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Nucleoside and nucleotide analogues have proven to be transformative in the treatment of viral infections and cancer. One branch of structural modification to deliver new nucleoside analogue classes explores replacement of canonical ribose oxygen with a sulfur atom. Whilst biological activity of such analogues has been shown in some cases, widespread exploration of this compound class is hitherto hampered by the lack of a straightforward and universal nucleobase diversification strategy. Herein, we present a synergistic platform enabling both biocatalytic nucleobase diversification from 4'-thiouridine in a one-pot process, and chemical functionalization to access new entities. This methodology delivers entry across pyrimidine and purine 4'-thionucleosides, paving a way for wider synthetic and biological exploration. We exemplify our approach by enzymatic synthesis of 5-iodo-4'-thiouridine on multi-milligram scale and from here switch to complete chemical synthesis of a novel nucleoside analogue probe, 5-ethynyl-4'-thiouridine. Finally, we demonstrate the utility of this probe to monitor RNA synthesis in proliferating HeLa cells, validating its capability as a new metabolic RNA labelling tool., (© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Objective: Cognitive training may benefit older adults with mild cognitive impairment (MCI), but the prognostic factors are not well-established., Methods: This study analyzed data from a 78-week trial with 107 participants with MCI, comparing computerized cognitive training (CCT) and computerized crossword puzzle training (CPT). Outcomes were changes in cognitive and functional measures from baseline. Linear mixed-effect models were used to identify prognostic factors for each intervention., Results: Baseline neuropsychological composite z-score was positively associated with cognitive and functional improvements for both interventions in univariable models, retaining significance in the final multivariable model for functional outcome in CPT ( P < 0.001). Apolipoprotein E e4 carriers had worse cognitive ( P = 0.023) and functional ( P = 0.001) outcomes than noncarriers for CPT but not CCT. African Americans showed greater functional improvements than non-African Americans in both CPT ( P = 0.001) and CCT ( P = 0.010). Better baseline odor identification was correlated with cognitive improvements in CPT ( P = 0.006) and functional improvements in CCT ( P < 0.001)., Conclusion: Baseline cognitive test performance, African American background, and odor identification ability are potential prognostic factors for improved outcomes with cognitive interventions in older adults with MCI. Apolipoprotein E e4 is associated with poor outcomes. Replication of these findings may improve the selection of cognitive interventions for individuals with MCI., Competing Interests: M.Q. received research grants from the National Science Foundation and National Institutes of Health (NIH). D.P.D. has received research grants from the National Institutes on Aging and Alzheimer’s Association and has served as a consultant on scientific advisory boards to Acadia, Corium, GSK, TauRx, and a DSMB for BioXcel. P.M.D. has received research grants from the NIH, DARPA, DOD, ONR, Salix, Avanir, Avid, Cure Alzhaimer’s Fund, Karen L. Wrenn Trust, US Highbush Blueberry Council, and Steve Aoki Foundation, and advisory/board fees from Apollo, Clearview, Lumos, Prospira, Keel Digital, Otsuka, Compass, Sermo, Nutricia, UMethod, and Transposon. He is a co-inventor of patents for the diagnosis or treatment of Alzheimer’s disease and a patent for infection detection. Also, owns shares in UMethod, Alzheon, Transposon, and MarvelBiome, the products of which are not discussed here. The remaining authors have received grant support from the NIH and declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Covering: 2019 to 2023Nucleoside analogues represent one of the most important classes of small molecule pharmaceuticals and their therapeutic development is successfully established within oncology and for the treatment of viral infections. However, there are currently no nucleoside analogues in clinical use for the management of bacterial infections. Despite this, a significant number of clinically recognised nucleoside analogues are known to possess some antibiotic activity, thereby establishing a potential source for new therapeutic discovery in this area. Furthermore, given the rise in antibiotic resistance, the discovery of new clinical candidates remains an urgent global priority and natural product-derived nucleoside analogues may also present a rich source of discovery space for new modalities. This Highlight, covering work published from 2019 to 2023, presents a current perspective surrounding the synthesis of natural purine nucleoside antibiotics. By amalgamating recent efforts from synthetic chemistry with advances in biosynthetic understanding and the use of recombinant enzymes, prospects towards different structural classes of purines are detailed.

Background: Computerized cognitive training (CCT) has emerged as a potential treatment option for mild cognitive impairment (MCI). It remains unclear whether CCT's effect is driven in part by expectancy of improvement., Objectives: This study aimed to determine factors associated with therapeutic expectancy and the influence of therapeutic expectancy on treatment effects in a randomized clinical trial of CCT versus crossword puzzle training (CPT) for older adults with MCI., Design: Randomized clinical trial of CCT vs CPT with 78-week follow-up., Setting: Two-site study - New York State Psychiatric Institute and Duke University Medical Center., Participants: 107 patients with MCI., Intervention: 12 weeks of intensive training with CCT or CPT with follow-up booster training over 78 weeks., Measurements: Patients rated their expectancies for CCT and CPT prior to randomization., Results: Patients reported greater expectancy for CCT than CPT. Lower patient expectancy was associated with lower global cognition at baseline and older age. Expectancy did not differ by sex or race. There was no association between expectancy and measures of everyday functioning, hippocampus volume, or apolipoprotein E genotype. Expectancy was not associated with change in measures of global cognition, everyday functioning, and hippocampus volume from baseline to week 78, nor did expectancy interact with treatment condition., Conclusions: While greater cognitive impairment and increased age was associated with low expectancy of improvement, expectancy was not associated with the likelihood of response to treatment with CPT or CCT., Competing Interests: Dr. Motter reports grants from National Institute of Mental Health, during the conduct of the study. Dr. Rushia has nothing to disclose. Dr. Qian has nothing to disclose. Charlie Ndouli has nothing to disclose. Adaora Nwosu has nothing to disclose. Dr. Petrella reports grants from National Institute on Aging, during the conduct of the study; grants from National Science Foundation, personal fees from Biogen, personal fees from Icometrix, other from Cortechs.ai, outside the submitted work. Dr. Doraiswamy reports grants from National Institute of Health, other from Lumos Labs, during the conduct of the study; grants from National Institute of Health, grants from Lilly/Advid, grants from US Highbush Blueberry Council, grants from Cure Alzheimer’s Fund, grants from Karen L Wrenn Trust, grants from Steve Aoki Fund, personal fees from Lumos Labs, personal fees from UMethod, personal fees from Vivli, personal fees from Nutricia, personal fees from Clearview, personal fees from Brain Forum, personal fees from Otsuka, personal fees from Cornell, personal fees from Nestle, non-financial support from AHEL, non-financial support from Live Love Laugh, other from Alzheon, other from Lumos Labs, other from Lululemon, other from Transposon, from Apollo, from Live Laugh Love, from Goldie Hawn Foundation, other from Transposon, other from UMethod, other from Evidation, other from Marvel Biome, other from Alzheon, outside the submitted work; In addition, Dr. Doraiswamy has a patent Diagnosis and treatment of dementia. Dr. Goldberg has nothing to disclose. Dr. Devanand reports grants from National Institute on Aging, during the conduct of the study; grants from Alzheimer’s Association, personal fees from Acadia, personal fees from Eisai, personal fees from Genentech, personal fees from Jazz, personal fees from TauRx, personal fees from Novo, personal fees from Nordisk, personal fees from Biogen, personal fees from BioExcel, outside the submitted work.

(Pre-)anthraquinones are widely distributed natural compounds and occur in plants, fungi, microorganisms, and animals, with atrochrysone (1) as the key biosynthetic precursor. Chemical analyses established mushrooms of the genus Cortinarius-the webcaps-as producers of atrochrysone-derived octaketide pigments. However, more recent genomic data did not provide any evidence for known atrochrysone carboxylic acid (4) synthases nor any other polyketide synthase (PKS) producing oligocyclic metabolites. Here, we describe an unprecedented class of non-reducing (NR-)PKS. In vitro assays with recombinant enzyme in combination with in vivo product formation in the heterologous host Aspergillus niger established CoPKS1 and CoPKS4 of C. odorifer as members of a new class of atrochrysone carboxylic acid synthases. CoPKS4 catalyzed both hepta- and octaketide synthesis and yielded 6-hydroxymusizin (6), along with 4. These first mushroom PKSs for oligocyclic products illustrate how the biosynthesis of bioactive natural metabolites evolved independently in various groups of life., (© 2022 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Background: Desensitization protocols for HLA-incompatible living donor kidney transplantation (ILDKT) vary across centers. The impact of these, as well as other practice variations, on ILDKT outcomes remains unknown., Methods: We sought to quantify center-level variation in mortality and graft loss following ILDKT using a 25-center cohort of 1358 ILDKT recipients with linkage to Scientific Registry of Transplant Recipients for accurate outcome ascertainment. We used multilevel Cox regression with shared frailty to determine the variation in post-ILDKT outcomes attributable to between-center differences and to identify any center-level characteristics associated with improved post-ILDKT outcomes., Results: After adjusting for patient-level characteristics, only 6 centers (24%) had lower mortality and 1 (4%) had higher mortality than average. Similarly, only 5 centers (20%) had higher graft loss and 2 had lower graft loss than average. Only 4.7% of the differences in mortality (P < 0.01) and 4.4% of the differences in graft loss (P < 0.01) were attributable to between-center variation. These translated to a median hazard ratio of 1.36 for mortality and 1.34 of graft loss for similar candidates at different centers. Post-ILDKT outcomes were not associated with the following center-level characteristics: ILDKT volume and transplanting a higher proportion of highly sensitized, prior transplant, preemptive, or minority candidates., Conclusions: Unlike most aspects of transplantation in which center-level variation and volume impact outcomes, we did not find substantial evidence for this in ILDKT. Our findings support the continued practice of ILDKT across these diverse centers., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Older (≥65) KT recipients differ from their younger counterparts in their immune response to immunosuppression (IS) and may have a different risk of malignancy after receiving induction., Methods: We identified 66 700 adult KT recipients treated with anti-thymocyte globulin (ATG) (n = 40 443) or interleukin-2 receptor antagonist (IL-2RA) (n = 26 327) induction (1/1/1999-12/31/2014) using USRDS/Medicare data. We estimated the risk of first-diagnosed post-KT malignancy associated with induction (ATG vs. IL-2RA) using Cox proportional hazard models. We then tested whether these risks differed between older and younger recipients (Wald test for interaction). Models incorporated inverse probability of treatment weights to adjust for confounders., Results: The 3-year cumulative incidences of any diagnosed malignancy were 11.5%. ATG was associated with a higher malignancy risk (HR = 1.12, 95%CI:1.06-1.18). This association differed (p interaction  = 0.04) between younger (HR = 1.12, 95%CI:1.06-1.18) and older recipients (HR = 1.03, 95%CI:0.96-1.09). ATG was also associated with higher risk of skin (HR = 1.18, 95%CI:1.08-1.29), lung (HR = 1.24, 95%CI:1.05-1.47), and ovary malignancies (HR = 1.94, 95%CI:1.08-3.48). However, only the association of ATG with post-KT skin malignancy differed (p interaction  = 0.01) between younger (HR = 1.18; 95%CI:1.08-1.29) and older (HR = 1.01; 95%CI:0.93-1.09) recipients., Conclusions: Compared with IL-2RA induction, ATG was associated with elevated post-KT malignancy risk but only among younger recipients. Transplant centers may need to tailor induction IS for younger recipients to mitigate malignancy risk., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The Kidney Allocation System (KAS) has resulted in fewer pediatric kidneys being allocated to pediatric deceased donor kidney transplant (pDDKT) recipients. This had prompted concerns that post-pDDKT outcomes may worsen. To study this, we used SRTR data to compare the outcomes of 953 pre-KAS pDDKT (age <18 years) recipients (December 4, 2012-December 3, 2014) with the outcomes of 934 post-KAS pDDKT recipients (December 4, 2014-December 3, 2016). We analyzed mortality and graft loss by using Cox regression, delayed graft function (DGF) by using logistic regression, and length of stay (LOS) by using negative binomial regression. Post-KAS recipients had longer pretransplant dialysis times (median 1.26 vs 1.07 years, P = .02) and were more often cPRA 100% (2.0% vs 0.1%, P = .001). Post-KAS recipients had less graft loss than pre-KAS recipients (hazard ratio [HR]: 0.35 0.54 0.83 , P = .005) but no statistically significant differences in mortality (HR: 0.29 0.72 1.83 , P = .5), DGF (odds ratio: 0.93 1.32 1.93 , P = .2), and LOS (LOS ratio: 0.96 1.06 1.19 , P = .4). After adjusting for donor-recipient characteristics, there were no statistically significant post-KAS differences in mortality (adjusted HR: 0.37 1.04 2.92 , P = .9), DGF (adjusted odds ratio: 0.94 1.41 2.13 , P = .1), or LOS (adjusted LOS ratio: 0.93 1.04 1.16 , P = .5). However, post-KAS pDDKT recipients still had less graft loss (adjusted HR: 0.38 0.59 0.91 , P = .02). KAS has had a mixed effect on short-term posttransplant outcomes for pDDKT recipients, although our results are limited by only 2 years of posttransplant follow-up., (© 2019 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Prenatal famine, resulting in intrauterine malnutrition, impacts offspring psychopathology later in adulthood. In addition, the specific impact of intrauterine malnutrition of different psychopathology differs by the timing of the exposure. Using a meta-analysis, the current study assessed the specific risk of developing affective, psychotic, and personality disorders. Studies were identified using PubMed and PsycINFO. Studies met the following criteria for inclusion in the analysis: availability in peer-reviewed English journals, use of human subjects, prenatal exposure to famine, and psychopathology in adulthood defined by diagnostic criteria as an outcome. Fixed effect relative risks (RRs) were calculated for affective, psychotic, and personality domains. Furthermore, timing of exposure was assessed as an effect modifier in our analysis, defined by the index trimester at the height of famine. Our meta-analysis found that adults exposed in utero during the 1 st trimester were at a significant increased risk of psychotic disorders (RR=1.46, 95% CI=1.08, 1.97, p=0.014), and personality disorders (RR=2.31, 95% CI=1.36, 3.92, p =0.002). Those exposed during the 2 nd trimester were at a significant increased risk of affective disorders (RR=1.45, 95% CI=1.22, 1.72, p <0.0001), and psychotic disorders (RR=1.46, 95% CI=1.13, 1.89, p=0.004). Similarly, those exposed in the 3 rd trimester were at a significant increased risk of affective disorders (RR=1.33, 95% CI=1.13, 1.57, p =0.0001), and psychotic disorders RR=1.47, 95% CI=1.10, 1.97, p=0.010). Our findings suggest that there is differential risk across the different domains of psychopathology by trimester of exposures. This meta-analysis underscores the need for further investigation into the mechanisms underlying prenatal maternal nutrition and offspring psychopathology where magnitude of elevated risk differs by the exposure timing during pregnancy.

Background: The impact of immunosuppressants on postoperative complications following colon resections for Crohn's disease remains controversial. This study aimed to compare postoperative outcomes between immunosuppressed and immunocompetent patients with Crohn's disease undergoing elective colon resection., Methods: Analysis of 30-day outcomes using a cohort from the American College of Surgeons National Surgical Quality Improvement Program colectomy-specific database was performed. The database is populated by trained clinical reviewers who collect 30-day postoperative outcomes for patients treated at participating North-American institutions. Adult patients who underwent an elective colectomy between 2011 and 2015 were included. Immunosuppression for Crohn's disease was predefined as use of regular corticosteroids or immunosuppressants within 30 days of the operation. Patients who received chemotherapy within 90 days of surgery, and patients who had disseminated cancer, preoperative shock, or emergency surgery were excluded. Primary outcome was infectious complications., Results: Three thousand eight hundred sixty patients with Crohn's disease required elective colon resection and met the inclusion criteria. Of these, 2483 were immunosuppressed and 1377 were immunocompetent. On multivariate analysis, the odds of infectious complications [OR 1.25; 95% CI (1.033-1.523)], overall surgical site infection [1.40; (1.128-1.742)], organ space surgical site infection [1.47; (1.094-1.984)], and anastomotic leak [1.51; (1.018-2.250)] were significantly higher for immunosuppressed compared to immunocompetent patients with Crohn's disease., Conclusions: Patients with Crohn's disease who were on immunosuppressant medications within 30 days of elective colectomy had significantly increased rates of infectious complications, overall surgical site infection, organ space surgical site infection, and anastomotic leak compared to patients who were not on immunosuppressive agents.

Objective: To evaluate the adequacy of fluoride levels in the public water system in Curitiba, state of Paraná, Brazil, as determined by two techniques (colorimetric and electrometric)., Methods: Data from independent measurements of fluoride in the public water system in Curitiba routinely performed by the city government were obtained for the period between January 2000 and July 2008. Mean levels of fluoride concentration were calculated for each of these years. After that, fluoride concentrations measured in 1 470 samples by the state water utility (SANEPAR) using the electrometric technique in 2006 and 2007 were compared with the corresponding levels measured by the city using the colorimetric method. The rate of samples meeting the standard for the city (0.8 ppmF), and below and above the standard, was calculated for both methods. Fluoride levels were compared between sanitary districts, months for the period between December 2007 and July 2008, and water treatment facilities., Results: The overall mean fluoride level between 2000 and 2008 was 0.7 ppmF based on the independent measurements. The comparison between techniques showed a higher mean fluoride level with the electrometric technique (0.743 ppmF ± 0.133) vs. the colorimetric technique (0.637 ppmF ± 0.164). The rate of samples meeting the ideal standard of 0.8 ppmF was 15.05% for the colorimetric and 63.97% for the electrometric technique; 62.03% and 22.85% of the samples were below that standard and 21.10% and 13.18% were above that standard, respectively. Fluoride levels were statistically significant (P < 0.001) for the comparison between sanitary districts and months., Conclusions: The choice of technique significantly influences the resulting levels of fluoride. Independent monitoring of fluoride levels should employ the same technique used by the water utility. Further studies should aim at defining which technique is the most adequate to determine fluoride concentration in public water systems.

In 1986, an outbreak of Moraxella follicular conjunctivitis occurred in girls attending a Navajo boarding school in New Mexico. We diagnosed 19 cases of culture-proven, and 21 of clinical conjunctivitis based on isolation of Moraxella from conjunctival cultures and the occurrence of symptoms significantly associated with positive culture. Sharing eye makeup was significantly associated with Moraxella-positive conjunctivitis (odds ratio [OR] = 7.2, P = .004) and showed a trend toward significance in those with clinical conjunctivitis (OR = 2.9, P = .09). Eyeliner and eye shadow were implicated (OR = 4.1, P less than .05). We cultured samples of 13 students' makeup; one third of the eyeliners were positive for Moraxella. Nasal carriage of Moraxella was found in 35 (44%) of the 79 female boarders and in 20 (21%) of 97 Navajo patients at two nearby clinics. In a prospective evaluation of the effect of patient education and rifampin therapy on the occurrence of conjunctivitis during an 11-month follow-up period, both types of intervention were successful in significantly reducing the rate of conjunctivitis when compared with that in a control group.