Smartphone pupillometry for detection of cerebral vasospasm after aneurysmal subarachnoid hemorrhage.

OBJECTIVES: Vasospasm is a complication of aneurysmal subarachnoid hemorrhage (aSAH) that can change the trajectory of recovery and is associated with morbidity and mortality. Earlier detection of vasospasm could improve patient outcomes. Our objective is to evaluate the accuracy of smartphone-based quantitative pupillometry in the detection of radiographic vasospasm and delayed cerebral ischemia (DCI) after aSAH. MATERIALS AND METHODS: We prospectively collected pupillary light reflex (PLR) parameters from patients with aSAH admitted to a neurocritical care unit at a single hospital twice daily using quantitative smartphone pupillometry recordings. PLR parameters included: Maximum pupil diameter, minimum pupil diameter, percent change in pupil diameter, latency in beginning of pupil constriction to light, mean constriction velocity, maximum constriction velocity, and mean dilation velocity. Two-tailed t-tests for independent samples were performed to determine changes in average concurrent PLR parameter values between the following comparisons: (1) patients with and without radiographic vasospasm (defined by angiography with the need for endovascular intervention) and (2) patients with and without DCI. RESULTS: 49 subjects with aSAH underwent 323 total PLR recordings. For PLR recordings taken with (n=35) and without (n=241) radiographic vasospasm, significant differences were observed in MIN (35.0 ± 7.5 pixels with vasospasm versus 31.6 ± 6.2 pixels without; p=0.002). For PLR recordings taken with (n=43) and without (n=241) DCI, significant differences were observed in MAX (48.9 ± 14.3 pixels with DCI versus 42.5 ± 9.2 pixels without; p<0.001). CONCLUSIONS: Quantitative smartphone pupillometry has the potential to be used to detect radiographic vasospasm and DCI after aSAH.

Patient characteristics associated with intended non-guideline chemotherapy in women with stage I-IIIA breast cancer.

BACKGROUND: Guidelines informing chemotherapy regimen selection are based on clinical trials with participants who do not necessarily represent general populations with breast cancer. Understanding who receives non-guideline regimens is important to understanding real-world chemotherapy administration and how it relates to patient outcomes. METHODS: Using data from the Optimal Breast Cancer Chemotherapy Dosing (OBCD) cohort study, based at Kaiser Permanente Northern California (2006-2019) and Kaiser Permanente Washington (2004-2015), we use logistic regression to examine the associations between patient characteristics and receipt of non-NCCN-guideline chemotherapy among 11,293 women with primary stage I-IIIA breast cancer receiving chemotherapy. RESULTS: Use of non-guideline regimens was strongly associated with several factors, including older age (OR≥80 vs 18-39: 5.25, 95%CI: 3.06-9.00)(p-trend=0.002) and human epidermal growth factor-2 status (ORHER2+ vs HER2-: 3.44; 95%CI: 3.06-3.87) and was less likely in women with larger tumor size (OR>5cm vs 0.1-≤0.5cm: 0.56; 95%CI: 0.36-0.87)(p-trend=0.01) and diagnosed in later years (OR2012-2019 vs 2005-2011: 0.80; 95%CI: 0.71-0.90). Factors associated varied by type of non-guideline regimen. For example, women with comorbidity and older age were more likely to receive non-guideline drug combinations in particular, while women with larger tumor size were less likely to receive non-guideline administration schedules. CONCLUSIONS: Non-guideline chemotherapy regimens are more likely in certain patient populations. IMPACT: These associations highlight that vulnerable patient populations may be less likely to receive guideline care and thus real-world studies are essential to understanding how the use of non-guideline regimens impacts patient outcomes in these groups.

Interferon subverts an AHR-JUN axis to promote CXCL13+ T cells in lupus.

Systemic lupus erythematosus (SLE) is prototypical autoimmune disease driven by pathological T cell-B cell interactions1,2. Expansion of T follicular helper (TFH) and T peripheral helper (TPH) cells, two T cell populations that provide help to B cells, is a prominent feature of SLE3,4. Human TFH and TPH cells characteristically produce high levels of the B cell chemoattractant CXCL13 (refs. 5,6), yet regulation of T cell CXCL13 production and the relationship between CXCL13+ T cells and other T cell states remains unclear. Here, we identify an imbalance in CD4+ T cell phenotypes in patients with SLE, with expansion of PD-1+/ICOS+ CXCL13+ T cells and reduction of CD96hi IL-22+ T cells. Using CRISPR screens, we identify the aryl hydrocarbon receptor (AHR) as a potent negative regulator of CXCL13 production by human CD4+ T cells. Transcriptomic, epigenetic and functional studies demonstrate that AHR coordinates with AP-1 family member JUN to prevent CXCL13+ TPH/TFH cell differentiation and promote an IL-22+ phenotype. Type I interferon, a pathogenic driver of SLE7, opposes AHR and JUN to promote T cell production of CXCL13. These results place CXCL13+ TPH/TFH cells on a polarization axis opposite from T helper 22 (TH22) cells and reveal AHR, JUN and interferon as key regulators of these divergent T cell states.

ß-Amino Acids Reduce Ternary Complex Stability and Alter the Translation Elongation Mechanism.

Templated synthesis of proteins containing non-natural amino acids (nnAAs) promises to expand the chemical space available to biological therapeutics and materials, but existing technologies are still limiting. Addressing these limitations requires a deeper understanding of the mechanism of protein synthesis and how it is perturbed by nnAAs. Here we examine the impact of nnAAs on the formation and ribosome utilization of the central elongation substrate: the ternary complex of native, aminoacylated tRNA, thermally unstable elongation factor, and GTP. By performing ensemble and single-molecule fluorescence resonance energy transfer measurements, we reveal that both the (R)- and (S)-ß2 isomers of phenylalanine (Phe) disrupt ternary complex formation to levels below in vitro detection limits, while (R)- and (S)-ß3-Phe reduce ternary complex stability by 1 order of magnitude. Consistent with these findings, (R)- and (S)-ß2-Phe-charged tRNAs were not utilized by the ribosome, while (R)- and (S)-ß3-Phe stereoisomers were utilized inefficiently. (R)-ß3-Phe but not (S)-ß3-Phe also exhibited order of magnitude defects in the rate of translocation after mRNA decoding. We conclude from these findings that non-natural amino acids can negatively impact the translation mechanism on multiple fronts and that the bottlenecks for improvement must include the consideration of the efficiency and stability of ternary complex formation.

Efficacy of Interceptor G2, Royal Guard and PermaNet 3.0 against pyrethroid-resistant Anopheles gambiae s.l. from Za-Kpota, southern Benin: an experimental hut trial.

BACKGROUND: The widespread use of insecticide-treated nets (ITNs) has significantly contributed to the reduction in malaria cases and deaths observed across Africa. Unfortunately, this control strategy is threatened by the rapid spread of pyrethroid resistance in malaria vectors. Dual-active-ingredient insecticidal nets are now available to mitigate the impact of pyrethroid resistance. To facilitate evidence-based decisions regarding product selection in specific use settings, data are needed on the efficacy of these different nets against local mosquito populations. METHODS: Two experimental hut trials were performed in Za-Kpota, southern Benin in 2021 to evaluate the performance of Interceptor G2 (BASF), Royal Guard (Disease Control Technologies) and PermaNet 3.0 (Vestergaard Frandsen), all dual-active-ingredient bednets, in comparison to untreated or standard pyrethroid-treated bednets, against free-flying wild Anopheles gambiae mosquitoes. The performance of some of these next-generation nets was compared to the same type of nets that have been in use for up to 2 years. Mosquitoes collected in the huts were followed up after exposure to assess the sublethal effects of treatments on certain life-history traits. RESULTS: The predominant species in the study site was Anopheles gambiae sensu stricto (An. gambiae s.s.). Both Anopheles coluzzii and An. gambiae s.s. were resistant to pyrethroids (deltamethrin susceptibility was restored by piperonyl butoxide pre-exposure). In the experimental hut trials, the highest blood-feeding inhibition (5.56%) was recorded for the Royal Guard net, relative to the standard PermaNet 2.0 net (44.44% inhibition). The highest 72-h mortality rate (90.11%) was recorded for the Interceptor G2 net compared to the PermaNet 2.0 net (56.04%). After exposure, the risk of death of An. gambiae sensu lato (An. gambiae s.l.) was 6.5-fold higher with the Interceptor G2 net and 4.4-fold higher with the PermaNet 3.0 net compared to the respective untreated net. Lower mosquito mortality was recorded with an aged Interceptor G2 net compared to a new Interceptor G2 net. Oviposition rates were lower in mosquitoes collected from huts containing ITNs compared to those of untreated controls. None of the mosquitoes collected from huts equipped with Royal Guard nets laid any eggs. CONCLUSIONS: The Royal Guard and Interceptor G2 nets showed a potential to significantly improve the control of malaria-transmitting vectors. However, the PermaNet 3.0 net remains effective in pyrethroid-resistant areas.

Patient characteristics associated with delayed time to adjuvant chemotherapy among women treated for stage I-IIIA breast cancer.

For patients with breast cancer, delays in chemotherapy initiation have been adversely associated with recurrence and survival. We evaluated patient-level factors associated with delayed chemotherapy initiation, from both diagnosis and surgery, in a community-based cohort of women with early-stage breast cancer. For the Optimal Breast Cancer Chemotherapy Dosing study, we identified a cohort of 34,109 women diagnosed with stage I-IIIA breast cancer at two U.S. integrated healthcare delivery systems between 2004 and 2019. We used logistic regression to calculate odds ratios (OR) and 95% confidence intervals (CI) to identify patient factors associated with delays in chemotherapy initiation after diagnosis (≥90 days) and surgery (≥60 days). Among 10,968 women receiving adjuvant chemotherapy, 21.1% experienced delays in chemotherapy initiation after diagnosis and 21.3% after surgery. Older age, non-Hispanic Black and Hispanic race and ethnicity, and ER+ and/or PR+ disease were associated with increased likelihood of delays to chemotherapy initiation after diagnosis and surgery. People diagnosed in 2012-2019 (vs. 2005-2011), with a higher grade and larger tumor size were less likely to experience delays. Other factors were associated with a higher likelihood of delays specifically from diagnosis (earlier stage, mastectomy vs. breast-conserving surgery), or surgery (higher comorbidity, increased nodal number). Women diagnosed with breast cancer who were at highest risk of progression and recurrence were less likely to experience delays in chemotherapy initiation after diagnosis and surgery. Understanding reasons for chemotherapy delays beyond patient factors may be potentially important to reduce risk of breast cancer recurrence and progression.

Partial coil embolization before surgical clipping of ruptured intracranial aneurysms.

OBJECTIVE: Intraoperative rupture (IOR) is the most common adverse event encountered during surgical clip obliteration of ruptured intracranial aneurysms. Besides increasing surgeon experience and early proximal control, no methods exist to decrease IOR risk. Thus, our objective was to assess if partial endovascular coil embolization to protect the aneurysm before clipping decreases IOR. METHODS: We conducted a retrospective analysis of patients with ruptured intracranial aneurysms that were treated with surgical clipping at two tertiary academic centers. We compared patient characteristics and outcomes of those who underwent partial endovascular coil embolization to protect the aneurysm before clipping to those who did not. The primary outcome was IOR. Secondary outcomes were inpatient mortality and discharge destination. RESULTS: We analyzed 100 patients. Partial endovascular aneurysm protection was performed in 27 patients. Age, sex, subarachnoid hemorrhage severity, and aneurysm location were similar between the partially-embolized and non-embolized groups. The median size of the partially-embolized aneurysms was larger (7.0 mm [interquartile range 5.95-8.7] vs. 4.6 mm [3.3-6.0]; P < 0.001). During surgical clipping, IOR occurred less frequently in the partially-embolized aneurysms than non-embolized aneurysms (2/27, 7.4%, vs. 30/73, 41%; P = 0.001). Inpatient mortality was 14.8% (4/27) in patients with partially-embolized aneurysms and 28.8% (21/73) in patients without embolization (P = 0.20). Discharge to home or inpatient rehabilitation was 74.0% in patients with partially-embolized aneurysms and 56.2% in patients without embolization (P = 0.11). A complication from partial embolization occurred in 2/27 (7.4%) patients. CONCLUSIONS: Preoperative partial endovascular coil embolization of ruptured aneurysms is associated with a reduced frequency of IOR during definitive treatment with surgical clip obliteration. These results and the impact of preoperative partial endovascular coil embolization on functional outcomes should be confirmed with a randomized trial.

Trends in chemotherapy use for early-stage breast cancer from 2006 to 2019.

BACKGROUND: Little is known about how use of chemotherapy has evolved in breast cancer patients. We therefore describe chemotherapy patterns for women with stage I-IIIA breast cancer in the Optimal Breast Cancer Chemotherapy Dosing (OBCD) Study using data from KPNC (Kaiser Permanente Northern California) and KPWA (Kaiser Permanente Washington). FINDINGS: Among 33,670 women, aged 18 + y, diagnosed with primary stage I-IIIA breast cancer at KPNC and KPWA from 2006 to 2019, we explored patterns of intravenous chemotherapy use, defined here as receipt of intravenous cytotoxic drugs and/or anti-HER2 therapies. We evaluated trends in chemotherapy receipt, duration over which chemotherapy was received, and number of associated infusion visits. In secondary analyses, we stratified by receipt of anti-HER2 therapies (trastuzumab and/or pertuzumab), given their longer duration. 38.9% received chemotherapy intravenously, declining from 40.2% in 2006 to 35.6% in 2019 (p-trend < 0.001). Among 13,089 women receiving chemotherapy, neoadjuvant treatment increased (4.1-14.7%; p-trend < 0.001), as did receipt of anti-HER2 therapies (20.8-30.9%) (p-trend < 0.001). The average treatment duration increased (5.3 to 6.0 months; p-trend < 0.001), as did the number of infusion visits (10.8 to 12.5; p-trend < 0.001). For those receiving anti-HER2 therapies, treatment duration and average number of visits decreased; among those not receiving anti-HER2 therapies, number of visits increased, with no change in duration. CONCLUSIONS: While the prevalence of chemotherapy receipt has decreased over time, the use of neoadjuvant chemotherapy has increased, as has use of anti-HER2 therapies; duration and number of administration visits have also increased. Understanding these trends is useful to inform clinical and administrative planning.

Illuminating the nanostructure of diffuse interfaces: Recent advances and future directions in reflectometry techniques.

Diffuse soft matter interfaces take many forms, from end-tethered polymer brushes or adsorbed surfactants to self-assembled layers of lipids. These interfaces play crucial roles across a multitude of fields, including materials science, biophysics, and nanotechnology. Understanding the nanostructure and properties of these interfaces is fundamental for optimising their performance and designing novel functional materials. In recent years, reflectometry techniques, in particular neutron reflectometry, have emerged as powerful tools for elucidating the intricate nanostructure of soft matter interfaces with remarkable precision and depth. This review provides an overview of selected recent developments in reflectometry and their applications for illuminating the nanostructure of diffuse interfaces. We explore various principles and methods of neutron and X-ray reflectometry, as well as ellipsometry, and discuss advances in their experimental setups and data analysis approaches. Improvements to experimental neutron reflectometry methods have enabled greater time resolution in kinetic measurements and elucidation of diffuse structure under shear or confinement, while innovation in analysis protocols has significantly reduced data processing times, facilitated co-refinement of reflectometry data from multiple instruments and provided greater-than-ever confidence in proposed structural models. Furthermore, we highlight some significant research findings enabled by these techniques, revealing the organisation, dynamics, and interfacial phenomena at the nanoscale. We also discuss future directions and potential advancements in reflectometry techniques. By shedding light on the nanostructure of diffuse interfaces, reflectometry techniques enable the rational design and tailoring of interfaces with enhanced properties and functionalities.

Epidemiology of early vs. Late recurrence among women with Early-Stage estrogen Receptor-Positive breast cancer in the pathways study.

BACKGROUND: Relatively little is known about the differences in prognostic factors for early vs late recurrence among women with early-stage estrogen receptor-positive (ER+) breast cancer. METHODS: We analyzed factors related to early (<5 years) vs late (≥5 years) recurrence in 2,992 women with stage I-IIB ER+ breast cancer in the Pathways Study, a prospective cohort of women with breast cancer enrolled between 2006 and 2013, with ascertainment of recurrence and death through December 2021. RESULTS: After a median follow-up of 13.3 years, 341 (13.8%) women had recurrences, including 181 (53.7%) with late recurrence. Higher stage and grade were associated with recurrence regardless of timing, whereas progesterone receptor (PR) negativity was associated with early but not late recurrence. Receipt of endocrine therapy was associated with reduced risk of overall recurrence, but the length of endocrine therapy was not significant in multivariable models. Minoritized racial and ethnic groups, including Asian, Black, and Hispanic women, had higher risk of early but not late recurrence, compared with non-Hispanic White women. The trend of higher risk of early recurrence among these groups remained after adjustment for clinical, demographic, and socioeconomic factors, but was statistically significant only in Asian women. CONCLUSIONS: Our study revealed potentially important distinctions for early vs late recurrence, including the associations with PR-negativity and self-identified race and ethnicity. Possible higher risk of early recurrence among Asian, Black, and Hispanic women provides novel evidence for the existence of disparities in cancer outcomes, even within the breast cancer subtype indicative of generally good prognosis.

The Influence of Dietary Isothiocyanates on the Effectiveness of Mitomycin C and Bacillus Calmette-Guérin in Treating Nonmuscle-Invasive Bladder Cancer.

PURPOSE: Nonmuscle-invasive bladder cancer (NMIBC) has high recurrence rates and is often treated with mitomycin C (MMC) and bacillus Calmette-Guérin (BCG). Their efficacy relies on phase 2 enzyme metabolism and immune response activation, respectively. Dietary isothiocyanates, phytochemicals in cruciferous vegetables, are phase 2 enzyme inducers and immunomodulators, and may impact treatment outcomes. We investigated the modifying effects of cruciferous vegetable and isothiocyanate intake on recurrence risk following MMC or BCG treatment. MATERIALS AND METHODS: Self-reported cruciferous vegetable intake, estimated isothiocyanate intake, and urinary isothiocyanate metabolites were collected from 1158 patients with incident NMIBC in the prospective Be-Well Study. Hazard ratios (HRs) and 95% CIs were calculated from Cox proportional hazards regression models for risk of first recurrences, and random effects Cox shared frailty models for multiple recurrences. RESULTS: Over median follow-up of 23 months, 343 (30%) recurrences occurred. Receipt of MMC and BCG was associated with decreased risks of first recurrence (MMC: HR = 0.58; 95% CI: 0.46-0.73; BCG: HR = 0.66; 95% CI: 0.49-0.88) and multiple recurrences (MMC: HR = 0.55; 95% CI: 0.44-0.68; BCG: HR = 0.72; 95% CI: 0.55-0.95). Patients receiving BCG and having high intake (>2.4 servings/mo), but not low intake, of raw cruciferous vegetables had reduced risk of recurrence (HR: 0.56; 95% CI: 0.36-0.86; P for interaction = .02) and multiple recurrences (HR: 0.51; 95% CI: 0.34-0.77; P for interaction < .001). The inverse association between MMC receipt and recurrence risk was not modified. CONCLUSIONS: For NMIBC patients who receive induction BCG, increasing consumption of raw cruciferous vegetables could be a promising strategy to attenuate recurrence risk.

Short-term cold exposure induces persistent epigenomic memory in brown fat.

Deficiency of the epigenome modulator histone deacetylase 3 (HDAC3) in brown adipose tissue (BAT) impairs the ability of mice to survive in near-freezing temperatures. Here, we report that short-term exposure to mild cold temperature (STEMCT: 15°C for 24 h) averted lethal hypothermia of mice lacking HDAC3 in BAT (HDAC3 BAT KO) exposed to 4°C. STEMCT restored the induction of the thermogenic coactivator PGC-1α along with UCP1 at 22°C, which is greatly impaired in HDAC3-deficient BAT, and deletion of either UCP1 or PGC-1α prevented the protective effect of STEMCT. Remarkably, this protection lasted for up to 7 days. Transcriptional activator C/EBPß was induced by short-term cold exposure in mouse and human BAT and, uniquely, remained high for 7 days following STEMCT. Adeno-associated virus-mediated knockdown of BAT C/EBPß in HDAC3 BAT KO mice erased the persistent memory of STEMCT, revealing the existence of a C/EBPß-dependent and HDAC3-independent cold-adaptive epigenomic memory.

Relative contribution of COVID-19 vaccination and SARS-CoV-2 infection to population-level seroprevalence of SARS-CoV-2 spike antibodies in a large integrated health system.

BACKGROUND: Understanding the relative contributions of SARS-CoV-2 infection-induced and vaccine-induced seroprevalence is key to measuring overall population-level seroprevalence and help guide policy decisions. METHODS: Using a series of six population-based cross-sectional surveys conducted among persons aged ≥7 years in a large health system with over 4.5 million members between May 2021 and April 2022, we combined data from the electronic health record (EHR), an electronic survey and SARS-CoV-2 spike antibody binding assay, to assess the relative contributions of infection and vaccination to population-level SARS-CoV-2 seroprevalence. EHR and survey data were incorporated to determine spike antibody positivity due to SARS-CoV-2 infection and COVID-19 vaccination. We used sampling and non-response weighting to create population-level estimates. RESULTS: We enrolled 4,319 persons over six recruitment waves. SARS-CoV-2 spike antibody seroprevalence increased from 83.3% (CI 77.0-88.9) in May 2021 to 93.5% (CI 89.5-97.5) in April 2022. By April 2022, 68.5% (CI 61.9-74.3) of the population was seropositive from COVID-19 vaccination only, 13.9% (10.7-17.9) from COVID-19 vaccination and prior diagnosed SARS-CoV-2 infection, 8.2% (CI 4.5-14.5) from prior diagnosed SARS-CoV-2 infection only and 2.9% (CI 1.1-7.6) from prior undiagnosed SARS-CoV-2 infection only. We found high agreement (≥97%) between EHR and survey data for ascertaining COVID-19 vaccination and SARS-CoV-2 infection status. CONCLUSIONS: By April 2022, 93.5% of persons had detectable SARS-CoV-2 spike antibody, predominantly from COVID-19 vaccination. In this highly vaccinated population and over 18 months into the pandemic, SARS-CoV-2 infection without COVID-19 vaccination was a small contributor to overall population-level seroprevalence.

Crystal Structure of Caryolan-1-ol Synthase, a Sesquiterpene Synthase Catalyzing an Initial Anti-Markovnikov Cyclization Reaction.

In a continuing effort to understand reaction mechanisms of terpene synthases catalyzing initial anti-Markovnikov cyclization reactions, we solved the X-ray crystal structure of (+)-caryolan-1-ol synthase (CS) from Streptomyces griseus , with and without an inactive analog of the FPP substrate, 2-fluorofarnesyl diphosphate (2FFPP), bound in the active site of the enzyme. The CS-2FFPP complex was solved to 2.65 Å resolution and showed the ligand in a linear, elongated orientation, incapable of undergoing the initial cyclization event to form a bond between carbons C1 and C11. Intriguingly, the apo CS structure (2.2 Å) also had electron density in the active site, in this case density that was well fit with a curled-up tetraethylene glycol molecule presumably recruited from the crystallization medium. The density was also well fit by a molecule of farnesene suggesting that the structure may mimic an intermediate along the reaction coordinate. The curled-up conformation of tetraethylene glycol was accompanied by dramatic rotamer shifts among active-site residues. Most notably, W56 was observed to undergo a 90° rotation between the 2FFPP complex and apo-enzyme structures, suggesting that it contributes to steric interactions that help curl the tetraethylene glycol molecule in the active site, and by extension perhaps also a derivative of the FPP substrate in the normal course of the cyclization reaction. In support of this proposal, the CS W56L variant lost the ability to cyclize the FPP substrate and produced only the linear terpene products farnesol and α- and ß-farnesene.

Modifying Effects of Genetic Variations on the Association Between Dietary Isothiocyanate Exposure and Non-muscle Invasive Bladder Cancer Prognosis in the Be-Well Study.

SCOPE: Dietary isothiocyanate (ITC) exposure from cruciferous vegetable (CV) intake may improve non-muscle invasive bladder cancer (NMIBC) prognosis. This study aims to investigate whether genetic variations in key ITC-metabolizing/functioning genes modify the associations between dietary ITC exposure and NMIBC prognosis outcomes. METHODS AND RESULTS: In the Bladder Cancer Epidemiology, Wellness, and Lifestyle Study (Be-Well Study), a prospective cohort of 1472 incident NMIBC patients, dietary ITC exposure is assessed by self-reported CV intake and measured in plasma ITC-albumin adducts. Using Cox proportional hazards regression models, stratified by single nucleotide polymorphisms (SNPs) in nine key ITC-metabolizing/functioning genes, it is calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for recurrence and progression. The rs15561 in N-acetyltransferase 1 (NAT1) is alter the association between CV intake and progression risk. Multiple SNPs in nuclear factor E2-related factor 2 (NRF2) and nuclear factor kappa B (NFκB) are modify the associations between plasma ITC-albumin adduct level and progression risk (pint < 0.05). No significant association is observed with recurrence risk. Overall, >80% study participants are present with at least one protective genotype per gene, showing an average 65% reduction in progression risk with high dietary ITC exposure. CONCLUSION: Despite that genetic variations in ITC-metabolizing/functioning genes may modify the effect of dietary ITCs on NMIBC prognosis, dietary recommendation of CV consumption may help improve NMIBC survivorship.

Review article: Contemporary management of gastrointestinal, pancreatic and hepatic toxicities of immune checkpoint inhibitors.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are effective oncologic agents which frequently cause immune-related adverse events (irAEs) which can impact multiple organ systems. Onco-Gastroenterology is a novel and emerging subspecialty within gastroenterology focused on cancer treatment-related complications. Gastroenterologists must be prepared to identify and manage diverse immune-mediated toxicities including enterocolitis, hepatitis, pancreatitis and other ICI-induced toxicities. AIM: To provide a narrative review of the epidemiology, diagnostic evaluation and management of checkpoint inhibitor-induced gastrointestinal and hepatic toxicities. METHODS: We searched Cochrane and PubMed databases for articles published through August 2023. RESULTS: Gastrointestinal and hepatic irAEs include most commonly enterocolitis and hepatitis, but also pancreatitis, oesophagitis, gastritis, motility disorders (gastroparesis) and other rarer toxicities. Guidelines from the National Comprehensive Cancer Network, American Society of Clinical Oncology and European Society for Medical Oncology, in combination with emerging cohort and clinical trial data, offer strategies for management of ICI toxicities. Evaluation of irAEs severity by formal classification and clinical stability, and a thorough workup for alternative etiologies which may clinically mimic irAEs underlie initial management. Treatments include corticosteroids, biologics and other immunosuppressive agents plus supportive care; decisions on dosing, timing and choice of steroid adjuncts and potential for subsequent checkpoint inhibitor dosing are nuanced and toxicity-specific. CONCLUSIONS: Expanding clinical trial and cohort data have clarified the epidemiology and clinical characteristics of gastrointestinal, pancreatic and hepatic toxicities of ICIs. Guidelines, though valuable, remain based principally on retrospective cohort data. Quality prospective, controlled studies may refine algorithms for treatment and potential immunotherapy rechallenge.

Estimating the effects of temperature on transmission of the human malaria parasite, Plasmodium falciparum.

Despite concern that climate change could increase the human risk to malaria in certain areas, the temperature dependency of malaria transmission is poorly characterized. Here, we use a mechanistic model fitted to experimental data to describe how Plasmodium falciparum infection of the African malaria vector, Anopheles gambiae, is modulated by temperature, including its influences on parasite establishment, conversion efficiency through parasite developmental stages, parasite development rate, and overall vector competence. We use these data, together with estimates of the survival of infected blood-fed mosquitoes, to explore the theoretical influence of temperature on transmission in four locations in Kenya, considering recent conditions and future climate change. Results provide insights into factors limiting transmission in cooler environments and indicate that increases in malaria transmission due to climate warming in areas like the Kenyan Highlands, might be less than previously predicted.

Beyond N-Alkylation: Synthesis, Structure, and Function of N-Amino Peptides.

The growing list of physiologically important protein-protein interactions (PPIs) has amplified the need for compounds to target topologically complex biomolecular surfaces. In contrast to small molecules, peptide and protein mimics can exhibit three-dimensional shape complementarity across a large area and thus have the potential to significantly expand the "druggable" proteome. Strategies to stabilize canonical protein secondary structures without sacrificing side-chain content are particularly useful in the design of peptide-based chemical probes and therapeutics.Substitution of the backbone amide in peptides represents a subtle chemical modification with profound effects on conformation and stability. Studies focused on N-alkylation have already led to broad-ranging applications in peptidomimetic design. Inspired by nonribosomal peptide natural products harboring amide N-oxidations, we envisioned that main-chain hydrazide and hydroxamate bonds would impose distinct conformational preferences and offer unique opportunities for backbone diversification. This Account describes our exploration of peptide N-amination as a strategy for stabilizing canonical protein folds and for the structure-based design of soluble amyloid mimics.We developed a general synthetic protocol to access N-amino peptides (NAPs) on solid support. In an effort to stabilize ß-strand conformation, we designed stitched peptidomimetics featuring covalent tethering of the backbone N-amino substituent to the preceding residue side chain. Using a combination of NMR, X-ray crystallography, and molecular dynamics simulations, we discovered that backbone N-amination alone could significantly stabilize ß-hairpin conformation in multiple models of folding. Our studies revealed that the amide NH2 substituent in NAPs participates in cooperative noncovalent interactions that promote ß-sheet secondary structure. In contrast to Cα-substituted α-hydrazino acids, we found that N-aminoglycine and its N'-alkylated derivatives instead stabilize polyproline II (PPII) conformation. The reactivity of hydrazides also allows for late-stage peptide macrocyclization, affording novel covalent surrogates of side-chain-backbone H-bonds.The pronounced ß-sheet propensity of Cα-substituted α-hydrazino acids prompted us to target amyloidogenic proteins using NAP-based ß-strand mimics. Backbone N-amination was found to render aggregation-prone lead sequences soluble and resistant to proteolysis. Inhibitors of Aß and tau identified through N-amino scanning blocked protein aggregation and the formation of mature fibrils in vitro. We further identified NAP-based single-strand and cross-ß tau mimics capable of inhibiting the prion-like cellular seeding activity of recombinant and patient-derived tau fibrils.Our studies establish backbone N-amination as a valuable addition to the peptido- and proteomimetic tool kit. α-Hydrazino acids show particular promise as minimalist ß-strand mimics that retain side-chain information. Late-stage derivatization of hydrazides also provides facile entry into libraries of backbone-edited peptides. We anticipate that NAPs will thus find applications in the development of optimally constrained folds and modulators of PPIs.