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Synthetic organic electrochemistry is recognized as one of the most sustainable forms of redox chemistry that can enable a wide variety of useful transformations. In this study, readily prepared pyrolytic carbon electrodes are explored in several powerful rAP transformations as well as C-C and C-N bond forming reactions. Pyrolytic carbon provides an alternative to classic amorphous carbon-based materials that are either expensive or ill-suited to large-scale flow reactions., (© 2024 Wiley‐VCH GmbH.)

Purpose: In this study, we aimed to develop an application that computes dose values resembling diagnostic reference level (DRL) conditions when disparity prevents direct dose comparisons between the national diagnostic reference levels in Japan 2020 (Japan DRLs_2020) and facility-specific computed tomography (CT) protocols., Methods: We developed an application using the R programming language and RStudio software that computes dose values and median values based on Japan DRLs_2020 imaging conditions following extraction of necessary information for dose calculations from the Radiation Dose Structured Report (RDSR) and Digital Imaging and Communications in Medicine (DICOM) tags. To ensure a user-friendly experience, we used the Shiny package to develop a graphical user interface that enables the application to operate seamlessly in web browsers., Results: The developed application successfully facilitated the calculation of dose and median values that aligned with the Japan DRLs_2020 for protocols whose imaging range and acquisition timing differed from those of the Japan DRLs_2020., Conclusion: By calculating dose values that align with DRL conditions, our application contributes to the implementation and optimization of dose management in CT for facilities that use diverse imaging protocols.

Electrolysis integrates renewable energy into chemical manufacturing and is key to sustainable chemistry. Controlling the waveform beyond direct current (DC) addresses the long-standing obstacle of chemoselectivity, yet it also expands the parameter set to optimize, creating a demand for theoretical predictions. Here, we report the first analytical theory for predicting chemoselectivity in an alternating current (AC) electrosynthesis. The mechanism is a selective reversal of the unwanted redox reaction during periods of opposite polarity, reflected in the final reaction outcome as a time-averaged effect. In the ideal scenario of all redox reactions being reversible, square AC waveform biases the outcome toward more overoxidation/over-reduction, whereas sine AC waveform exhibits the opposite effect. However, in a more realistic scenario of some redox reactions being quasi-reversible, sine AC may behave mostly like square AC. These predictions are in numerical agreement with model experiments employing acetophenone and align qualitatively with the literature precedent. Collectively, this study provides theoretical proof for a growing trend that promotes changing waveforms to overcome limitations challenging to address by varying canonical electrochemical parameters.

Background: Risk factors for alcohol withdrawal delirium include heavy drinking, prior alcohol withdrawal delirium or convulsions, nondrug sedative use, and a history of tachycardia, withdrawal, and infections., Case Presentation: A 76-year-old man with a history of heavy drinking and type 2 diabetes was hospitalized for hypothermia, rhabdomyolysis, and acute renal failure after a typhoon. He developed alcohol withdrawal symptoms 24 h after his last drink, leading to severe withdrawal delirium characterized by restlessness, delusions, and altered consciousness. Treatment included lorazepam, in addition to comprehensive care for his physical condition. His condition fluctuated, especially at night, with his psychiatric symptoms exacerbated by his physical illnesses, suggesting delirium due to the coexistence of severe and multiple physical illnesses. After 44 days, following substantial improvements in both mental and physical health with perospirone, the patient was discharged., Conclusion: This case emphasizes the need for multidisciplinary collaboration in the treatment of such patients, especially during disasters, and the importance of long-term monitoring for elderly patients with alcohol dependence syndrome after a disaster., (© 2024 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Neuropsychopharmacology.)

Electrophilic halogenation is a widely used tool employed by medicinal chemists to either pre-functionalize molecules for further diversity or incorporate a halogen atom into drugs or drug-like compounds to solve metabolic problems or modulate off-target effects. Current methods to increase the power of halogenation rely on either the invention of new reagents or activating commercially available reagents with various additives such as Lewis or Brønsted acids, Lewis bases and hydrogen-bonding activators. There is a high demand for new reagents that can halogenate otherwise unreactive compounds under mild conditions. Here we report the invention of a class of halogenating reagents based on anomeric amides, taking advantage of the energy stored in the pyramidalized nitrogen of N-X anomeric amides as a driving force. These robust halogenating methods are compatible with a variety of functional groups and heterocycles, as exemplified on over 50 compounds (including 13 gram-scale examples and 1 flow chemistry scale-up)., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

A sustainable society requires high-energy storage devices characterized by lightness, compactness, a long life and superior safety, surpassing current battery and supercapacitor technologies. Single-walled carbon nanotubes (SWCNTs), which typically exhibit great toughness, have emerged as promising candidates for innovative energy storage solutions. Here we produced SWCNT ropes wrapped in thermoplastic polyurethane elastomers, and demonstrated experimentally that a twisted rope composed of these SWCNTs possesses the remarkable ability to reversibly store nanomechanical energy. Notably, the gravimetric energy density of these twisted ropes reaches up to 2.1 MJ kg -1 , exceeding the energy storage capacity of mechanical steel springs by over four orders of magnitude and surpassing advanced lithium-ion batteries by a factor of three. In contrast to chemical and electrochemical energy carriers, the nanomechanical energy stored in a twisted SWCNT rope is safe even in hostile environments. This energy does not deplete over time and is accessible at temperatures ranging from -60 to +100 °C., (© 2024. The Author(s).)

Aim: There is limited evidence regarding predictors of changes in suicidal ideation (SI) in patients with major depressive disorder (MDD). The objective of this study was to describe changes in SI over a 6-month period and identify their predictors from naturalistic observations of MDD patients., Methods: In the cross-sectional analysis, we examined 257 patients with MDD at the first-visit assessment. Among the patients, 119 who completed the 6-month assessment (completers) were included in the longitudinal analysis. For the evaluation of depressive symptoms, including SI, the Quick Inventory of Depressive Symptomatology-Japanese version was administered at both the first-visit and follow-up assessments. At baseline, we also administered the Japanese version of the Ten Item Personality Inventory to assess personality traits and the PRIME Screen-Revised to assess psychotic symptoms., Results: In the cross-sectional analysis of first-visit patients, 36.2% (93/257) exhibited SI. Among completers, 14.3% (17/119) had prolonged SI. Among the completers with SI at the first-visit assessment, 38.6% (17/44) had SI at the follow-up assessment (prolonged SI). In linear regression models including all completers, prolonged SI was positively associated with endorsement of suspiciousness/persecutory ideas and negatively associated with higher age., Conclusion: More than one-third of completers who had SI at the first-visit assessment experienced prolonged SI (SI at follow-up). Our findings can help clinicians predict the course of MDD by identifying associated demographic and clinical characteristics., (© 2024 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Neuropsychopharmacology.)

Background: Vortioxetine, known for its efficacy in treating depression through its effects on various neurotransmitters, has not been previously reported to induce syndrome of inappropriate secretion of antidiuretic hormone (SIADH)., Case Presentation: This case report describes a 74-year-old man with major depressive disorder who developed SIADH 1 week after starting treatment with vortioxetine. SIADH is characterized by symptoms such as headache, nausea, disorientation, and seizures, stemming from hyponatremia (123 mEq/L), without dehydration or edema. Vortioxetine was discontinued, and an alternative drug, mianserin, was initiated. The patient was restricted from drinking water due to hyponatremia. The serum Na concentration improved over time to within the normal range by the second week after admission., Conclusion: This is the first case report of vortioxetine-induced SIADH., (© 2024 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Neuropsychopharmacology.)

C-C linked glutarimide-containing structures with direct utility in the preparation of cereblon-based degraders (PROTACs, CELMoDs) can be assessed in a single step from inexpensive, commercial α-bromoglutarimide through a unique Brønsted-acid assisted Ni-electrocatalytic approach. The reaction tolerates a broad array of functional groups that are historically problematic and can be applied to the simplified synthesis of dozens of known compounds that have only been procured through laborious, wasteful, multi-step sequences. The reaction is scalable in both batch and flow and features a trivial procedure wherein the most time-consuming aspect of reaction setup is weighing out the starting materials., (© 2024 Wiley‐VCH GmbH.)

The synthesis of quaternary carbons often requires numerous steps and complex conditions or harsh reagents that act on heavily engineered substrates. This is largely a consequence of conventional polar-bond retrosynthetic disconnections that in turn require multiple functional group interconversions, redox manipulations, and protecting group chemistry. Here, we report a simple catalyst and reductant combination that converts two types of feedstock chemicals, carboxylic acids and olefins, into tetrasubstituted carbons through quaternization of radical intermediates. An iron porphyrin catalyst activates each substrate by electron transfer or hydrogen atom transfer, and then combines the fragments using a bimolecular homolytic substitution (S H 2) reaction. This cross-coupling reduces the synthetic burden to procure numerous quaternary carbon---containing products from simple chemical feedstocks.

Chiral aminoalcohols are omnipresent in bioactive compounds. Conventional strategies to access this motif involve multiple-step reactions to install the requisite functionalities stereoselectively using conventional polar bond analysis. This study reveals that a simple chiral oxazolidine-based carboxylic acid can be readily transformed to substituted chiral aminoalcohols with high stereochemical control by Ni-electrocatalytic decarboxylative arylation. This general, robust, and scalable coupling can be used to synthesize a variety of medicinally important compounds, avoiding protecting and functional group manipulations, thereby dramatically simplifying their preparation.

Background: Constipation is a common adverse effect of antipsychotics, but little investigation has been conducted. We aimed to address the factors associated with the initiation of laxative use in the same patients with schizophrenia over a 20-year period., Methods: We enrolled patients with schizophrenia attending each hospital (n = 14) from April 1, 2021, and retrospectively examined all prescriptions as of April 1, 2016, 2011, 2006, and 2001, every 5 years starting in 2021, for this population. 716 participants with complete data were included in the analysis. The Cochran Q test followed by Bonferroni correction and the Cochran-Armitage trend test were used to determine the differences and trends of the frequency of each laxative. Multivariate logistic regression analysis was performed to assess the factors on the initiation of laxative use over a 20-year period., Results: Of the patients, 25.1% were treated with laxatives in 2001, and 34.1% were treated in 2021. The numbers of patients treated with any laxatives significantly differed over the 20-year period, with a significant increasing trend. In all laxatives, the numbers of patients treated with magnesium oxide, lubiprostone and elobixibat differed with a significant increasing trend. Female sex, age, the total DZP equivalent dose, and the doses of levomepromazine maleate, olanzapine, quetiapine, zotepine, lithium, and carbamazepine in 2021 were significant factors associated with the initiation of laxative use over the 20-year period., Conclusions: Careful monitoring is needed for patients treated with levomepromazine maleate, olanzapine, quetiapine and zotepine. Optimizing prescriptions according to treatment guidelines could reduce antipsychotic-induced constipation., (© 2023 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Neuropsychopharmacology.)

Context: Tramadol is conditionally recommended for cancer pain and is a less expensive drug compared to strong opioids. Thus, tramadol may help reduce health care costs., Objectives: To investigate factors that predict the clinical efficacy of tramadol for cancer pain., Methods: A retrospective study using electronic medical records was conducted on patients who received tramadol for cancer pain from January 2016 to December 2020. Patients who continued tramadol for >28 days or discontinued tramadol before 28 days owing to pain improvement were considered as clinical efficacy cases., Results: We identified 183 eligible patients; 104 cases had clinical efficacy. The median starting tramadol daily dose was 100 mg, and the median administration duration was 22 days. Overall, 169 patients (92.3%) discontinued tramadol; pain improvement was the most common reason (34.9%). Age (>70 years), a performance status of 0-1, and an albumin-bilirubin grade of 1 were independent predictors for the clinical efficacy of tramadol. Patients with multiple predictors had significantly higher achievement rates than those without., Conclusion: Tramadol could have greater clinical efficacy for cancer pain in patients who are elderly, have good performance status, and have good liver function., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Aim: This study examined the collective characteristics of nurses and their stress coping style., Methods: We conducted a cluster analysis of the stress coping strategies of 841 nurses belonging to Dokkyo Medical University Hospital, as measured by the Brief COPE (Coping Orientation to Problems Experienced). We also conducted multivariate analyses of each cluster's sociodemographic characteristics, personality traits, depressive symptoms, work attitudes, sense of fairness, and turnover intention., Results: The results of cluster analysis using the standardized z scores of the Brief COPE demonstrated that the study participants were classified into three clusters. The "emotional-response type" tended to favor the use of emotional support, venting, and self-blame. The "reality-escape type" tended to prefer alcohol and substance use, behavioral resignation, use of instrumental support, and lack of acceptance. The "problem-solving type" tended to prefer planning, positive reframing, and acceptance and to dislike "alcohol and substance use" and behavioral disengagement. A multinomial logistic regression analysis revealed that compared to the problem-solving type, the emotional-response type had a lower job title, a higher "neuroticism" score on the TIPI-J, and a higher K6 score. However, compared to the problem-solving type, the reality-escape type was younger, consumed more alcohol and substances, and had a higher K6 score., Conclusions: Stress coping styles were found to be associated with substance use, depressive symptoms, and personality traits among nurses in higher education institutions. Thus, the results suggest that nurses who choose maladaptive stress coping styles require mental support and early identification of depressive symptoms and alcohol problems., (© 2023 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Neuropsychopharmacology.)

Modern retrosynthetic analysis in organic chemistry is based on the principle of polar relationships between functional groups to guide the design of synthetic routes 1 . This method, termed polar retrosynthetic analysis, assigns partial positive (electrophilic) or negative (nucleophilic) charges to constituent functional groups in complex molecules followed by disconnecting bonds between opposing charges 2-4 . Although this approach forms the basis of undergraduate curriculum in organic chemistry 5 and strategic applications of most synthetic methods 6 , the implementation often requires a long list of ancillary considerations to mitigate chemoselectivity and oxidation state issues involving protecting groups and precise reaction choreography 3,4,7 . Here we report a radical-based Ni/Ag-electrocatalytic cross-coupling of substituted carboxylic acids, thereby enabling an intuitive and modular approach to accessing complex molecular architectures. This new method relies on a key silver additive that forms an active Ag nanoparticle-coated electrode surface 8,9 in situ along with carefully chosen ligands that modulate the reactivity of Ni. Through judicious choice of conditions and ligands, the cross-couplings can be rendered highly diastereoselective. To demonstrate the simplifying power of these reactions, concise syntheses of 14 natural products and two medicinally relevant molecules were completed., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

A mild, scalable (kg) metal-free electrochemical decarboxylation of alkyl carboxylic acids to olefins is disclosed. Numerous applications are presented wherein this transformation can simplify alkene synthesis and provide alternative synthetic access to valuable olefins from simple carboxylic acid feedstocks. This robust method relies on alternating polarity to maintain the quality of the electrode surface and local pH, providing a deeper understanding of the Hofer-Moest process with unprecedented chemoselectivity., (© 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Aim: Patients with autism spectrum disorder (ASD) are prone to develop overt psychosis and share symptom presentations with those with schizophrenia (SZ). This study aimed to explore differences in the distributions of psychotic symptoms among first-visit patients with ASD, SZ, or a nonpsychiatric diagnosis (N-PD)., Methods: Data from first-visit patients were retrospectively collected from medical records from the Department of Psychiatry, Dokkyo Medical University Hospital between June 2019 and May 2021. A total of 254 patients with data on the PRIME Screen-Revised (PS-R) assessments were included in our analysis. In the hospital, all psychiatric diagnoses were based on the DSM-5 diagnostic criteria., Results: In the ASD, SZ, and N-PD groups, endorsements of perplexity and delusional mood were 15.6% (7/45), 41.5% (44/106), and 1.1% (1/88), and those of perceptual abnormalities were 11.1% (5/45), 40.6% (43/106), and 2.3% (2/88), respectively. Trend analysis clarified that the endorsement of these psychotic symptoms increased from N-PD to ASD and SZ. In the multivariate-adjusted multinomial logistic regression analysis, the ASD and N-PD groups were compared with the SZ group. Higher age and the presence of perceptual abnormalities were associated with lack of an ASD diagnosis, whereas male sex, lack of perplexity and delusional mood, and lack of perceptual abnormalities were associated with N-PD., Conclusion: Our results are preliminary; however, a detailed assessment of positive symptoms might facilitate differentiation between ASD and SZ., (© 2023 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Neuropsychopharmacology.)

Target identification involves deconvoluting the protein target of a pharmacologically active, small-molecule ligand, a process that is critical for early drug discovery yet technically challenging. Photoaffinity labelling strategies have become the benchmark for small-molecule target deconvolution, but covalent protein capture requires the use of high-energy ultraviolet light, which can complicate downstream target identification. Thus, there is a strong demand for alternative technologies that allow for controlled activation of chemical probes to covalently label their protein target. Here we introduce an electroaffinity labelling platform that leverages the use of a small, redox-active diazetidinone functional group to enable chemoproteomic-based target identification of pharmacophores within live cell environments. The underlying discovery to enable this platform is that the diazetidinone can be electrochemically oxidized to reveal a reactive intermediate useful for covalent modification of proteins. This work demonstrates the electrochemical platform to be a functional tool for drug-target identification., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

The first practical, fully stereoselective P(V)-radical hydrophosphorylation is presented herein by using simple, limonene-derived reagent systems. A set of reagents have been developed that upon radical initiation react smoothly with olefins and other radical acceptors to generate P -chiral products, which can be further diversified (with conventional 2e - chemistry) to a range of underexplored bioisosteric building blocks. The reactions have a wide scope with excellent chemoselectivity, and the unexpected stereochemical outcome has been supported computationally and experimentally. Initial ADME studies are suggestive of the promising properties of this rarely explored chemical space.

Purpose: Immune checkpoint inhibitors (ICI) ushered in a new era for the treatment of non-small cell lung cancer (NSCLC). However, they carry the risk of immune-related adverse events (irAEs). Recently, various studies have been conducted on the predictive factors for irAEs, but there are no reports focusing only on ICI plus platinum agents. The present study aimed to identify the risk factors for irAEs due to ICI combined with platinum-based induction immunochemotherapy in NSCLC patients, focusing only on the period of combined therapy and excluding the period of ICI maintenance therapy., Methods: This retrospective study included 315 NSCLC patients who started ICI combined with platinum-based chemotherapy treatment at 14 hospitals between December 2018 and March 2021. A logistic regression analysis was used to explore the predictive factors., Results: Fifty patients (15.9%) experienced irAEs. A multivariate analysis revealed that squamous cell carcinoma (P = 0.021; odds ratio [OR]: 2.30; 95% confidence interval [Cl]: 1.14-4.65), anti-programmed death 1 antibody (anti-PD-1) plus anti-cytotoxic T-lymphocyte antigen-4 antibody (anti-CTLA-4) regimens (P < 0.01; OR: 22.10; 95% Cl: 5.60-87.20), and neutrophil-to-lymphocyte rate (NLR) < 3 (P < 0.01; OR: 2.91; 95% Cl: 1.35-6.27) were independent predictive factors for irAEs occurrence., Conclusion: Squamous cell carcinoma, anti-PD-1 plus anti-CTLA-4 regimens, and NLR < 3 may be predictive factors for the occurrence of irAEs due to induction immunochemotherapy in patients with NSCLC. By focusing on the potential risk of irAEs in patients with these factors, irAEs can be appropriately managed from an early stage., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Low health literacy has been associated with adverse outcomes in health maintenance and the course of chronic physical illness. In particular, anxiety disorders can also affect one's physical health, causing issues including cardiovascular, respiratory, gastrointestinal and immune system disorders. However, there are no reports on physical health literacy among Japanese patients with mental illness., Patients and Methods: A patient background questionnaire, the Japanese version of the Ten-Item Personality Inventory, and the Japanese version of the Health Literacy Scale (HLS-EU-Q47; European Health Literacy Survey Questionnaire) were distributed face to face to 1000 psychiatric outpatients. A total of 785 valid responses including 211 patients with schizophrenia, 261 patients with mood disorders, and 234 patients with anxiety disorders were obtained by mail., Results: Health literacy was "limited" in 52% of patients with schizophrenia, 51% of those with mood disorders, and 38% of those with anxiety disorders. Among patients with mood disorders, there were no differences between those with major depressive disorder and those with bipolar disorder. Anxiety disorders were associated with higher health literacy than schizophrenia and mood disorders (odds ratio (OR) 1.85, 95% confidence interval (95% CI) 1.07, 3.34), and in terms of personality, neuroticism (OR 0.85, 95% CI 0.75, 0.97) and openness (OR 0.85, 95% CI 0.74, 0.98) were associated with limited health literacy, while agreeableness (OR 1.36, 95% CI 1.18, 1.57) and extraversion OR 1.34, 95% CI 1.17, 1.52) were associated with higher health literacy., Conclusion: The results of this study indicate limited health literacy in patients with mental illness, in particular, limited health literacy in outpatients with schizophrenia and mood disorders. In addition, gender and some personality traits were associated with physical health literacy. Based on these results, physical health education should be individualized., Competing Interests: Dr Norio Yasui-Furukori reports grants from Mochida Pharmaceutical, Yoshitomi Yakuhin, grants from Tsumura, Mitsubishi-Sumitomo Pharmaceutical, Otsuka Pharmaceutical, Viatris Pharmaceutical and from Takeda Pharmaceutical, outside the submitted work. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Sato et al.)

Background: Recent pharmacoepidemiology data show an increase in the proportion of patients receiving second-generation antipsychotic (SGA) monotherapy, but no studies have analyzed the same patients over a long period of time. Therefore, in this study, we retrospectively evaluated schizophrenia patients with available data for 20 years to determine whether the drug treatments in the same patients have changed in the past 20 years., Methods: The study began in April 2021 and was conducted in 15 psychiatric hospitals in Japan. Schizophrenia patients treated in the same hospital for 20 years were retrospectively examined for all prescriptions in 2016, 2011, 2006, and 2001 (ie, every 5 years)., Results: The mean age of the 716 patients surveyed in 2021 was 61.7 years, with 49.0% being female. The rate of antipsychotic monotherapy use showed a slight increasing trend over the past 20 years; the rate of SGA use showed a marked increasing trend from 28.9% to 70.3% over the past 20 years, while the rate of SGA monotherapy use showed a gradual increasing trend over the past 20 years. The rates of concomitant use of anticholinergics, antidepressants, anxiolytics/sleep medications, and mood stabilizers showed decreasing, flat, flat, and flat trends over the past 20 years, respectively., Conclusion: The results of this study showed a slow but steady substitution of SGAs for first-generation antipsychotics (FGAs) over time, even in the same patients., Competing Interests: Dr. Kensuke Miyazaki reports personal fees from Sumitomo Dainippon Pharma Co., Ltd., outside the submitted work. Professor Kazutaka Shimoda reports grants from Novartis Pharma KK, Dainippon Sumitomo Pharma Co., Astellas Pharma Inc., Meiji Seika Pharma Co., Ltd., Eisai Co., Ltd., Pfizer Inc., Otsuka Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Takeda Pharmaceutical Co., Ltd.; personal fees from Eisai Co., Ltd, Mitsubishi Tanabe Pharma Corporation, Takeda Pharmaceutical Co., Ltd., Meiji Seika Pharma Co., Ltd., Janssen Pharmaceutical Co., Shionogi & Co. Ltd., Dainippon Sumitomo Pharma Co., Daiichi Sankyo Co., and Pfizer Inc., outside the submitted work. The remaining authors report no other conflicts of interest in this work., (© 2023 Yasui-Furukori et al.)

The Kolbe reaction forms carbon-carbon bonds through electrochemical decarboxylative coupling. Despite more than a century of study, the reaction has seen limited applications owing to extremely poor chemoselectivity and reliance on precious metal electrodes. In this work, we present a simple solution to this long-standing challenge: Switching the potential waveform from classical direct current to rapid alternating polarity renders various functional groups compatible and enables the reaction on sustainable carbon-based electrodes (amorphous carbon). This breakthrough enabled access to valuable molecules that range from useful unnatural amino acids to promising polymer building blocks from readily available carboxylic acids, including biomass-derived acids. Preliminary mechanistic studies implicate the role of waveform in modulating the local pH around the electrodes and the crucial role of acetone as an unconventional reaction solvent for Kolbe reaction.

A seemingly minor change to a reactant is shown to cause a change in reaction mechanisms. Conjugate addition of organocopper reagents to bicyclic α,β-unsaturated lactams derived from pyroglutaminol is determined by the nature of the aminal group. Aminals derived from aldehydes give anti addition; those from ketones give syn addition. Divergence in diastereoselection occurs because the substrates react by different mechanisms, ultimately due to a small but significant difference in pyramidalization of the aminal nitrogen.

Indonesians face serious health issues that arise from malnutrition, particularly in children who are under unfavorable dietary environments. The present study established a school meal program consisting of dietary and educational interventions and evaluated its impact on promoting continuous improvement in dietary behavior among junior and senior high school students in Indonesia. A total of 319 students belonging to an Islamic Boarding School participated in the pre-post intervention study for 9 months. All participants were assessed based on their Knowledge, Attitude, and Practice (KAP). A subgroup of 115 participants who were anemic and underweight was examined for dietary intake, nutrition status, and hemoglobin level. The KAP test scores for both nutrition and hygiene showed a significant increase for all students and the undernutrition group post-intervention. Protein, iron, and vitamin C intake significantly improved. Although there were no significant improvements in nutrition status, there was a significant increase in the hemoglobin level and a reduction in the prevalence of anemia from 42.6% to 21.7%. Thus, school meal program that combines dietary and educational interventions may effectively improve anemia in undernourished students as well as enhance the knowledge, attitudes, and practices related to health, nutrition, and hygiene in junior and senior high school students.

Aim: Nurses are an essential human resource for the healthcare system. However, high turnover of nurses is a current issue. Reducing the high turnover of nurses is crucial for facilitating the sustainable provision of care in hospitals. The purpose of this study was to explore the factors affecting nurses' intentions to leave among nurses in an advanced medical center., Methods: Using a cross-sectional design, we conducted a questionnaire survey of nurses working at an academic medical center in August 2020. Of the 1063 distributed questionnaires, there were 821 (77.2%) valid responses. The questionnaire included items on the Kessler 6 (K6), New Brief Job Stress Questionnaire (New BJSQ), Organizational Justice Questionnaire (OJQ), and intention to leave a hospital job., Results: Overall, the mean age of the nurses was 34.3 ± 10.1 years and 87.8% (721/821) of them were female. Among respondents, 19.5% (160/821) had a strong intention to leave. After adjusting for all the variables, a logistic regression analysis revealed that longer working hours, job rank (staff nurse), work-self-balance positive (imbalance), workplace harassment (no bullying), and interactional justice (unfair supervisor) were determinants associated with strong intentions to leave., Conclusions: Approximately one-fifth of nurses working at advanced medical center had a strong intention to leave. However, our findings can help managers predict the turnover of nurses by understanding occupational characteristics. Managing work-self-balance and treating staff fairly could improve work environments. Further research focusing on the outcome of actual turnover rather than intention to leave is needed., Competing Interests: Kazutaka Shimoda has received research support from Novartis Pharma, Dainippon Sumitomo Pharma, Astellas Pharma, Meiji Seika Pharma, Eisai, Pfizer, Otsuka Pharmaceutical, Daiichi Sankyo, and Takeda Pharmaceutical and honoraria from Eisai, Mitsubishi Tanabe Pharma, Takeda Pharmaceutical, Meiji Seika Pharma, Janssen Pharmaceutical, Shionogi, Dainippon Sumitomo Pharma, Daiichi Sankyo, and Pfizer. The remaining authors declare no conflict of interest., (© 2022 The Authors. Psychiatry and Clinical Neurosciences Reports published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology.)

Aim: Balancing between personal and working life of nurses is important to increase their job satisfaction and to continue their careers. Our purpose was to investigate the relationship between nurses and work-self balance (WSB) at different phases of life, such as age, marriage and raising children, and the occupational factors that influence WSB that can be used to improve the work environment for nurses., Methods: Using a self-administered questionnaire, we asked about gender, age, marital status, presence of children, working hours, and night shift. Occupational stresses, including WSB, were assessed with the New Brief Job Stress Questionnaire (New BJSQ) and the Organizational Justice Questionnaire (OJQ). The total number of unmarried and married respondents was 819. We investigated whether marital status and cohabiting children make a difference in WSB in the three age groups (less than 30 years, 31-40 years, and more than 41 years) using a Mann-Whitney U test. In addition, we examined occupational factors affecting WSB using multiple regression analysis., Results: The value of WSB negative was significantly greater in the group of married persons than in the group of unmarried persons ( p  < 0.05) and was significantly greater in the group with cohabiting children than in the group without cohabiting children ( p  < 0.01) only in the group aged 31-40 years. Multiple regression analysis indicated that significant occupational factors affecting WSB differed by each age group., Conclusion: This survey showed that the factors and degree of WSB vary according to the generation and family environment of nurses., Competing Interests: The authors declare no conflict of interest.N/A, (© 2022 The Authors. Psychiatry and Clinical Neurosciences Reports published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology.)

Background: Childbearing-aged female patients and elderly patients with bipolar disorder need special attention for pharmacological treatments, but current guidelines provide little information on their pharmacological treatment. In particular, the risk/benefit balance of pharmacological treatment for childbearing-aged females with bipolar disorder is a growing concern. Therefore, we aimed to address the effect of age and sex on psychotropic drug prescription for outpatients with bipolar disorder., Methods: The MUlticenter treatment SUrvey for BIpolar disorder in Japanese psychiatric clinics (MUSUBI) study was conducted, and data on age, sex, and details of pharmacological treatment were collected., Results: A total of 3106 outpatients were included in this study. Among young females (age  ≤ 39), 25% were prescribed valproate. There was no significant difference in the frequency and daily dose of valproate prescription for young females among all groups. Valproate prescriptions were significantly less frequent among young males and more frequent among middle-aged males. Lithium prescriptions were significantly less frequent among young females and more frequent among older males (age  ≥ 65) and older females. Lamotrigine prescriptions were significantly more frequent among young males and young females and less frequent among older males and older females. Carbamazepine prescriptions were significantly less frequent among young males and more frequent among older males., Conclusions: Biased information about the risk and safety of valproate and lithium for young females was suggested, and further study to correct this bias is needed. Older patients were prescribed lithium more commonly than lamotrigine. Further studies are needed to determine the actual pharmacotherapy for elderly individuals., (© 2022. The Author(s).)

Simple access to aryl sulfinates from aryl iodides and bromides is reported using an inexpensive Ni-electrocatalytic protocol. The reaction exhibits a broad scope, uses stock solution of simple SO 2 as sulfur source, and can be scaled up in batch and recycle flow settings. The limitations of this reaction are clearly shown and put into context by benchmarking with state-of-the-art Pd-based methods., (© 2022 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Cross-coupling between two similar or identical functional groups to form a new C-C bond is a powerful tool to rapidly assemble complex molecules from readily available building units, as seen with olefin cross-metathesis or various types of cross-electrophile coupling 1,2 . The Kolbe electrolysis involves the oxidative electrochemical decarboxylation of alkyl carboxylic acids to their corresponding radical species followed by recombination to generate a new C-C bond 3-12 . As one of the oldest known Csp 3 -Csp 3 bond-forming reactions, it holds incredible promise for organic synthesis, yet its use has been almost non-existent. From the perspective of synthesis design, this transformation could allow one to agnostically execute syntheses without regard to polarity or neighbouring functionality just by coupling ubiquitous carboxylates 13 . In practice, this promise is undermined by the strongly oxidative electrolytic protocol used traditionally since the nineteenth century 5 , thereby severely limiting its scope. Here, we show how a mildly reductive Ni-electrocatalytic system can couple two different carboxylates by means of in situ generated redox-active esters, termed doubly decarboxylative cross-coupling. This operationally simple method can be used to heterocouple primary, secondary and even certain tertiary redox-active esters, thereby opening up a powerful new approach for synthesis. The reaction, which cannot be mimicked using stoichiometric metal reductants or photochemical conditions, tolerates a range of functional groups, is scalable and is used for the synthesis of 32 known compounds, reducing overall step counts by 73%., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Conventional chemical and even electrochemical Birch-type reductions suffer from a lack of chemoselectivity due to a reliance on alkali metals or harshly reducing conditions. This study reveals that a simpler avenue is available for such reductions by simply altering the waveform of current delivery, namely rapid alternating polarity (rAP). The developed method solves these issues, proceeding in a protic solvent, and can be easily scaled up without any metal additives or stringently anhydrous conditions.

Background: Leukoencephalopathy is identified during the administration of anticancer drugs. Symptoms vary from neurological symptoms to psychiatric symptoms depending on the site of damage. There have been no previous reports of suicide attempts due to drug-induced leukoencephalopathy., Case Presentation: The patient was diagnosed with diffuse large B-cell lymphoma (DLBCL) infiltrating the pharyngeal lesion. Rituximab + methotrexate + oncovin + procarbazine (R-MPV) therapy, a methotrexate-containing chemotherapy, was initiated. At the end of the fifth course, the patient attempted suicide by hanging with an appliance cord, which was associated with delusion. A head MRI scan showed no evidence of lymphoma recurrence, but white matter lesions around the ventricles showed progression., Conclusion: We report the case of a patient in whom drug-induced leukoencephalopathy related to methotrexate led to a suicide attempt. In addition to monitoring brain tumors, daily monitoring of psychiatric and neurological symptoms is important for patients with methotrexate-induced encephalopathy., (© 2021 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Neuropsychopharmacology.)

Challenges in the selective manipulation of functional groups (chemoselectivity) in organic synthesis have historically been overcome either by using reagents/catalysts that tunably interact with a substrate or through modification to shield undesired sites of reactivity (protecting groups). Although electrochemistry offers precise redox control to achieve unique chemoselectivity, this approach often becomes challenging in the presence of multiple redox-active functionalities. Historically, electrosynthesis has been performed almost solely by using direct current (DC). In contrast, applying alternating current (AC) has been known to change reaction outcomes considerably on an analytical scale but has rarely been strategically exploited for use in complex preparative organic synthesis. Here we show how a square waveform employed to deliver electric current-rapid alternating polarity (rAP)-enables control over reaction outcomes in the chemoselective reduction of carbonyl compounds, one of the most widely used reaction manifolds. The reactivity observed cannot be recapitulated using DC electrolysis or chemical reagents. The synthetic value brought by this new method for controlling chemoselectivity is vividly demonstrated in the context of classical reactivity problems such as chiral auxiliary removal and cutting-edge medicinal chemistry topics such as the synthesis of PROTACs.

The formation of aryl-alkyl ether bonds through cross coupling of alcohols with aryl halides represents a useful strategic departure from classical S N 2 methods. Numerous tactics relying on Pd-, Cu-, and Ni-based catalytic systems have emerged over the past several years. Herein we disclose a Ni-catalyzed electrochemically driven protocol to achieve this useful transformation with a broad substrate scope in an operationally simple way. This electrochemical method does not require strong base, exogenous expensive transition metal catalysts (e.g., Ir, Ru), and can easily be scaled up in either a batch or flow setting. Interestingly, e-etherification exhibits an enhanced substrate scope over the mechanistically related photochemical variant as it tolerates tertiary amine functional groups in the alcohol nucleophile., (© 2021 Wiley-VCH GmbH.)

Background: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced or recurrent non-small cell lung cancer (NSCLC). They cause immune-related adverse events (irAEs), but the underlying mechanisms and predictors remain to be fully elucidated. In this retrospective study, we investigated the association between pretreatment neutrophil-to-lymphocyte ratio (NLR) and the occurrence of irAEs., Methods: The study involved 115 patients with NSCLC who started ICI-only treatment in our hospital between January 2016 and April 2020., Results: Forty-five patients (39.1%) had irAEs, and pretreatment NLR was significantly lower in the irAEs group than in the non-irAEs group (2.8 vs. 4.1; p = 0.036). The cutoff value of the NLR was 2.86 (area under curve, 0.62; sensitivity, 0.56; specificity, 0.71), and the incidence rate of irAEs was significantly higher in the NLR < 2.86 group than in the NLR ≥2.86 group (p = 0.004; odds ratio [OR]: 3.12; 95% confidence interval [CI]: 1.43-6.84). The multivariate analysis showed that the NLR was significantly associated with the occurrence of irAEs (p = 0.016; OR: 2.69; 95% CI: 1.21-6.01)., Conclusions: Low pretreatment NLR may be a predictive factor for the occurrence of irAEs. By focusing on the potential risk of irAEs in patients with a low pretreatment NLR, irAEs can be appropriately managed from an early period., (© 2021 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Background: Concern regarding the benefit/risk ratio of the long-term use of benzodiazepines (BDZs) and Z-drugs is increasing. To prevent the risk of dependence in BDZ long-term use, it is essential to understand the attitudes of patients and psychiatrists toward BDZ treatment. The aims of this investigation were to 1) obtain information on patients' attitudes with long-term BDZ use and their referring psychiatrists' attitudes toward BDZ treatment, including their perception of the difficulty of reducing the dose of BDZs, and 2) identify discrepancies between patients' and psychiatrists' perceptions., Methods: A brief questionnaire was constructed to investigate the attitudes of patients receiving BDZ treatment and their referring psychiatrists. Our sample comprised 155 patients who received BDZ treatment for more than one year and their referring eight psychiatrists. Both the patients and their psychiatrists completed our questionnaire between August 2017 and December 2017., Results: Of the patients, 13% felt that it was more difficult to reduce the dose of BDZs than their referring psychiatrists (type A discrepancy), while 25% felt that it was less difficult (type B discrepancy). In the multivariate logistic regression analysis, the female sex and both the patients' ("psychotherapy plus BDZs was necessary" and "it was necessary to increase the dose of BDZs") and psychiatrists' beliefs ("short-term prescription was justified") were associated with type A discrepancies. Type B discrepancies were associated with psychiatrists' beliefs that the patient's wishes justified the use of BDZs and that the cessation of treatment with BDZs would lead to the deterioration of their rapport with their patients., Conclusion: To overcome the discrepancies in the attitudes of patients and psychiatrists toward the cessation of BDZ treatment, it is necessary to promote patient-centered care involving patient psychoeducation and practice guidelines for the decision-making process. Further studies investigating the promotion of patient-centered care to reduce BDZ use are needed., Competing Interests: Norio Yasui-Furukori reports personal fees from Mochida, Otsuka Pharmaceuticals, Dainippon-Sumitomo, and MSD, outside the submitted work. The remaining authors declare that they have no competing interests to report., (© 2021 Kawamata et al.)

The site-specific oxidation of strong C(sp 3 )-H bonds is of uncontested utility in organic synthesis. From simplifying access to metabolites and late-stage diversification of lead compounds to truncating retrosynthetic plans, there is a growing need for new reagents and methods for achieving such a transformation in both academic and industrial circles. One main drawback of current chemical reagents is the lack of diversity with regard to structure and reactivity that prevents a combinatorial approach for rapid screening to be employed. In that regard, directed evolution still holds the greatest promise for achieving complex C-H oxidations in a variety of complex settings. Herein we present a rationally designed platform that provides a step toward this challenge using N -ammonium ylides as electrochemically driven oxidants for site-specific, chemoselective C(sp 3 )-H oxidation. By taking a first-principles approach guided by computation, these new mediators were identified and rapidly expanded into a library using ubiquitous building blocks and trivial synthesis techniques. The ylide-based approach to C-H oxidation exhibits tunable selectivity that is often exclusive to this class of oxidants and can be applied to real-world problems in the agricultural and pharmaceutical sectors.

Plasma glutamate concentrations are constant despite dynamic changes in diets. Most likely, virtually all the dietary glutamate is metabolized in the gut. The present study investigated permeability and metabolism of dietary glutamate in a Caco-2 intestinal epithelial cell layer model by tracing the fate of [U- 13 C] or [ 15 N]glutamate added to the apical medium. For comparison, several other labelled essential and non-essential amino acids were tested as well. Almost all the labelled glutamate in the apical medium (98% and 96% at 24 h of the culture, respectively) was incorporated in the cell layer, while it barely appeared at the basolateral side, indicating an almost complete utilization of glutamate. Indeed, the 13 C was incorporated into alanine, proline, ornithine, and glutamine, and the 15 N was incorporated into alanine, glutamine, ornithine, proline, branched chain amino acids and also found as ammonia indicative of oxidation. In contrast, substantial apical-to-basolateral transport of amino acids (8-85% of uptake) other than glutamate and aspartate was evident in studies using amino acid tracers labelled with 13 C, 15 N or D. These results suggest that the intestinal epithelial cell monolayer utilizes dietary glutamate which adds to maintaining glutamate homeostasis in the body.

What Is Known and Objective: We investigated the elimination efficiency and pharmacokinetics (PK) parameters of vancomycin (VCM) in patients undergoing continuous haemodiafiltration (CHDF) using a polyethyleneimine-coated polyacrylonitrile membrane (AN69ST) for dosage adjustment., Methods: We conducted a retrospective study of CHDF patients treated with VCM from December 2017 to August 2019. We calculated PK parameters of VCM and determined the 24-hour dose required to maintain the target trough concentration of VCM (VCM &#95;trough )., Results and Discussion: The average (95% CI) volume of distribution and total clearance of VCM were 75.5 L (63.7-87.3 L) and 1.84 L/h (1.38-2.30 L/h), respectively, and the elimination rate constant and half-life were 0.026/h (0.017-0.034/h) and 31.2 h (22.8-39.5 h), respectively. The average AN69ST clearance of VCM (CL &#95;CHDF ) was 0.69 L/h (0.52-0.86 L/h). The estimated average doses required to maintain VCM &#95;trough of 10, 15 and 20 μg/mL were 623.1 mg (379.8-866.4 mg), 934.6 mg (569.7-1299.5 mg) and 1246.2 mg (759.6-1732.8 mg), respectively., What Is New and Conclusion: The PK of VCM and CL &#95;CHDF of AN69ST were clarified. These results suggest that it is possible to adjust the dose of VCM in using AN69ST, which efficiently removes cytokines, and contributes to improvement of serious infections., (© 2020 John Wiley & Sons Ltd.)

Wolffia is a genus of protein-rich aquatic plants. Mankai, a cultivated strain of Wolffia globosa , contains more than 40 % protein based on dry matter evaluation. Furthermore, Mankai is nutritionally excellent as a food material, and is expected to be applicable to various products as a substitute for animal protein. A battery of toxicological studies was conducted on the dried product of Mankai (Dry Mankai), with the expectation to utilize it as a raw material for food applications. Dry Mankai was not genotoxic in a bacterial reverse mutation test and in vitro micronucleus assay. In the subchronic toxicity study, rats were provided Dry Mankai in the diet at levels of 0 %, 5 %, 10 %, or 20 % (w/w), equivalent to 0, 3.18, 6.49, and 13.16 g/kg/day for males and 0, 3.58, 7.42, and 15.03 g/kg/day for females, respectively. No adverse effects that could be attributable to treatment were observed in clinical observations, body weight, food consumption, ophthalmology, hematology and blood chemistry, urinalysis, and macroscopic and microscopic findings. According to the repeated-dose study in rats, the no observed adverse effect level of Dry Mankai was 20 % (w/w) for both sexes (13.16 and 15.03 g/kg/day for males and females, respectively)., Competing Interests: The authors are planning to develop Dry Mankai as a food product in Japan, the U.S, and Europe., (© 2020 The Author(s).)

The appeal and promise of synthetic organic electrochemistry have been appreciated over the past century. In terms of redox chemistry, which is frequently encountered when forging new bonds, it is difficult to conceive of a more economical way to add or remove electrons than electrochemistry. Indeed, many of the largest industrial synthetic chemical processes are achieved in a practical way using electrons as a reagent. Why then, after so many years of the documented benefits of electrochemistry, is it not more widely embraced by mainstream practitioners? Erroneous perceptions that electrochemistry is a "black box" combined with a lack of intuitive and inexpensive standardized equipment likely contributed to this stagnation in interest within the synthetic organic community. This barrier to entry is magnified by the fact that many redox processes can already be accomplished using simple chemical reagents even if they are less atom-economic. Time has proven that sustainability and economics are not strong enough driving forces for the adoption of electrochemical techniques within the broader community. Indeed, like many synthetic organic chemists that have dabbled in this age-old technique, our first foray into this area was not by choice but rather through sheer necessity. The unique reactivity benefits of this old redox-modulating technique must therefore be highlighted and leveraged in order to draw organic chemists into the field. Enabling new bonds to be forged with higher levels of chemo- and regioselectivity will likely accomplish this goal. In doing so, it is envisioned that widespread adoption of electrochemistry will go beyond supplanting unsustainable reagents in mundane redox reactions to the development of exciting reactivity paradigms that enable heretofore unimagined retrosynthetic pathways. Whereas the rigorous physical organic chemical principles of electroorganic synthesis have been reviewed elsewhere, it is often the case that such summaries leave out the pragmatic aspects of designing, optimizing, and scaling up preparative electrochemical reactions. Taken together, the task of setting up an electrochemical reaction, much less inventing a new one, can be vexing for even seasoned organic chemists. This Account therefore features a unique format that focuses on addressing this exact issue within the context of our own studies. The graphically rich presentation style pinpoints basic concepts, typical challenges, and key insights for those "electro-curious" chemists who seek to rapidly explore the power of electrochemistry in their research.

In response to the lack of authenticated mutagenicity/genotoxicity studies on MSG monohydrate, a series of genotoxicity studies conducted under GLP and according to globally accepted test guidelines (e.g., OECD) was performed. A bacterial reverse mutation test using Salmonella typhimurium (TA100, TA1535, TA98 and TA1537) and Escherichia coli (WP2 uvrA) at concentrations up to 5000 μg/plate, an in vitro chromosomal aberration test in CHL/IU cells at concentrations up to 10 mmol/L (1.9 mg/mL), a mouse lymphoma tk assay at concentrations up to 10 mmol/L (1.9 mg/mL), an in vitro micronucleus test in human peripheral blood lymphocytes at concentrations up to 10 mmol/L (1871 μg/mL), and an in vivo micronucleus test in bone marrow of rats that were gavaged with up to 2000 mg/kg bw were investigated. MSG monohydrate did not cause mutagenicity in any bacterial strain, did not induce chromosomal aberrations in CHL/IU cells or gene mutation in mouse lymphoma cells, was not clastogenic or aneugenic to human lymphocytes, and did not induce micronuclei in erythrocytes of rats when compared with vehicle controls. These results show that MSG is not mutagenic or genotoxic under the study conditions., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Intra-articular (IA) injection of hyaluronic acid (HA) (IA-HA) is a well-recognized treatment option for pain associated with symptomatic knee osteoarthritis (OA). IA-HA products differ in their HA content, molecular weight, cross-linking, and source of HA. These differences are assumed to affect the biocompatibility of the IA-HA products once injected inside the knee joint., Methods: In the present study, we investigated the biocompatibility of three multiple-injection IA-HA products available in the global market. These included SUPARTZ FX™, a medium range molecular weight HA derived from rooster comb (Avian-HA); ORTHOVISC®, a high range molecular weight HA obtained through biological fermentation (Bio-HA); and SYNVISC®, a high molecular weight cross-linked hyaluronan derived from rooster comb (Avian-CL-HA). Rabbit knee joint tissues were histologically and biochemically examined after IA injection of the products. Furthermore, we compared the amounts of impurities in the IA-HA products., Results: IA injection of Avian-CL-HA into rabbit knee joints induced the aggregation of inflammatory cells, infiltration of eosinophils, and an increase in the number of cells in the synovial fluid. However, these effects were not seen in the Avian-HA and Bio-HA groups. The residual protein content and the contaminant levels of bacterial endotoxins were below the limit of quantitation in all HA products. Avian-CL-HA contained relatively a large amount of (1 → 3)-β-D-glucan, but this was below the lower limit of quantification in the other HA products., Conclusions: The present results clearly demonstrate that the biocompatibility of Avian-HA is comparable to that of Bio-HA, and they were both considered to have a favorable safety profile for the treatment of symptomatic OA of the knee. However, immunostimulatory activity was observed after injection of Avian-CL-HA: this might be a result of its unique cross-linking structure and/or the considerable amount of (1 → 3)-β-D-glucan impurity present in the formulation.

Hindered ethers are of high value for various applications; however, they remain an underexplored area of chemical space because they are difficult to synthesize via conventional reactions 1,2 . Such motifs are highly coveted in medicinal chemistry, because extensive substitution about the ether bond prevents unwanted metabolic processes that can lead to rapid degradation in vivo. Here we report a simple route towards the synthesis of hindered ethers, in which electrochemical oxidation is used to liberate high-energy carbocations from simple carboxylic acids. These reactive carbocation intermediates, which are generated with low electrochemical potentials, capture an alcohol donor under non-acidic conditions; this enables the formation of a range of ethers (more than 80 have been prepared here) that would otherwise be difficult to access. The carbocations can also be intercepted by simple nucleophiles, leading to the formation of hindered alcohols and even alkyl fluorides. This method was evaluated for its ability to circumvent the synthetic bottlenecks encountered in the preparation of 12 chemical scaffolds, leading to higher yields of the required products, in addition to substantial reductions in the number of steps and the amount of labour required to prepare them. The use of molecular probes and the results of kinetic studies support the proposed mechanism and the role of additives under the conditions examined. The reaction manifold that we report here demonstrates the power of electrochemistry to access highly reactive intermediates under mild conditions and, in turn, the substantial improvements in efficiency that can be achieved with these otherwise-inaccessible intermediates.

A simple and robust method for electrochemical alkyl C-H fluorination is presented. Using a simple nitrate additive, a widely available fluorine source (Selectfluor), and carbon-based electrodes, a wide variety of activated and unactivated C-H bonds were converted to their C-F congeners. The scalability of the reaction was also demonstrated with a 100 gram preparation of fluorovaline.

C-N cross-coupling is one of the most valuable and widespread transformations in organic synthesis. Largely dominated by Pd- and Cu-based catalytic systems, it has proven to be a staple transformation for those in both academia and industry. The current study presents the development and mechanistic understanding of an electrochemically driven, Ni-catalyzed method for achieving this reaction of high strategic importance. Through a series of electrochemical, computational, kinetic, and empirical experiments, the key mechanistic features of this reaction have been unraveled, leading to a second generation set of conditions that is applicable to a broad range of aryl halides and amine nucleophiles including complex examples on oligopeptides, medicinally relevant heterocycles, natural products, and sugars. Full disclosure of the current limitations and procedures for both batch and flow scale-ups (100 g) are also described.

Reductive electrosynthesis has faced long-standing challenges in applications to complex organic substrates at scale. Here, we show how decades of research in lithium-ion battery materials, electrolytes, and additives can serve as an inspiration for achieving practically scalable reductive electrosynthetic conditions for the Birch reduction. Specifically, we demonstrate that using a sacrificial anode material (magnesium or aluminum), combined with a cheap, nontoxic, and water-soluble proton source (dimethylurea), and an overcharge protectant inspired by battery technology [tris(pyrrolidino)phosphoramide] can allow for multigram-scale synthesis of pharmaceutically relevant building blocks. We show how these conditions have a very high level of functional-group tolerance relative to classical electrochemical and chemical dissolving-metal reductions. Finally, we demonstrate that the same electrochemical conditions can be applied to other dissolving metal-type reductive transformations, including McMurry couplings, reductive ketone deoxygenations, and epoxide openings., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)