (RR=13.6, 95 %CI: 8.14-19.3), and elevated C-reactive protein levels (RR=6.42, 95 %CI: 1.58-10.13) were significantly associated with mortality or ICU transfer during hospitalization. After hospital discharge, 38 patients (16 %) were rehospitalized within 30 days. Antiretroviral therapy reduced the risk of 30-day rehospitalization (HR=0.21, p = 0.01). During the 180-day follow-up, 13 patients (5.5 %) died. Survival analyses identified severe pneumonia and age ≥ 60 years as risk factors for 180-day mortality., Conclusions: Multiple pulmonary coinfections are associated with severe outcomes in in-patients with HIV-1 infection. Effective management of both HIV-1 and pulmonary infections is crucial to reduce hospitalization rates and mortality risk., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

I started my research career (in 1965) on interferon by identifying polyacrylic acid (PAA) as an interferon inducer. Poly(I).poly(C), discovered by Maurice Hilleman's group, proved to be more potent as an interferon inducer, and through its mRNA, we were able to clone and express human β-interferon. The discovery of the reverse transcriptase (RT) by Temin and Baltimore (in 1970) brought me to the detection of suramin as a powerful RT inhibitor and enabled Sam Broder and his colleagues to identify suramin as the first inhibitor of HIV replication. In this capacity, it was subsequently superseded by AZT and other 2',3'-dideoxynucleoside (ddN) analogs, including d4T. In collaboration with Antonín Holý, we discovered several acyclic nucleoside phosphonates as potent inhibitors of both HIV and HBV (hepatitis B virus) replication. In collaboration with Paul Janssen, we identified various non-nucleoside RT inhibitors (NNRTIs) of HIV-1 replication. Of the nucleotide RT inhibitors (NtRTTs), tenofovir emerged as the most promising congener. It was derivatized to its oral prodrugs TDF and TAF. To enhance their efficacy, they were combined with other anti-HIV drugs, and two of them were pursued (and found efficacious) in the Pre-Exposure Prophylaxis (PrEP) of HIV infections.

Patients with diabetes are at increased risk of HBV infection; however, the effects of HBV infection and anti-HBV therapy on the management of type 1 diabetes (T1D), type 2 diabetes (T2D), and latent autoimmune diabetes in adults (LADA) remain unclear. From 2016 to 2023, we recruited a multicenter cohort of 355 HBV-infected inpatients, including 136 with T1D, 140 with T2D, and 79 with LADA. The control group included 525 HBV-uninfected inpatients, comparing 171 with T1D, 204 with T2D and 150 with LADA. We employed propensity-score matching between cases and controls to minimize confounding effects. Hemoglobin A1c (HbA1c) was monitored at baseline and at months 1, 2, and 3. At baseline, median HbA1c was significantly higher in HBV-infected patients compared to their HBV-uninfected controls: T1D (10.4% vs. 7.5%, p < 0.01), T2D (9.6% vs. 8.6%, p = 0.01), and LADA (9.4% vs. 8.4%, p = 0.03). Baseline HbA1c levels were significantly lower in HBV-treated patients compared to those HBV-untreated patients, regardless of whether they were on antidiabetic therapy (p < 0.05). A 90-day follow-up consistently indicated lower HbA1c levels at baseline, as well as at months 1, 2, and 3 among HBV-treated patients with T1D, T2D, or LADA. Both univariate and multivariate analyses identified HBV therapy (OR = 0.44, p < 0.001) and antidiabetic treatment(OR = 0.51, p = 0.031) as protective factors for glycemic control in HBV-infected patients with diabetes. Poor glycemic control is found in HBV-infected patients with diabetes, but the intervention of anti-HBV therapy and antidiabetic treatment contributes to improved glycemic control in HBV-infected patients with T1D, T2D, or LADA., (© 2025 Wiley Periodicals LLC.)

Introduction: 22q11 deletion syndrome (22q11DS) results from a microdeletion on chromosome 22 and is the most common microdeletion disorder in humans, affecting 1 in 2148 live births. Clinical manifestations vary widely among individuals and across different life stages. Effective management requires the involvement of a specialized multidisciplinary team. This study aims to explore the experiences of healthcare professionals in caring for the families of children with 22q11DS, focusing on their challenges, rewards, and coping strategies., Methods: Data for this interview study were collected as part of a broader mixed methods research project aimed at enhancing the psychosocial well-being of children aged 3-15 years with 22q11DS and their families. The qualitative aspect of this study focused on capturing the experiences of healthcare professionals involved in their care, recruited purposively through collaborators and snowball sampling methods. Reflexive thematic analysis of semi-structured interviews was performed after verbatim transcription., Results: Twenty healthcare providers from different specialties were interviewed. The majority had a working experience of more than 10 years and were part of a 22q11DS clinic. After data analysis, four themes (and many sub-themes) were identified that were all related to the topic of uncertainty: acknowledging uncertainty, sharing uncertainty, acting on uncertainty and coping with uncertainty. Many experts showed a sense of humbleness when caring for the families and most of the participants emphasized the role of peer support and multidisciplinary teams., Conclusion: Our study reveals how healthcare professionals manage the uncertainty associated with 22q11DS, highlighting the importance of peer support and multidisciplinary team collaboration. Providers recognize the limits of their medical expertise and value the perspectives of families living with the condition. Their coping strategies play a critical role in handling uncertainty and suggest a need for further emphasis in the literature on the experiences of healthcare professionals dealing with rare diseases., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2025 Ayoub et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

As an important part of anti-AIDS therapy, HIV-1 non-nucleoside reverse transcriptase inhibitors are plagued by resistance and toxicity issues. Taking our reported XJ-18b1 as lead compound, we designed a series of novel diarypyrimidine derivatives by employing a scaffold hopping strategy to discover potent NNRTIs with improved anti-resistance properties and drug-like profiles. The most active compound 3k exhibited prominent inhibitory activity against wild-type HIV-1 (EC 50  = 0.0019 μM) and common mutant strains including K103 N (EC 50  = 0.0019 μM), L100I (EC 50  = 0.0087 μM), E138K (EC 50  = 0.011 μM), along with low cytotoxicity and high selectivity index (CC 50  = 21.95 μM, SI = 11478). Additionally, compound 3k demonstrated antiviral activity against HIV-2 with EC 50 value of 6.14 μM. The enzyme-linked immunosorbent assay validated that 3k could significantly inhibit the activity of HIV-1 reverse transcriptase (IC 50  = 0.025 μM). Furthermore, molecular dynamics simulation studies were performed to illustrate the potential binding mode and binding free energy of the RT-3k complex, and in silico prediction revealed that 3k possessed favorable drug-like profiles. Collectively, 3k proved to be a promising lead compound for further optimization to obtain anti-HIV drug candidates., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Introduction: The death of a child has a tremendous impact on parents' lives. The experience of parents who have lost a child to cancer may differ from other bereavement experiences, including other childhood and adulthood causes of death, because of the uncertainty of the prognosis, the aggressive treatment, and the potential for regret about treatment decisions. Bereavement care remains scarce, and effective interventions to meet the diverse needs of parents have not been defined., Objective: To provide insights on bereaved parents' experiences, their needs, and wishes of support following the loss of their child to cancer., Methods: We conducted 18 qualitative, in-depth, semi-structured interviews with 23 bereaved parents (seven fathers, 16 mothers), and used reflexive thematic analysis to analyze the data., Results: Parents received both informal and professional support. Regarding informal support, parents expressed a high level of ambivalence rooted in grief illiteracy. Parents also recognized their own struggles to express what forms of informal support they would have liked to receive. Support provided by healthcare professionals, institutions, and organizations involved in the children's care or in bereavement was inconsistent due to personnel time constraints, interpersonal relationships, or disruptions due to the COVID-19 pandemic. These factors could result in parents not having access to certain forms of support or not receiving long-term support., Conclusion: Improving grief literacy may strengthen informal support and make discussions of grief and death less taboo. Institutional policies, training, and networking may help to ensure that support provided by healthcare professionals, institutions, and organizations is less vulnerable to inconsistencies., (© 2024 The Author(s). Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) play a crucial role in combination antiretroviral therapy (cART). To further enhance their antiviral activity and anti-resistance properties, we developed a series of novel NNRTIs, by specifically targeting tolerant region I of the NNRTI binding pocket. Among them, compound 9t-2 displayed excellent anti-HIV-1 potency against wild-type and prevalent mutant strains with EC 50 values between 0.0019 and 0.012 μM. This outperformed the positive drugs ETR, NVP and RPV. Aslo, ELISA results confirmed that these compounds can effectively inhibit the activity of HIV-1 RT. Molecular dynamics (MD) simulation studies indicated that the thiomorpholine-1,1-dioxide moiety of 9t-2 is capable of establishing additional interactions with residues P225, F227 and P236 in the tolerant region I, which contributed to its enhanced activity. Compound 9t-2 possessed negligible inhibitory effect on the five main CYP isoenzymes (IC 50  > 10 μM), indicating a low potential for inducing CYP-mediated drug-drug interactions. In conclusion, compound 9t-2, with its enhanced anti-resistance properties, stands out as a promising lead compound for further optimization towards discovering the new generation of anti-HIV agents., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024. Published by Elsevier Masson SAS.)

Considering the nonideal antiresistance efficacy of our previously reported non-nucleoside reverse transcriptase inhibitor 7 , a series of novel piperidine-diarylpyrimidine derivatives were designed through expanding solvent/protein region occupation. The representative compound 15f proved to be exceptionally potent against Y188L (EC 50 = 23 nM), F227L + V106A (EC 50 = 15 nM) and RES056 (EC 50 = 45 nM), significantly better than 7 . This analog exerted strong inhibition against wild-type HIV-1 (EC 50 = 3 nM) and single mutant strains (L100I, K103N, Y181C, E138 K). Notably, its cytotoxicity and selectivity (CC 50 = 18.23 μM, SI = 6537) were 4-fold better than etravirine and rilpivirine. Additionally, it exhibited minimal suppression of CYP isoenzymes and hERG, indicating low potential for drug-drug interactions and cardiotoxicity. No significant acute toxicity and tissue damage at a dose of 2 g/kg were revealed. These findings lay the groundwork for the advancement of 15f as a highly potent, safe, and broad-spectrum NNRTI for HIV therapy.

Among the most prominent realizations of Morris J. Robins in the antiviral nucleoside chemistry are (i) the synthesis of 8-substituted (methyl-, amino-, bromo-, iodo) derivatives of acyclovir, (ii) xylotubercidin as an inhibitor of herpes simplex virus (HSV) infections, (iii) the anti-HIV activity of the 2',3'-dideoxyriboside of 2,6-diaminopurine (ddDAPR) and the 3'-azido- and 3'-fluoro derivatives thereof (AzddDAPR and FddDAPR, respectively), (iv) the potentiating effect of ribavirin on the anti-HIV activity of 2',3'-dideoxyinosine (ddI) and ddDAPR, (v) S-adenosylhomocysteine hydrolase (SAH) inhibitors principally active against vaccinia virus (VV) and vesicular stomatitis virus (VSV), and (vi) furo[2,3-d]pyrimidinone derivatives active against varicella-zoster virus (VZV).

In addressing the urgent need for novel HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) to combat drug resistance, we employed CuAAC click chemistry to construct a diverse 312-member diarylpyrimidine (DAPY) derivative library. This rapid synthesis approach facilitated the identification of A6N36, demonstrating exceptional HIV-1 RT inhibitory activity. Moreover, it was demonstrated with EC 50 values of 1.8-8.7 nM for mutant strains L100I, K103 N, Y181C, and E138K, being equipotent or superior to that of ETR. However, A6N36's efficacy was compromised against specific resistant strains (Y188L, F227L + V106A and RES056), highlighting a need for further optimization. Through scaffold hopping, we optimized this lead to develop 10c, which exhibited broad-spectrum activity with EC 50 values ranging from 3.2 to 57.5 nM and superior water solubility. Molecular docking underscored the key interactions of 10c within the NNIBP. Our findings present 10c as a promising NNRTI lead, illustrating the power of click chemistry and rational design in combatting HIV-1 resistance., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Background: A series of 3,5-benzylidene-4-piperidones, 1a - n , were prepared to evaluate the hypothesis that the placement of different groups in the ortho-location of the aryl rings led to compounds with greater cytotoxic potencies than structural analogs. Methods: The bioevaluation of 1a - n was undertaken using human Molt/4C8 and CEM cells as well as murine L1210 cells. Correlations were sought between the interplanar angles θ A and θ B and the cytotoxic potencies. A QSAR analysis was also undertaken. In order to evaluate whether these compounds demonstrated greater toxicity to neoplasms than non-malignant cells, 1a - n were evaluated against HSC-2, HSC-3, HSC-4 and HL60 neoplasms as well as non-malignant HGF, HPC and HPLF cells. Results: A positive correlation was noted between the interplanar angle θ A of one of the aryl rings and the adjacent olefinic linkage with IC 50 values in the Molt4/C8 screens. The QSAR analysis revealed a positive correlation between the Hansch pi (π) value of the aryl substituents and the IC 50 values of the compounds towards the Molt4/C8 and CEM cells. The dienones in series 1 demonstrated higher tumor-selective toxicity towards HSC-2, HSC-3, HSC-4 and HL-60 neoplasms than HGF, HPC and HPLF cells. Conclusions: The bioevaluations revealed some support for greater cytotoxic potencies to be displayed by compounds having ortho-substituents.

This article presents the rapid identification of novel indolylarylsulfone (IAS) derivatives as potent non-nucleoside reverse transcriptase inhibitors (NNRTIs) for HIV-1 through a miniaturized click-chemistry-based combinatorial library approach. Utilizing copper(i)-catalyzed azide-alkyne cycloaddition (CuAAC), a reliable and biocompatible click chemistry technique, the researchers synthesized and characterized a series of IAS derivatives. Several compounds selected through the in situ enzyme inhibition assay demonstrated promising activity in subsequent cellular level tests. Notably, compound C1N4 displayed the most potent anti-HIV-1 IIIB activity with an EC 50 of 0.024 μM and low cytotoxicity (CC 50 > 215.88 μM). Molecular docking studies provided insights into the binding mode of these novel compounds within the NNIBP, aiding in the structure-based design of future NNRTIs. The findings underscore the potential of click chemistry in the discovery of new anti-HIV agents with improved efficacy and safety profiles., Competing Interests: The authors declare no conflicts of interest., (This journal is © The Royal Society of Chemistry.)

Our previously disclosed biphenyl-DAPY 3 emerged as a potent inhibitor against WT HIV-1 and various mutant strains. Yet, its journey toward clinical application was thwarted by pronounced cytotoxicity and low selectivity (CC 50 = 6 μM, SI = 3515). The safety improvement approach we employed in this work entailed the incorporation of diverse heteroaromatic substituents at the C5 position to exploit the tolerant regions of the NNRTIs' binding pocket through fragment addition-based drug design strategy, ultimately leading to the identification of a series of novel heteroaromatic-biphenyl-DAPYs. The exemplary compound 10d revealed a striking reduction in cytotoxicity (CC 50 > 272.81 μM), nearly 45.5 times lower than 3 , while showcasing 15-fold increase in selectivity (SI > 52632). This analog sustained exceptional anti-HIV-1 activity against both WT HIV-1 (EC 50 = 5 nM) and various mutant strains. Compared to 3 , a markedly slower rate of metabolism in human liver microsomes of 10d was observed. Its pharmacokinetic profile was equally captivating, featuring excellent oral bioavailability ( F = 57.4%). Moreover, 10d exhibited a delicate sensitivity toward CYP, minimal inhibition of hERG, and no detectable acute toxicity in vivo. These enchanting findings illuminated the potential of 10d as a promising candidate for HIV-1 therapy.

Starting from our previously reported nonnucleoside reverse transcriptase inhibitor (NNRTI, 3), continuous efforts were made to enhance its potency and safety through a structure-based drug design strategy. This led to the discovery of a series of novel piperidine-biphenyl-diarylpyrimidines (DAPYs). Compound 10p, the most active compound in this series, exhibited an EC 50 value of 6 nM against wide-type HIV-1 strain, which was approximately 560-fold more potent than the initial compound 3 (EC 50  = 3.36 μM). Furthermore, significant improvements were observed in cytotoxicity and selectivity (CC 50  > 202.17 μM, SI > 33144) compared to compound 3 (CC 50  = 14.84 μM, SI = 4). Additionally, compound 10p demonstrated increased inhibitory activity against clinically mutant virus strains (EC 50  = 7-63 nM). Further toxicity evaluation revealed that compound 10p exhibited minimal CYP enzyme and hERG inhibition. Importantly, single-dose acute toxicity testing did not result in any fatalities or noticeable pathological damage in mice. Therefore, compound 10p can be regarded as a lead candidate for guiding further development of biphenyl-diarylpyrimidine NNRTIs with favorable druggability for HIV therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

In this era spanning more than 60 years (from the early 1960s till today (2023), a broad variety of actors played a decisive role: Piet De Somer, Tom C. Merigan, Paul A. Janssen, Maurice Hilleman, and Georges Smets. Two protagonists (Antonín Holý and John C. Martin) formed with me a unique triangle (the Holý Trinity). Walter Fiers' group (with the help of Jean Content) contributed to the cloning of human β-interferon, and Piet Herdewijn accomplished the chemical synthesis of an array of anti-HIV 2',3'-dideoxynucleoside analogues. Rudi Pauwels, Masanori Baba, Dominique Schols, Johan Neyts, Lieve Naesens, Anita Van Lierde, Graciela Andrei, Robert Snoeck and Dirk Daelemans, as members of my team, helped me in achieving the intended goal, the development of a selective therapy for virus infections. The collaboration with "Lowie" (Guangdi Li) generated a new dimension for the future., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Many acyclic nucleoside phosphonates such as cidofovir, adefovir dipivoxil, tenofovir disoproxil fumarate, and tenofovir alafenamide have been marketed for the treatment or prophylaxis of infectious diseases. Here, this review highlights potent acyclic nucleoside phosphonates for their potential in the treatment of retrovirus (e.g., human immunodeficiency virus) and DNA virus (e.g., adeno-, papilloma-, herpes- and poxvirus) infections. If properly assessed and/or optimized, some potent acyclic nucleoside phosphonates can be possibly applied in the control of current and emerging infectious diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Inspired by our previous work on the modification of diarylpyrimidine-typed non-nucleoside reverse transcriptase inhibitors (NNRTIs) and the reported crystallographic studies, a series of novel amino acids (analogues)-substituted thiophene[3,2- d ]pyrimidine derivatives were designed and synthesized by targeting the solvent-exposed region of the NNRTI-binding pocket. The biological evaluation results showed that compound 5k was the most active inhibitor, exhibiting moderate-to-excellent potency against HIV-1 wild-type (WT) and a panel of NNRTI-resistant strains, with EC 50 values ranging from 0.042 μM to 7.530 μM. Of special note, 5k exhibited the most potent activity against single-mutant strains (K103N and E138K), with EC 50 values of 0.031 μM and 0.094 μM, being about 4.3-fold superior to EFV (EC 50 = 0.132 μM) and 1.9-fold superior to NVP (EC 50 = 0.181 μM), respectively. In addition, 5k demonstrated lower cytotoxicity (CC 50 = 27.9 μM) and higher selectivity index values. The HIV-1 reverse transcriptase (RT) inhibition assay was further performed to confirm their binding target. Moreover, preliminary structure-activity relationships (SARs) and molecular docking studies were also discussed in order to provide valuable insights for further structural optimizations. In summary, 5k turned out to be a promising NNRTI lead compound for further investigations of treatments for HIV-1 infections.

Background: The discourse surrounding medical artificial intelligence (AI) often focuses on narratives that either hype the technology's potential or predict dystopian futures. AI narratives have a significant influence on the direction of research, funding, and public opinion and thus shape the future of medicine., Objective: The paper aims to offer critical reflections on AI narratives, with a specific focus on medical AI, and to raise awareness as to how people working with medical AI talk about AI and discharge their "narrative responsibility.", Methods: Qualitative semistructured interviews were conducted with 41 participants from different disciplines who were exposed to medical AI in their profession. The research represents a secondary analysis of data using a thematic narrative approach. The analysis resulted in 2 main themes, each with 2 other subthemes., Results: Stories about the AI-physician interaction depicted either a competitive or collaborative relationship. Some participants argued that AI might replace physicians, as it performs better than physicians. However, others believed that physicians should not be replaced and that AI should rather assist and support physicians. The idea of excessive technological deferral and automation bias was discussed, highlighting the risk of "losing" decisional power. The possibility that AI could relieve physicians from burnout and allow them to spend more time with patients was also considered. Finally, a few participants reported an extremely optimistic account of medical AI, while the majority criticized this type of story. The latter lamented the existence of a "magical theory" of medical AI, identified with techno-solutionist positions., Conclusions: Most of the participants reported a nuanced view of technology, recognizing both its benefits and challenges and avoiding polarized narratives. However, some participants did contribute to the hype surrounding medical AI, comparing it to human capabilities and depicting it as superior. Overall, the majority agreed that medical AI should assist rather than replace clinicians. The study concludes that a balanced narrative (that focuses on the technology's present capabilities and limitations) is necessary to fully realize the potential of medical AI while avoiding unrealistic expectations and hype., (©Giorgia Lorenzini, Laura Arbelaez Ossa, Stephen Milford, Bernice Simone Elger, David Martin Shaw, Eva De Clercq. Originally published in JMIR AI (https://ai.jmir.org), 19.08.2024.)

HIV-1 reverse transcriptase (RT) has received great attention as an attractive therapeutic target for acquired immune deficiency syndrome (AIDS), but the inevitable drug resistance and side effects have always been major challenges faced by non-nucleoside reverse transcriptase inhibitors (NNRTIs). This work aimed to identify novel chemotypes of anti-HIV-1 agents with improved drug-resistance profiles, reduced toxicity, and excellent druggability. A series of diarylpyrimidine (DAPY) derivatives were prepared via structural modifications of the leads K-5a2 and 25a . Among them, 15a with dimethylphosphine oxide moiety showed the most prominent antiviral potency against all of the tested viral panel, being 1.6-fold (WT, EC 50  = 1.75 nmol/L), 3.0-fold (L100I, EC 50  = 2.84 nmol/L), 2.4-fold (K103N, EC 50  = 1.27 nmol/L), 3.3-fold (Y181C, EC 50  = 5.38 nmol/L), 2.9-fold (Y188L, EC 50  = 7.96 nmol/L), 2.5-fold (E138K, EC 50  = 4.28 nmol/L), 4.8-fold (F227L/V106A, EC 50  = 3.76 nmol/L) and 5.3-fold (RES056, EC 50  = 15.8 nmol/L) more effective than that of the marketed drug ETR. Molecular docking results illustrated the detailed interactions formed by compound 15a and WT, F227L/V106A, and RES056 RT. Moreover, 15a ·HCl carried outstanding pharmacokinetic ( t 1/2  = 1.32 h, F  = 40.8%) and safety profiles (LD 50  > 2000 mg/kg), which demonstrated that 15a HCl is a potential anti-HIV-1 drug candidate., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors.)

Background: Using extracorporeal membrane oxygenation (ECMO) in paediatric and neonatal intensive care units (PICU/NICU) creates ethical challenges and carries a high risk for moral distress, burn out and team conflicts., Aim: The study aimed to gain a more comprehensive understanding of the underlying factors affecting moral distress when using ECMO for infants and children by examining the attitudes of ECMO nurses., Methods: Four focus groups discussions were conducted with 21 critical care nurses working in a Swiss University Children's Hospital. Purposive sampling was adopted to identify research participants. The data were analysed using reflexive thematic analysis., Results: Unlike "miracle machine" stories in online media reports, specialized nurses working in PICU/NICU expressed both their hopes and fears towards this technology. Their accounts also contained references to events and factors that triggered experiences of moral distress: the unspeakable nature of the death of a child or infant; the seemingly lack of honest and transparent communication with parents; the apparent loss of situational awareness among doctors; the perceived lack of recognition for the role of nurses and the variability in end-of-life decision-making; the length of time it takes doctors to take important treatment decisions; and the resource intensity of an ECMO treatment., Conclusion: The creation of a multidisciplinary moral community with transparent information among all involved health care professionals and the definition of clear treatment goals as well as the implementation of paediatric palliative care for all paediatric ECMO patients should become a priority if we want to alleviate situations of moral distress., Relevance for Clinical Practice: The creation of a multidisciplinary moral community, clear treatment goals and the implementation of palliative care for all paediatric ECMO patients are crucial to alleviate situations of moral distress for nurses, and thus to improve provider well-being and the quality of patient care in PICU/NICU., (© 2024 The Authors. Nursing in Critical Care published by John Wiley & Sons Ltd on behalf of British Association of Critical Care Nurses.)

Targeting Ribonuclease H (RNase H) has been considered a viable strategy for HIV therapy. In this study, a series of novel thiazolo[3, 2-a]pyrimidine derivatives were firstly designed and synthesized as potential inhibitors of HIV-1 RNase H. Among these compounds, A28 exhibited the most potent inhibition against HIV-1 RNase H with an IC 50 value of 4.14 μM, which was about 5-fold increase in potency than the hit compound A1 (IC 50  = 21.49 μM). To gain deeper insights into the structure-activity relationship (SAR), a CoMFA model was constructed to yield reasonable statistical results (q 2  = 0.658 and R 2  = 0.969). Results from magnesium ion chelation experiments and molecular docking studies revealed that these thiazolopyrimidine inhibitors may exert their inhibitory activity by binding to an allosteric site on RNase H at the interface between subunits p51 and p66. Furthermore, this analog demonstrated favorable physicochemical properties. Our findings provide valuable groundwork for further development of allosteric inhibitors targeting HIV-1 RNase H., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

In pursuit of enhancing the anti-resistance efficacy and solubility of our previously identified NNRTI 1, a series of biphenyl-quinazoline derivatives were synthesized employing a structure-based drug design strategy. Noteworthy advancements in anti-resistance efficacy were discerned among some of these analogs, prominently exemplified by compound 7ag, which exhibited a remarkable 1.37 to 602.41-fold increase in potency against mutant strains (Y181C, L100I, Y188L, F227L + V106A, and K103N + Y181C) in comparison to compound 1. Compound 7ag also demonstrated comparable anti-HIV activity against both WT HIV and K103N, albeit with a marginal reduction in activity against E138K. Of significance, this analog showed augmented selectivity index (SI > 5368) relative to compound 1 (SI > 37764), Nevirapine (SI > 158), Efavirenz (SI > 269), and Etravirine (SI > 1519). Moreover, it displayed a significant enhancement in water solubility, surpassing that of compound 1, Etravirine, and Rilpivirine. To elucidate the underlying molecular mechanisms, molecular docking studies were undertaken to probe the critical interactions between 7ag and both WT and mutant strains of HIV-1 RT. These findings furnish invaluable insights driving further advancements in the development of DAPYs for HIV therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Ribonuclease H (RNase H) was identified as an important target for HIV therapy. Currently, no RNase H inhibitors have reached clinical status. Herein, a series of novel thiazolone[3,2- a ]pyrimidine-containing RNase H inhibitors were developed, based on the hit compound 10i , identified from screening our in-house compound library. Some of these derivatives exhibited low micromolar inhibitory activity. Among them, compound 12b was identified as the most potent inhibitor of RNase H (IC 50 = 2.98 μM). The experiment of magnesium ion coordination was performed to verify that this ligand could coordinate with magnesium ions, indicating its binding ability to the catalytic site of RNase H. Docking studies revealed the main interactions of this ligand with RNase H. A quantitative structure activity relationship (QSAR) was also conducted to disclose several predictive mathematic models. A molecular dynamics simulation was also conducted to determine the stability of the complex. Taken together, thiazolone[3,2- a ]pyrimidine can be regarded as a potential scaffold for the further development of RNase H inhibitors.

NNRTI is an important component of the highly active antiretroviral therapy (HAART), but the rapid emergence of drug resistance and poor pharmacokinetics limited their clinical application. Herein, a series of novel aryl triazolone dihydropyridines (ATDPs) were designed by structure-guided design with the aim of improving drug resistance profiles and pharmacokinetic profiles. Compound 10n (EC 50 = 0.009-17.7 μM) exhibited the most active potency, being superior to or comparable to that of doravirine (DOR) against the whole tested viral panel. Molecular docking was performed to clarify the reason for its higher resistance profiles. Moreover, 10n demonstrated excellent pharmacokinetic profile ( T 1/2 = 5.09 h, F = 108.96%) compared that of DOR ( T 1/2 = 4.4 h, F = 57%). Additionally, 10n was also verified to have no in vivo acute or subacute toxicity (LD 50 > 2000 mg/kg), suggesting that 10n is worth further investigation as a novel oral NNRTIs for HIV-1 therapy.

The HIV capsid (CA) protein is a promising target for anti-AIDS treatment due to its critical involvement in viral replication. Herein, we utilized the well-documented CA inhibitor PF74 as our lead compound and designed a series of low-molecular-weight phenylalanine derivatives. Among them, compound 7t exhibited remarkable antiviral activity with a high selection index (EC 50  = 0.040 µM, SI = 2815), surpassing that of PF74 (EC 50  = 0.50 µM, SI = 258). Furthermore, when evaluated against the HIV-2 strain, 7t (EC 50  = 0.13 µM) demonstrated approximately 14-fold higher potency than that of PF74 (EC 50  = 1.76 µM). Insights obtained from surface plasmon resonance (SPR) revealed that 7t exhibited stronger target affinity to the CA hexamer and monomer in comparison to PF74. The potential interactions between 7t and the HIV-1 CA were further elucidated using molecular docking and molecular dynamics simulations, providing a plausible explanation for the enhanced target affinity with 7t over PF74. Moreover, the metabolic stability assay demonstrated that 7t (T 1/2  = 77.0 min) significantly outperforms PF74 (T 1/2  = 0.7 min) in human liver microsome, exhibiting an improvement factor of 110-fold. In conclusion, 7t emerges as a promising drug candidate warranting further investigation., (© 2024 Wiley Periodicals LLC.)

In this study, a novel series of diarylpyrimidine derivatives with Fsp 3 -enriched spirocycles were designed and synthesized to further explore the chemical space of the hydrophobic channel of the NNRTI-binding pocket. The biological evaluation results showed that most of the compounds displayed effective inhibitory potency against the HIV-1 wild-type strain, with EC 50 values ranging from micromolar to submicromolar levels. Among them, TT6 turned out to be the most effective inhibitor with an EC 50 value of 0.17 μM, demonstrating up to 47 times more active than that of reference drug 3TC (EC 50  = 8.01 μM). More encouragingly, TT6 was found to potently inhibit the HIV-1 mutant strain K103N with an EC 50 value of 0.69 μM, being about 6-fold more potent than 3TC (EC 50  = 3.68 μM) and NVP (EC 50  = 4.62 μM). Furthermore, TT6 exhibited the most potent inhibitory activity toward HIV-1 reverse transcriptase with an IC 50 value of 0.33 μM. Additionally, molecular simulation studies were conducted to investigate the binding modes between TT6 and NNRTI-binding pocket, which may provide valuable clues for the follow-up structural optimizations., (© 2024 John Wiley & Sons Ltd.)

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are an important component of anti-acquired immunodeficiency syndrome treatment regimen. In the present work, with the previously reported compound K-16c as lead, a series of novel 2,4,5-trisubstituted pyrimidine derivatives were designed based on the cocrystal structure of K-16c/RT, with the aim to improve the anti-human immunodeficiency virus type-1 (HIV-1) activities and metabolic stability properties. Compound 11b1 exhibited the most potent antiviral activity against wild-type (WT) and a panel of single mutant HIV-1 strains (EC 50  = 2.4-12.4 nM), being superior to or comparable to those of the approved drug etravirine. Meanwhile, 11b1 exhibited moderate cytotoxicity (CC 50  = 4.96 μM) and high selectivity index (SI = 1189) toward HIV-1 WT strain. As for HIV-1 RT inhibition test, 11b1 possessed excellent inhibitory potency (IC 50  = 0.04 μM) and confirmed its target was RT. Moreover, the molecular dynamics simulation was performed to elucidate the improved drug resistance profiles. Moreover, 11b1 was demonstrated with favorable safety profiles and pharmacokinetic properties in vivo, indicating that 11b1 is a potential anti-HIV-1 drug candidate worthy of further development., (© 2024 Wiley Periodicals LLC.)

With our continuous endeavors in seeking potent anti-HIV-1 agents, we reported here the discovery, biological characterization, and druggability evaluation of a class of nonnucleoside reverse transcriptase inhibitors. To fully explore the chemical space of the NNRTI-binding pocket, novel series of dihydrothiopyrano [3,2- d ]pyrimidines were developed by employing the structure-based design strategy. Most of the derivatives were endowed with prominent antiviral activities against HIV-1 wild-type and resistant strains at nanomolar levels. Among them, compound 23h featuring the aminopiperidine moiety was identified as the most potent inhibitor, with EC 50 values ranging from 3.43 to 21.4 nmol/L. Especially, for the challenging double-mutants F227L + V106A and K103N + Y181C, 23h exhibited 2.3- to 14.5-fold more potent activity than the first-line drugs efavirenz and etravirine. Besides, the resistance profiles of 23h achieved remarkable improvement compared to efavirenz and etravirine. The binding target of 23h was further confirmed to be HIV-1 reverse transcriptase. Molecular modeling studies were also performed to elucidate the biological evaluation results and give guidance for the optimization campaign. Furthermore, no apparent inhibition of the major CYP450 enzymes and hERG channel was observed for 23h . Most importantly, 23h was characterized by good pharmacokinetic properties and excellent safety in vivo . Collectively, 23h holds great promise as a potential candidate for its effective antiviral efficacy and favorable drug-like profiles., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors.)

Background: Higher levels of socioeconomic deprivation have been consistently associated with increased risk of premature mortality, but a detailed analysis by causes of death is lacking in Belgium. We aim to investigate the association between area deprivation and all-cause and cause-specific premature mortality in Belgium over the period 1998-2019., Methods: We used the 2001 and 2011 Belgian Indices of Multiple Deprivation to assign statistical sectors, the smallest geographical units in the country, into deprivation deciles. All-cause and cause-specific premature mortality rates, population attributable fraction, and potential years of life lost due to inequality were estimated by period, sex, and deprivation deciles., Results: Men and women living in the most deprived areas were 1.96 and 1.78 times more likely to die prematurely compared to those living in the least deprived areas over the period under study (1998-2019). About 28% of all premature deaths could be attributed to socioeconomic inequality and about 30% of potential years of life lost would be averted if the whole population of Belgium faced the premature mortality rates of the least deprived areas., Conclusion: Premature mortality rates have declined over time, but inequality has increased due to a faster pace of decrease in the least deprived areas compared to the most deprived areas. As the causes of death related to poor lifestyle choices contribute the most to the inequality gap, more effective, country-level interventions should be put in place to target segments of the population living in the most deprived areas as they are facing disproportionately high risks of dying., (© 2024. The Author(s).)

This review article will describe the (wide) variety of approaches that I envisaged to develop a specific therapy for viral infections: (i) interferon and its inducers, (ii) HSV, VZV and CMV inhibitors, (iii) NRTIs (nucleoside reverse transcriptase inhibitors), NtRTIs (nucleotide reverse transcriptase inhibitors) and NNRTIs (non-nucleoside reverse transcriptase inhibitors) as HIV inhibitors, (iv) NtRTIs as HBV inhibitors, and finally, (v) the transition of an HIV inhibitor to a stem cell mobilizer, as exemplified by AMD-3100 (Mozobil ® ).

HIV-1 reverse transcriptase (RT) is considered as one of the most significant targets for the anti-HIV-1 drug design due to their determined mechanism and well-decoded crystal structure. As a part of our continuous efforts towards the development of potent HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) by exploiting the tolerant region I of NNRTIs binding pocket (NNIBP), the miniaturized parallel synthesis via CuAAC click chemistry reaction followed by in situ biological screening have been performed in this work. The in situ enzyme inhibition screening results showed that 14 compounds exhibited higher or equivalent inhibitory activity compared to the lead K-5a2 and ETR. Anti-HIV-1 activity results indicated that C1N51 displayed the most potent activity (EC 50  = 0.01-0.26 μM) against wild-type and a panel of NNRTIs-resistant strains. Moreover, the molecular simulation demonstrated that the newly introduced triazole ring could develop new hydrogen bonds with Lys103 and Pro236, which explained the feasibility of introducing triazole in the tolerant region I of the RT binding pocket., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Optimization of compound 11L led to the identification of novel HIV capsid modulators, quinazolin-4-one-bearing phenylalanine derivatives, displaying potent antiviral activities against both HIV-1 and HIV-2. Notably, derivatives 12a2 and 21a2 showed significant improvements, with 2.5-fold over 11L and 7.3-fold over PF74 for HIV-1, and approximately 40-fold over PF74 for HIV-2. The X-ray co-crystal structures confirmed the multiple pocket occupation of 12a2 and 21a2 in the binding site. Mechanistic studies revealed a dual-stage inhibition profile, where the compounds disrupted capsid-host factor interactions at the early stage and promoted capsid misassembly at the late stage. Remarkably, 12a2 and 21a2 significantly promoted capsid misassembly, outperforming 11L, PF74, and LEN. The substitution of easily metabolized amide bond with quinolin-4-one marginally enhanced the stability of 12a2 in human liver microsomes compared to controls. Overall, 12a2 and 21a2 highlight their potential as potent HIV capsid modulators, paving the way for future advancements in anti-HIV drug design.

The aim of the study is to rethink the ethics of advanced motherhood. In the literature, delayed childbearing is usually discussed in the context of reproductive justice, and in relationship to ethical issues associated with the use and risk of assisted reproductive technologies. We aim to go beyond these more "traditional" ways in which reproductive ethics is framed by revisiting ethics itself through the lens of the figure of the so-called "older" mother. For this purpose, we start by exploring some of the deep seated socio-cultural discourses in the context of procreation: ageism, ableism and the widespread bias towards geneticism and pronatalism. Afterwards, we provide a critical overview of the key arguments against or in support of advanced motherhood. We then briefly discuss how entrenchment by both sides has produced an impasse in the debate on the ethics of advanced motherhood and proceed by arguing that it is fundamental to bring about a change in this narrative. For this purpose, we will revisit the feminist usage of the concept of vulnerability which will allow us both to criticize culturally prescribed norms about motherhood and to address the painful reality of age-related fertility decline. In the last section, we argue that instead of defining "older" motherhood as an ethical problem, we should problematize the fact that female reproductive ageing is an understudied and ill-sourced topic. We believe that allocating resources to research to better understand female reproductive ageing is not only ethically permissible, but might even be ethically desirable., (© 2023. The Author(s).)

Background: Palliative care (PC) is an integral part of cancer treatment. However, data on service availability is limited in childhood cancers., Aim: To describe the availability of PC services in paediatric oncology centres across Europe, and to identify barriers and facilitators for implementing and providing paediatric palliative care (PPC)., Methods: Paediatric oncology centres across Europe were invited to complete an online questionnaire., Results: A total of 158 paediatric oncology centres from 27 European countries participated. More than half of the centres (n=102, 64.6%) reported offering specialised PPC (defined as 24/7 coverage services with specialized physician and a multidisciplinary team). Most centres included a multidisciplinary care team (n=123, 80.9%) and PC at home (n=105, 69.1%). In 38.7% centres, service capacity was reported to be lower than demand. In most centres, PC consultation was initiated for a refractory neoplasm (n=126, 81.2%). Few centres (n=11, 7.1%) offered PC consultation at the time of a new cancer diagnosis. Eighty-two centres (52.6%) reported having bereavement services. Negative parental perception (n=99, 64.7%) and late referrals (n=91, 59.5%) were major barriers to implementation perceived by health care providers., Conclusion: Our results suggest that specialised PPC is available in more than half of paediatric oncology settings across Europe. Although half have had PPC available for >10 years, many cannot fulfil the demand for service. Barriers to implementation (i.e., parental education, staff training) should be addressed, with resources and services further expanded to cover the demand for PPC, including bereavement care., Competing Interests: Author declarations (includes financial disclosures) All authors declare no conflicts of interest Declaration of interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Study Question: What is the existing empirical literature on the psychosocial health and wellbeing of the parents and offspring born at an advanced parental age (APA), defined as 40 years onwards?, Summary Answer: Although the studies show discrepancies in defining who is an APA parent and an imbalance in the empirical evidence for offspring, mothers, and fathers, there is a drive towards finding psychotic disorders and (neuro-)developmental disorders among the offspring; overall, the observed advantages and disadvantages are difficult to compare., What Is Known Already: In many societies, children are born to parents at advanced ages and there is rising attention in the literature towards the consequences of this trend., Study Design Size Duration: The systematic search was conducted in six electronic databases (PubMed including Medline, Embase, Scopus, PsycInfo, CINAHL, and SocINDEX) and was limited to papers published between 2000 and 2021 and to English-language articles. Search terms used across all six electronic databases were: ('advanced parental age' OR 'advanced maternal age' OR 'advanced paternal age' OR 'advanced reproductive age' OR 'late parent*' OR 'late motherhood' OR 'late fatherhood') AND ('IVF' OR 'in vitro fertilization' OR 'in-vitro-fertilization' OR 'fertilization in vitro' OR 'ICSI' OR 'intracytoplasmic sperm injection' OR 'reproductive techn*' OR 'assisted reproductive technolog*' OR 'assisted reproduction' OR 'assisted conception' OR 'reproduction' OR 'conception' OR 'birth*' OR 'pregnan*') AND ('wellbeing' OR 'well-being' OR 'psycho-social' OR 'social' OR 'ethical' OR 'right to reproduce' OR 'justice' OR 'family functioning' OR 'parental competenc*' OR 'ageism' OR 'reproductive autonomy' OR 'outcome' OR 'risk*' OR 'benefit*')., Participants/materials Setting Methods: The included papers were empirical studies in English published between 2000 and 2021, where the study either examined the wellbeing and psychosocial health of parents and/or their children, or focused on parental competences of APA parents or on the functioning of families with APA parents. A quality assessment of the identified studies was performed with the QATSDD tool. Additionally, 20% of studies were double-checked at the data extraction and quality assessment stage to avoid bias. The variables sought were: the geographical location, the year of publication, the methodological approach, the definitions of APA used, what study group was at the centre of the research, what research topic was studied, and what advantages and disadvantages of APA were found., Main Results and the Role of Chance: A total number of 5403 articles were identified, leading to 2543 articles being included for title and abstract screening after removal of duplicates. This resulted in 98 articles included for a full-text reading by four researchers. Ultimately, 69 studies were included in the final sample. The key results concerned four aspects relevant to the research goals. (i) The studies showed discrepancies in defining who is an APA parent. (ii) There was an imbalance in the empirical evidence produced for different participant groups (mothers, fathers, and offspring), with offspring being the most studied study subjects. (iii) The research topics studied underlined the increased risks of neuro-developmental and psychotic disorders among offspring. (iv) The observed advantages and disadvantages were varied and could not be compared, especially for the offspring of APA parents., Limitations Reasons for Caution: Only English-language studies, published between 2000 and 2021, found in the above-mentioned databases were considered for this review., Wider Implications of the Findings: More research is necessary to understand the risks and benefits of building a family at an APA for the offspring when they reach adulthood. Furthermore, studies that explore the perspective of older fathers and older parents from non-Western societies would be highly informative., Study Funding/competing Interests: The writing of this manuscript was permitted by financial support provided by the Swiss National Science Foundation (Weave/Lead Agency funding program, grant number 10001AL&#95;197415/1, project title 'Family Building at Advanced Parental Age: An Interdisciplinary Approach'). The funder had no role in the drafting of this manuscript and the views expressed therein are those of the authors. The authors have no conflicts of interest., Registration Number: This systematic review is registered in Prospero: CRD42022304564., Competing Interests: The authors have no conflicts of interest to declare., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

To develop more potent HIV-1 inhibitors against a variety of NNRTIs-resistant strains, a series of 5-cyano substituted diarylpyridines was designed based on the cocrystal structural analysis. Among them, I-5b showed the greatest potency (EC 50  = 5.62-171 nM) against the wild-type (WT) and mutant HIV-1 strains. Especially for K103 N, I-5b exhibited outstanding activity with EC 50 values of 9.37 nM, being much superior to that of NVP (EC 50  = 5128 nM) and EFV (EC 50  = 114 nM) and comparable to that of ETR (EC 50  = 3.45 nM). In addition, the target of all compounds was turned out to be HIV-1 RT with moderate RT enzyme inhibitory activity (IC 50  = 0.094-12.0 μM). Moreover, the binding mode of representative compounds with RT was elaborated via molecular docking., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Our recent great interest in developing 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) analogs for HIV therapy identified a potent non-nucleoside reverse transcriptase inhibitor (NNRTI) 3 (EC 50  = 0.01681 μM), but its therapeutic efficacy was limited by its poor anti-resistance potency. This prompted us to search for potential HEPT analogs with broad-spectrum activities, leading to the generation of a series of novel HEPT analogs through exploring the chemical space of the solvent - protein interface. Encouraging improvements in anti-resistance efficacy were observed in some of these analogs, with the most promising compound 7 g being 3 to 26 - fold more potent than 3 against five mutant strains (E138K, Y181C, L100I, K103N, and Y188L). This analog surpassed the activity and selectivity of compound 3 by approximately 2-fold (EC 50  = 0.007468 μM, SI = 4260). Furthermore, it was found to demonstrate feeble inhibition of CYP and hERG in vitro, and no in vivo acute toxicity. This study will further enrich the structure-activity relationships (SARs) of the HEPT scaffold, providing new guidance for the development of NNRTIs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Bictegravir (BIC), a second-generation integrase strand-transfer inhibitor (INSTI) with high resilience to INSTI-resistance mutations, is integrated as a key component of Biktarvy® - a fixed-dose once-daily triple-drug regimen of bictegravir (BIC), emtricitabine (FTC) plus tenofovir alafenamide (TAF). Based on the accumulated evidence from HIV clinical trials and real-world studies, the clinical effectiveness of BIC + FTC + TAF has been proven non-inferior to other fixed-dose once-daily combinations such as dolutegravir + FTC + TAF and dolutegravir + abacavir + lamivudine. Biktarvy also shows limited drug-drug interactions and a high barrier to drug resistance. According to recent HIV guidelines, BIC + FTC + TAF is recommended as initial and long-term therapy for the treatment of HIV infection. For the pre-exposure prophylaxis, tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF) remains advisable, but BIC may be possibly added to TDF or TAF. In the development of a long-acting once-monthly regimen, the novel nano-formulation of BIC + FTC + TAF could be possibly developed in the future., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

To enhance the anti-HIV-1 efficacy and solubility of our previously documented NNRTI 1, a collection of innovative quinoline-substituted DAPY derivatives were devised using heteroaromatic replacement strategy. The results of biological evaluation revealed that the representative compound 5h possessed the highest inhibitory activity against wild-type HIV-1 and selectivity index (EC 50  = 0.0018 μM, SI > 166667), which were obviously better than that of 1 (EC 50  = 0.00978 μM, SI > 37764), NVP (EC 50  = 0.059 μM, SI > 158), EFV (EC 50  = 0.028 μM, SI > 269), and ETR (EC 50  = 0.0029 μM, SI > 1519). The water solubility of compound 5h was remarkably improved, surpassing that of 1, ETR and RPV. Additionally, this compound exerted significantly enhanced anti-resistance potency, compared to 1, and displayed comparable activity to ETR against WT RT of HIV-1 (IC 50  = 0.011 μM). To elucidate the underlying molecular mechanisms, molecular docking studies were conducted to investigate the crucial interactions between 5h and WT/mutant strains of HIV-1. These findings provide valuable insights and drive further advancements in the development of DAPYs for HIV therapy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Taking our previously reported HIV-1 NNRTIs BH-11c and XJ-10c as lead compounds, series of novel diarypyrimidine derivatives bearing six-membered non-aromatic heterocycles were designed to improve anti-resistance and drug-like profiles. According to the three rounds of in vitro antiviral activity screening, compound 12g was the most active inhibitor against wild-type and five prevalent NNRTI-resistant HIV-1 strains with EC 50 values ranging from 0.024 to 0.0010 μM. This is obviously better than the lead compound BH-11c and the approved drug ETR. Detailed structure-activity relationship was investigated to provide valuable guidance for further optimization. The MD simulation study indicated that 12g could form additional interactions with residues around the binding site in HIV-1 RT, which provided reasonable explanations for its improved anti-resistance profile compared to ETR. Furthermore, 12g showed significant improvement in water solubility and other drug-like properties compared to ETR. The CYP enzymatic inhibitory assay indicated that 12g was unlikely to induce CYP-mediated drug-drug interactions. 12g pharmacokinetics parameters were investigated and it displayed a long half-life of 6.59 h in vivo. The properties of compound 12g make it a promising lead compound for the development of new generation of antiretroviral drugs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Masson SAS.)

A carbon-carbon linkage is created when a methyl group is implanted on dUMP, thus resulting in the formation of dTMP by thymidylate synthase. The methyl group is deleted by aromatase when androgens are converted to estrogens. The methyl group is rearranged with the help of vitamin B12 in the isomerization of methylmalonyl-CoA to succinyl-CoA. S-adenosylmethionine (SAM) serves as the universal methyl donor involved in the biosynthesis of adrenaline and creatine(phosphate). It also interferes with the 5'-mRNA capping and the degradation of catecholamines (i.e. adrenaline, noradrenaline). Cholesterol could be viewed as a conglomeration of methyl groups. Finally, as part of valine, two methyl functions participate in the origin of one of the most frequent hereditary diseases on earth, sickle cell anemia., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

In the current landscape of antiretroviral options, there remains an urgent need for novel non-nucleoside reverse transcriptase inhibitors (NNRTIs) with improved resistance profiles and safety properties. Herein, a series of novel tetrahydropyrido[4,3- d ]pyrimidine derivatives were discovered utilizing the "escape from flatland" strategy. The most potent inhibitor 10c was endowed with broad-spectrum antiviral activity and improved resistance profiles against NNRTI-resistant variants compared to efavirenz and etravirine. Molecular simulations were investigated to furnish insights into the biological results. Drug-likeness assessment showed that 10c exhibited desirable physicochemical properties and in vitro metabolic stability. Notably, lower cytochrome P450 inhibition and human ether-à-go-go-related gene blockade liability were observed for 10c than those for etravirine and rilpivirine. Besides, 10c was characterized by excellent in vivo safety properties without acute/subacute toxicity and organ pathological damage. Overall, our multiparameter optimization campaign led to the identification of 10c with excellent antiviral activities and favorable drug-like profiles that could serve as an ideal drug candidate for further development.

Considering the undesirable metabolic stability of our recently identified NNRTI 5 ( t 1/2 = 96 min) in human liver microsomes, we directed our efforts to improve its metabolic stability by introducing a new favorable hydroxymethyl side chain to the C-5 position of pyrimidine. This strategy provided a series of novel methylol-biphenyl-diarylpyrimidines with excellent anti-HIV-1 activity. The best compound 9g was endowed with remarkably improved metabolic stability in human liver microsomes ( t 1/2  = 2754 min), which was about 29-fold longer than that of 5 ( t 1/2  = 96 min). This compound conferred picomolar inhibition of WT HIV-1 (EC 50  = 0.9 nmol/L) and low nanomolar activity against five clinically drug-resistant mutant strains. It maintained particularly low cytotoxicity (CC 50  = 264 μmol/L) and good selectivity (SI = 256,438). Molecular docking studies revealed that compound 9g exhibited a more stable conformation than 5 due to the newly constructed hydrogen bond of the hydroxymethyl group with E138. Also, compound 9g was characterized by good safety profiles. It displayed no apparent inhibition of CYP enzymes and hERG. The acute toxicity assay did not cause death and pathological damage in mice at a single dose of 2 g/kg. These findings paved the way for the discovery and development of new-generation anti-HIV-1 drugs., Competing Interests: The authors declared no conflicts of interest., (© 2023 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.)

HIV-1 capsid (CA) is an attractive target for its indispensable roles in the viral life cycle. We report the design, synthesis, and mechanistic study of a novel series of 2-piperazineone peptidomimetics as HIV capsid modulators by mimicking the structure of host factors binding to CA. F-Id-3o was the most potent compound from the synthesized series, with an anti-HIV-1 EC 50 value of 6.0 μM. However, this series of compounds showed a preference for HIV-2 inhibitory activity, in which Id-3o revealed an EC 50 value of 2.5 μM (anti-HIV-2 potency), an improvement over PF74. Interestingly, F-Id-3o did bind HIV-1 CA monomers and hexamers with comparable affinity, unlike PF74, consequently showing antiviral activity in the early and late stages of the HIV-1 lifecycle. Molecular dynamics simulations shed light on F-Id-3o and Id-3o binding modes within the HIV-1/2 CA protein and provide a possible explanation for the increased anti-HIV-2 potency. Metabolic stability assays in human plasma and human liver microsomes indicated that although F-Id-3o has enhanced metabolic stability over PF74, further optimization is necessary. Moreover, we utilized computational prediction of drug-like properties and metabolic stability of F-Id-3o and PF74, which correlated well with experimentally derived metabolic stability, providing an efficient computational pipeline for future preselection based on metabolic stability prediction. Overall, the 2-piperazineone-bearing peptidomimetics are a promising new chemotype in the CA modulators class with considerable optimization potential., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (This journal is © The Royal Society of Chemistry.)

Indolylarylsulfones (IASs) are classical HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) with a unique scaffold and possess potent antiviral activity . To address the high cytotoxicity and improve safety profiles of IASs, we introduced various sulfonamide groups linked by alkyl diamine chain to explore the entrance channel of non-nucleoside inhibitors binding pocket. 48 compounds were designed and synthesized to evaluate their anti-HIV-1 activities and reverse transcriptase inhibition activities. Especially, compound R 10 L 4 was endowed with significant inhibitory activity towards wild-type HIV-1 (EC 50(WT)  = 0.007 μmol/L, SI = 30,930) as well as a panel of single-mutant strains exemplified by L100I (EC 50  = 0.017 μmol/L, SI = 13,055), E138K (EC 50  = 0.017 μmol/L, SI = 13,123) and Y181C (EC 50  = 0.045 μmol/L, SI = 4753) which were superior to Nevirapine and Etravirine. Notably, R 10 L 4 was characterized with significantly reduced cytotoxicity (CC 50  = 216.51 μmol/L) and showed no remarkable in vivo toxic effects (acute and subacute toxicity). Moreover, the computer-based docking study was also employed to characterize the binding mode between R 10 L 4 and HIV-1 RT. Additionally, R 10 L 4 presented an acceptable pharmacokinetic profile. Collectively, these results deliver precious insights for next optimization and indicate that the sulfonamide IAS derivatives are promising NNRTIs for further development., (© 2023 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.)