Development of a generalized pharmacokinetic model to characterize clinical pharmacokinetics of monomethyl auristatin E-based antibody-drug conjugates.

AIMS: This study aims to develop a generalized pharmacokinetic (PK) model for monomethyl auristatin E (MMAE)-based antibody-drug conjugates (ADCs) that can simultaneously capture the PK of multiple ADC analytes commonly measured in the clinic. METHODS: A comprehensive literature review was conducted to collect PK data on MMAE-based ADCs from clinical trials. From each study, PK profiles of total antibody, the ADC, conjugated MMAE, and unconjugated MMAE, were extracted. These data were pooled and dose-normalized to evaluate the generalizability of PK across various ADCs and dose levels. Upon confirming PK generalizability, a generalized PK model for MMAE-based ADCs was developed using the entire dataset. Furthermore, exposure metrics ( C max and AUC) reported across the range of doses were combined to establish linear relationships between dose and exposure metrics for MMAE-based ADCs. RESULTS: A total of 109 PK profiles from 18 distinct MMAE-based ADCs were gathered. The dose-normalized PK profiles supported the generalizability of PK for MMAE-based ADCs. A generalized PK model was developed, which enabled capturing the PK data for 4 ADC analytes across all collected MMAE-based ADCs. A linear relationship between dose and PK exposure metrics was established, enabling the prediction of typical exposure values across different doses for MMAE-based ADCs. CONCLUSIONS: This study comprehensively analysed clinical PK data from different valine-citrulline (vc)-MMAE-based ADCs. The generalized PK model developed here serves as an important tool for a priori prediction of the PK for multiple ADC analytes in clinical settings and lays the foundation for establishing generalized exposure-response and exposure-toxicity correlations for MMAE-based ADCs.

Aza-Achmatowicz rearrangement coupled with intermolecular aza-Friedel-Crafts enables total syntheses of uleine and aspidosperma alkaloids.

Aspidosperma and uleine alkaloids belong to the large family of monoterpene indole alkaloids with diverse biological activities and thus have attracted extensive synthetic interest. Reported is the development of a new synthetic strategy that allows direct C3-C2' linkage of indoles with functionalized 2-hydroxypiperidines to construct the core common to all aspidoserma and uleine alkaloids. Such indole-piperidine linkage is enabled by coupling aza-Achmatowicz rearrangement (AAR) with indoles via an intermolecular aza-Friedel-Crafts (iAFC) reaction. This AAR-iAFC reaction proceeds under mild acidic conditions with wide tolerance of functional groups (33 examples). The synthetic application of the AAR-iAFC method was demonstrated with collective total syntheses of 3 uleine-type and 6 aspidosperma alkaloids: (+)-3-epi-N-nor-dasycarpidone, (+)-3-epi-dasycarpidone, (+)-3-epi-uleine, 1,2-didehydropseudoaspidospermidine, 1,2-dehydroaspidospermidine, vincadifformine, winchinine B, aspidospermidine, and N-acetylaspidospermidine. We expect that this AAR-iAFC strategy is applicable to other monoterpene indole alkaloids with the C3-C2' linkage of indoles and piperidines.

Comparative effectiveness of non-pharmacological interventions on sleep in individuals with chronic musculoskeletal pain: A systematic review with network meta-analysis.

This network meta-analysis aimed to estimate the comparative effectiveness of non-pharmacological interventions on sleep in individuals with chronic musculoskeletal pain. Seven databases were systematically searched up to February 2023. A random-effects network meta-analysis in a frequentist framework was performed to synthesize continuous data as standardized mean differences (SMD) along with a 95% confidence interval (95% CI). A total of 15,641 records were identified, and 107 randomized controlled trials involving 8,121 participants were included. Of 14 identified interventions, eight were significantly more effective than passive control in improving sleep quality at immediate post-intervention (SMDs = 0.67-0.74), with cognitive behavioral therapy (CBT) being the most effective treatment (SMD = 0.74, 95% CI: 0.45-1.03). Only CBT demonstrated sustained effects at short-term (SMD = 1.56; 95% CI: 0.62-2.49) and mid-term (SMD = 1.23; 95% CI: 0.44-2.03) follow-ups. Furthermore, CBT significantly improved subjective (SMD = 0.64; 95% CI: 0.25-1.03) and objective (SMD = 0.30; 95% CI: 0.01-0.59) sleep efficiency compared with passive control at immediate post-intervention. Our findings support CBT as the first-line treatment for improving sleep in individuals with chronic musculoskeletal pain, given its superior effectiveness across multiple sleep outcomes and its sustainable effects until mid-term follow-up. However, the certainty of evidence for these interventions in improving sleep quality was very low to low.

Does Laterality in Breast Cancer still have the Importance to be Studied? A Meta-analysis of Patients with Breast Cancer.

BACKGROUND: Breast cancer (BC) is one of the most common cancers in the world. Studies show that left-sided BC in pre and post-menopausal women leads to double the risk of worse morbidity and mortality and the reasons are uncertain. Finding the relationship between BC laterality and other possible risk factors can be advantageous for the prognosis of BC. OBJECTIVE: This present study aimed to analyze the relationship between BC laterality and possible risk factors. METHODS: A total of 6089 studies were screened. 23 studies from 1971 to 2021 met the inclusion criteria and were included in the meta-analysis. A pooled relative risk was generated via meta-analysis with a 95% confidence interval. RESULTS: Left-side BC laterality was significant (p < 0.00001) in the women populations compared to the right side based on the pooled size with possible high-risk factors, including handedness, older women, body mass index, people with black skin, invasive type carcinoma, and estrogen receptor-negative BC. These findings suggest that there may be a complex interplay of genetic, environmental, and lifestyle factors that contribute to left-side BC laterality. CONCLUSION: Results suggest an increased rate of BC on the left side, with high-risk factors contributing to BC laterality, which may be useful in predicting prognosis. This study provides significant insights into the relationship between high-risk factors and BC laterality. By identifying potential risk factors associated with left-side BC, it may be possible to improve the ability to predict prognosis and develop more targeted treatment strategies. This information could be particularly useful for healthcare providers and patients, as it may guide decisions regarding screening, prevention, and treatment, ultimately improving patient outcomes and reducing the overall burden of BC.

BiBr3 -Mediated Intramolecular Aza-Prins Cyclization of Aza-Achmatowicz Rearrangement Products: Asymmetric Total Synthesis of Suaveoline and Sarpagine Alkaloids.

An intramolecular aza-Prins cyclization of aza-Achmatowicz rearrangement products was developed in which bismuth tribromide (BiBr3 ) plays a dual role as an efficient Lewis acid and source of the bromide nucleophile. This approach enables the facile construction of highly functionalized 9-azabicyclo[3.3.1]nonanes (9-ABNs), which are valuable synthetic building blocks and a powerful platform for the synthesis of a variety of alkaloid natural products and drug molecules. Suitable substrates for the aza-Prins cyclization include 1,1-disubstituted alkenes, 1,2-disubstituted alkenes, alkynes, and allenes, with good to excellent yields observed. Finally, we showcase the application of this new approach to the enantioselective total synthesis of six indole alkaloids: (-)-suaveoline (1), (-)-norsuaveoline (2), (-)-macrophylline (3), (+)-normacusine B (4), (+)-Na -methyl-16-epipericyclivine (5) and (+)-affinisine (6) in a total of 9-14 steps. This study significantly expands the synthetic utility of the aza-Achmatowicz rearrangement, and the strategy (aza-Achmatowicz/aza-Prins) is expected to be applicable to the total synthesis of other members of the big family of macroline and sarpagine indole alkaloids.

Marine Alkaloid Lepadins E and H Induce Ferroptosis for Cancer Chemotherapy.

Induction of ferroptosis emerges as an effective method for cancer treatment. With massive efforts to elucidate the ferroptosis mechanism, the development of new ferroptosis inducers proceeds rather slowly, with only a few small molecules identified. Herein, we report our discovery of marine alkaloid lepadins E and H as a new class of ferroptosis inducers. Our in vitro studies show that lepadins E and H exhibit significant cytotoxicity, promote p53 expression, increase ROS production and lipid peroxides, reduce SLC7A11 and GPX4 levels, and upregulate ACSL4 expression, all of which consistently support induction of ferroptosis through the classical p53-SLC7A11-GPX4 pathway. Our animal model study of lepadin H confirms its in vivo antitumor efficacy with negligible toxicity to normal organs. This work elucidates the mode of action of lepadins (E and H) and verifies their in vivo efficacy as a new class of ferroptosis inducers for anticancer therapy with translational potential.

INSurVeyor: improving insertion calling from short read sequencing data.

Insertions are one of the major types of structural variations and are defined as the addition of 50 nucleotides or more into a DNA sequence. Several methods exist to detect insertions from next-generation sequencing short read data, but they generally have low sensitivity. Our contribution is two-fold. First, we introduce INSurVeyor, a fast, sensitive and precise method that detects insertions from next-generation sequencing paired-end data. Using publicly available benchmark datasets (both human and non-human), we show that INSurVeyor is not only more sensitive than any individual caller we tested, but also more sensitive than all of them combined. Furthermore, for most types of insertions, INSurVeyor is almost as sensitive as long reads callers. Second, we provide state-of-the-art catalogues of insertions for 1047 Arabidopsis Thaliana genomes from the 1001 Genomes Project and 3202 human genomes from the 1000 Genomes Project, both generated with INSurVeyor. We show that they are more complete and precise than existing resources, and important insertions are missed by existing methods.

Predictors, Mediators and Moderators of Police Work-Related Stress: A Scoping Review.

Owing to the complication in organisation, the dangerous job nature and the rise of demonstrations and protests across the world in the past decade, police work-related stress has become a topic of global concern. This review aimed to provide an understanding of predictors, mediators and moderators of police work-related stress from a multi-level perspective. Using a scoping review approach underpinned by the six-stage methodological framework, studies were found from six electronic databases (MEDLINE, Web of Science, Sociological Abstracts, Scopus, PsycINFO and PsychiatryOnline) and grey literature sources. Thirty studies were yielded across 35,446 participants from 12 locations. This review contributes to a systematic understanding of the factors affecting police work-related stress by identifying six predictors, four mediators and three moderators. It then discusses limitations and future research.

Electrochemical oxidative rearrangement of tetrahydro-ß-carbolines in a zero-gap flow cell.

Oxidative rearrangement of tetrahydro-ß-carbolines (THßCs) is one of the most efficient methods for the synthesis of biologically active spirooxindoles, including natural products and drug molecules. Here, we report the first electrochemical approach to achieve this important organic transformation in a flow cell. The key to the high efficiency was the use of a multifunctional LiBr electrolyte, where the bromide (Br-) ion acts as a mediator and catalyst and lithium ion (Li+) acts as a likely hydrophilic spectator, which might considerably reduce diffusion of THßCs into the double layer and thus prevent possible nonselective electrode oxidation of indoles. Additionally, we build a zero-gap flow cell to speed up mass transport and minimize concentration polarization, simultaneously achieving a high faradaic efficiency (FE) of 96% and an outstanding productivity of 0.144 mmol (h-1 cm-2). This electrochemical method is demonstrated with twenty substrates, offering a general, green path towards bioactive spirooxindoles without using hazardous oxidants.

Work-Family Conflicts, Stress, and Turnover Intention Among Hong Kong Police Officers Amid the COVID-19 Pandemic.

Although work stress, turnover intention, and work-family conflicts among police officers have been extensively investigated, no studies have explored these issues simultaneously under the context of the coronavirus pandemic. Clearly, both work and family domains have been drastically affected by this global health crisis, and it is likely that each domain has a distinctive impact on work outcomes. Using survey data based on a representative random sample of 335 police officers in Hong Kong, this study examines the impacts of resource losses and gains across family and work domains on occupational stress and turnover intention amid the pandemic. A multiple regression indicates that both family-to-work and work-to-family conflicts lead to work stress and turnover intention among police officers. Among officers, supervisory support is negatively associated with turnover intention and moderates the impact of work-to-family conflicts on turnover intention. Finally, measures to mitigate work stress during public health disasters are discussed.

Single-Cell Analysis Reveals Major Histocompatibility Complex II‒Expressing Keratinocytes in Pressure Ulcers with Worse Healing Outcomes.

Pressure ulcer (PU) is a chronic wound often seen in patients with spinal cord injury and other bed-bound individuals, particularly in the elderly population. Despite its association with high mortality, the pathophysiology of PU remains poorly understood. In this study, we compared single-cell transcriptomic profiles of human epidermal cells from PU wound edges with those from uninjured skin and acute wounds in healthy donors. We identified significant shifts in the cell composition and gene expression patterns in PU. In particular, we found that major histocompatibility complex class II‒expressing keratinocytes were enriched in patients with worse healing outcomes. Furthermore, we showed that the IFN-γ in PU-derived wound fluid could induce major histocompatibility complex II expression in keratinocytes and that these wound fluid‒treated keratinocytes inhibited autologous T-cell activation. In line with this observation, we found that T cells from PUs enriched with major histocompatibility complex II+ keratinocytes produced fewer inflammatory cytokines. Overall, our study provides a high-resolution molecular map of human PU compared with that of acute wounds and intact skin, providing insights into PU pathology and the future development of tailored wound therapy.

Midlatency auditory evoked potentials during anesthesia in children: A narrative review.

The brain is considered as the major target organ of anesthetic agents. Despite that, a reliable means to monitor its function during anesthesia is lacking. Mid latency auditory evoked potentials are known to be sensitive to anesthetic agents and might therefore be a measure of hypnotic state in pediatric patients. This review investigates the available literature describing various aspects of mid latency auditory evoked potential monitoring in pediatric anesthesia.

Whole-Body Pharmacokinetics and Physiologically Based Pharmacokinetic Model for Monomethyl Auristatin E (MMAE).

Monomethyl auristatin E (MMAE) is one of the most commonly used payloads for developing antibody-drug conjugates (ADC). However, limited studies have comprehensively evaluated the whole-body disposition of MMAE. Consequently, here, we have investigated the whole-body pharmacokinetics (PK) of MMAE in tumor-bearing mice. We show that while MMAE is rapidly eliminated from the plasma, it shows prolonged and extensive distribution in tissues, blood cells, and tumor. Highly perfused tissues (e.g., lung, kidney, heart, liver, and spleen) demonstrated tissue-to-plasma area under the concentration curve (AUC) ratios > 20, and poorly perfused tissues (e.g., fat, pancreas, skin, bone, and muscle) had ratios from 1.3 to 2.4. MMAE distribution was limited in the brain, and tumor had 8-fold higher exposure than plasma. A physiological-based pharmacokinetic (PBPK) model was developed to characterize the whole-body PK of MMAE, which accounted for perfusion/permeability-limited transfer of drug in the tissue, blood cell distribution of the drug, tissue/tumor retention of the drug, and plasma protein binding. The model was able to characterize the PK of MMAE in plasma, tissues, and tumor simultaneously, and model parameters were estimated with good precision. The MMAE PBPK model presented here can facilitate the development of a platform PBPK model for MMAE containing ADCs and help with their preclinical-to-clinical translation and clinical dose optimization.

The Hexaco-60, the Dark Triad and Scholastic Cheating.

Previous studies have found inconsistent results regarding the personality predictors of scholastic cheating. This study investigated whether personality was a predictor of scholastic cheating using the HEXACO-60 personality inventory and the Dark Triad (DT). A sample of 252 students completed the online questionnaire. Results from a one-way ANOVA showed that scholastic cheating was more common in associate degree/diploma/foundation students and undergraduate students than postgraduate students. Year of study or student status (local or international students) had no effect on scholastic cheating. MANOVA showed that academic qualification, year of study, and student status had no effect on reasons for cheating. A structural equation model (SEM) found that scholastic cheating was positively predicted by unmitigated achievement and psychopathy. Psychopathy emerged as the strongest significant predictor of scholastic cheating. These results supported the view that dark personality is relevant for understanding scholastic cheating.

Monitoring Depth of Hypnosis: Mid-Latency Auditory Evoked Potentials Derived aepEX in Children Receiving Desflurane-Remifentanil Anesthesia.

BACKGROUND: The aepEXplus monitoring system, which uses mid-latency auditory evoked potentials to measure depth of hypnosis, was evaluated in pediatric patients receiving desflurane-remifentanil anesthesia. METHODS: Seventy-five patients, 1-18 years of age (stratified for age; 1-3, 3-6, 6-18 years, for subgroup analyses), were included in this prospective observational study. The aepEX and the bispectral index (BIS) were recorded simultaneously, the latter serving as a reference. The ability of the aepEX to detect different levels of consciousness, defined according to the University of Michigan Sedation Scale, investigated using prediction probability (Pk), and receiver operating characteristic (ROC) analysis, served as the primary outcome parameter. As a secondary outcome parameter, the relationship between end-tidal desflurane and the aepEX and BIS values were calculated by fitting in a nonlinear regression model. RESULTS: The Pk values for the aepEX and the BIS were, respectively, .68 (95% CI, 0.53-0.82) and .85 (95% CI, 0.73-0.96; P = .02). The aepEX and the BIS had an area under the ROC curve of, respectively, 0.89 (95% CI, 0.80-0.95) and 0.76 (95% CI, 0.68-0.84; P = .04). The maximized sensitivity and specificity were, respectively, 81% (95% CI, 61%-93%) and 86% (95% CI, 74%-94%) for the aepEX at a cutoff value of >52, and 69% (95% CI, 56%-81%) and 70% (95% CI, 57%-81%) for the BIS at a cutoff value of >65. The age-corrected end-tidal desflurane concentration associated with an index value of 50 (EC50) was 0.59 minimum alveolar concentration (interquartile range: 0.38-0.85) and 0.58 minimum alveolar concentration (interquartile range: 0.41-0.70) for, respectively, the aepEX and BIS (P = .69). Age-group analysis showed no evidence of a difference regarding the area under the ROC curve or EC50. CONCLUSIONS: The aepEX can reliably differentiate between a conscious and an unconscious state in pediatric patients receiving desflurane-remifentanil anesthesia.

Copy number variation profile in noninvasive prenatal testing (NIPT) can identify co-existing maternal malignancies: Case reports and a literature review.

OBJECTIVE: The coexistence of maternal malignancy and pregnancy has received increasing attention in Noninvasive prenatal testing (NIPT) studies. Malignancy in pregnant women potentially affects the copy number variation (CNV) profile in NIPT results. Only one case of hematologic cancer has been reported in a Hong-Kong pregnant women, and solid tumors have never been reported in pregnant Chinese women. CASE REPORT: The patients with dysgerminoma and cervical cancer showed aberrant chromosomal aneuploidies in NIPT and concordant patterns of genome disruption in tumor tissues. The genomic aberrations in the gastric cancer patient had similar copy number variation pattern of gastric cancer. CONCLUSION: The findings in this study and the literature review further validate the effect of maternal malignancy on the copy number variation profile in NIPT data and strengthen the possibility of detecting malignant tumors with NIPT in the future.

Use, applicability and reliability of depth of hypnosis monitors in children - a survey among members of the European Society for Paediatric Anaesthesiology.

BACKGROUND: To assess the thoughts of practicing anaesthesiologists about the use of depth of hypnosis monitors in children. METHODS: Members of the European Society for Paediatric Anaesthesiology were invited to participate in an online survey about their thoughts regarding the use, applicability and reliability of hypnosis monitoring in children. RESULTS: The survey achieved a response rate of 30% (N = 168). A total of 138 completed surveys were included for further analysis. Sixty-eight respondents used hypnosis monitoring in children (Users) and 70 did not (Non-users). Sixty-five percent of the Users reported prevention of intra-operative awareness as their main reason to apply hypnosis monitoring. Among the Non-users, the most frequently given reason (43%) not to use hypnosis monitoring in children was the perceived lack or reliability of the devices in children. Hypnosis monitoring is used with a higher frequency during propofol anaesthesia than during inhalation anaesthesia. Hypnosis monitoring is furthermore used more frequently in children > 4 years than in younger children. An ideal hypnosis monitor should be reliable for all age groups and any (combination of) anaesthetic drug. We found no agreement in the interpretation of monitor index values and subsequent anaesthetic interventions following from it. CONCLUSIONS: Prevention of intraoperative awareness appears to be the most important reason to use hypnosis monitoring in children. The perceived lack of reliability of hypnosis monitoring in children is the most important reasons not to use it. No consensus currently exists on how to adjust anaesthesia according to hypnosis monitor index values in children.

A reciprocal relationship between reactive oxygen species and mitochondrial dynamics in neurodegeneration.

Mitochondrial fragmentation due to fission/fusion imbalance has often been linked to mitochondrial dysfunction and apoptosis in neurodegeneration. Conventionally, it is believed that once mitochondrial morphology shifts away from its physiological tubular form, mitochondria become defective and downstream apoptotic signaling pathways are triggered. However, our study shows that beta-amyloid (Aß) induces morphological changes in mitochondria where they become granular-shaped and are distinct from fragmented mitochondria in terms of both morphology and functions. Accumulation of mitochondrial reactive oxygen species triggers granular mitochondria formation, while mitoTEMPO (a mitochondria-targeted superoxide scavenger) restores tubular mitochondrial morphology within Aß-treated neurons. Interestingly, modulations of mitochondria fission and fusion by genetic and pharmacological tools attenuated not only the induction of granular mitochondria, but also mitochondrial superoxide levels in Aß-treated neurons. Our study shows a reciprocal relationship between mitochondrial dynamics and reactive oxygen species and provides a new potential therapeutic target at early stages of neurodegenerative disease pathogenesis.

Physical inactivity is a strong risk factor for stroke in the oldest old: Findings from a multi-ethnic population (the Northern Manhattan Study).

Background The fastest growing segment of the population is those age ≥80 who have the highest stroke incidence. Risk factor management is complicated by polypharmacy-related adverse events. Aims To characterize the impact of physical inactivity for stroke by age in a multi-ethnic prospective cohort study (NOMAS, n = 3298). Methods Leisure time physical activity was assessed by a validated questionnaire and our primary exposure was physical inactivity (PI). Participants were followed annually for incident stroke. We fit Cox-proportional hazard models to calculate hazard ratios and 95% confidence intervals (HR 95% CI) for the association of PI and other risk factors with risk of stroke including two-way interaction terms between the primary exposures and age (<80 vs. ≥80). Results The mean age was 69 ± 10.3 years and 562 (17%) were ≥80 at enrolment. PI was common in the cohort (40.8%). Over a median of 14 years, we found 391 strokes. We found a significant interaction of age ≥80 on the risk of stroke with PI ( p = 0.03). In stratified models, PI versus any activity (adjusted HR 1.60, 95%CI 1.05-2.42) was associated with an increased risk of stroke among those ≥80. Conclusion Physical inactivity is a treatable risk factor for stroke among those older than age 80. Improving activity may reduce the risk of stroke in this segment of the population.

Leisure-time physical activity associates with cognitive decline: The Northern Manhattan Study.

OBJECTIVE: Because leisure-time physical activity (LTPA) is protective against incident dementia, we hypothesized that LTPA is protective against decline in domain-specific cognitive performance. METHODS: As part of the Northern Manhattan Study, LTPA was ascertained at enrollment using a validated in-person questionnaire. We assessed cognition in participants in the Northern Manhattan Study MRI substudy using a standard neuropsychological examination (NPE) (n = 1,228), and a repeat examination was performed 5 years later (n = 876). LTPA was summarized as the maximum intensity of any activity performed, classified as none to light intensity (physical inactivity) (90%) vs moderate to heavy intensity (10%). The NPE was subcategorized using standardized z scores over validated domains: processing speed, semantic memory, episodic memory, and executive function. We used multivariable linear regression models to examine the association of LTPA with initial and change in cognitive performance. Analyses were adjusted for sociodemographics, cardiovascular disease risk factors, and MRI findings (white matter hyperintensity volume, silent brain infarcts, cerebral volume). RESULTS: No/low levels of LTPA were associated with worse executive function, semantic memory, and processing speed scores on the first NPE. The associations were slightly attenuated and no longer significant after adjusting for vascular risk factors. Cognitively unimpaired participants reporting no/low LTPA vs moderate/high levels declined more over time in processing speed (ß = -0.231 ± 0.112, p = 0.040) and episodic memory (ß = -0.223 ± 0.117, p = 0.057) adjusting for sociodemographic and vascular risk factors. CONCLUSIONS: A low level of LTPA is independently associated with greater decline in cognitive performance over time across domains.