Acylative Dynamic Kinetic Resolution of Secondary Alcohols: Tandem Catalysis by HyperBTM and Bäckvall's Ruthenium Complex.

Non-enzymatic dynamic kinetic resolution (DKR) of secondary alcohols by enantioselective acylation using an isothiourea-derived HyperBTM catalyst and racemization of slowly reacting alcohol by Bäckvall's ruthenium complex is reported. The DKR approach features high enantioselectivities (up to 99:1), employs easy-to-handle crystalline 4-nitrophenyl isobutyrate as the acylating reagent, and proceeds at room temperature and under an ambient atmosphere. The stereoinduction model featuring cation-π system interactions between the acylated HyperBTM catalyst and π electrons of an alcohol aryl subunit has been elaborated by DFT calculations.

Naturally Occurring Isocoumarins Derivatives from Endophytic Fungi: Sources, Isolation, Structural Characterization, Biosynthesis, and Biological Activities.

Recently, the metabolites separated from endophytes have attracted significant attention, as many of them have a unique structure and appealing pharmacological and biological potentials. Isocoumarins represent one of the most interesting classes of metabolites, which are coumarins isomers with a reversed lactone moiety. They are produced by plants, microbes, marine organisms, bacteria, insects, liverworts, and fungi and possessed a wide array of bioactivities. This review gives an overview of isocoumarins derivatives from endophytic fungi and their source, isolation, structural characterization, biosynthesis, and bioactivities, concentrating on the period from 2000 to 2019. Overall, 307 metabolites and more than 120 references are conferred. This is the first review on these multi-facetted metabolites from endophytic fungi.

Impact of donor lung pathogenic bacteria on patient outcomes in the immediate post-transplant period.

BACKGROUND: Patient outcomes post-lung transplant remain inferior to other types of solid organ transplantation. We investigated whether the presence of potentially pathogenic bacteria (PPB) in donor lung bronchial cultures was associated with adverse outcomes postoperatively. METHODS: All patients who underwent lung transplantation between August 2015 and April 2017 at the University of Kentucky Medical Center were retrospectively reviewed. Retransplants, patients with bronchiectasis (including cystic fibrosis), and individuals who received organs from donation after cardiac death (DCD) donors were excluded. The remaining subjects were separated into two groups: individuals whose donor bronchial cultures grew PPB, and those whose cultures either returned negative for PPB or were sterile. 30-day mortality rates as well as the incidence of grade 3 primary graft dysfunction (PGD) and acute kidney injury (AKI) at both 24 and 72 hours post-transplant were calculated. The duration of mechanical ventilation postoperatively was also recorded. RESULTS: Thirty two subjects comprised the study population. 20 patients (63%) had growth of PPB on donor cultures, while 12 (37%) did not. Patients with PPB had a significantly greater number of days on the ventilator postoperatively compared to those with no PPB (mean = 11.3 and median = 5.0 vs mean = 5.8 and median = 3.0, respectively, P = 0.0232). Subsequent regression analysis revealed this association to not be influenced by recipient lung allocation score (LAS), donor age, donor smoking history, recipient mean pulmonary artery pressure (mPAP) value, and/or use of cardiopulmonary bypass at the time of transplantation. Neither 30-day survival nor incidence of Grade 3 PGD and AKI at 24 or 72 hours post-transplant differed between the two groups (P > 0.05). CONCLUSION: The recovery of PPB in donor lung cultures was associated with a longer duration of mechanical ventilation postoperatively in lung transplant recipients.

Update on the Use of Botulinum Toxin Therapy for Focal and Task-Specific Dystonias.

Focal dystonia is defined by anatomical distribution and represents a distinct entity from generalized dystonia. Task-specific dystonia occurs in the context of specific patterns of movement. Botulinum neurotoxin (BoNT) injections are the treatment of choice in most cases. Several formulations are available; the approved indications, dosing, and some administration details, differ between them. The major forms of focal and task-specific dystonia are reviewed, along with the evidence for BoNT therapy, the expected benefit and side effects, and practical points guiding the injections.

Mendelian randomisation applied to drug development in cardiovascular disease: a review.

Despite increased expenditure, productivity of the pharmaceutical industry has decreased and currently 90% of developed molecules entering phase II and phase III clinical trials fail to gain regulatory approval. Most of these failures are due to lack of therapeutic efficacy rather than lack of safety, suggesting that drug development failures may often be due to poor drug target validation. Currently, drug targets are largely validated using in vitro assays and animal models which may not translate well to human disease. Emerging methods from human genetics, such as Mendelian randomisation (MR), can enable the validation of putative biomarker drug targets in humans prior to the initiation of clinical trials. MR studies can provide evidence as to whether genetically determined levels of a biomarker influence disease aetiology, enabling investigators to infer whether the biomarker is causal. We review the extent to which MR techniques may be helpful in biomarker validation by assessing the concordance between the results from MR studies and phase III clinical trials for lipid therapy in cardiovascular disease. Our findings show that concordance is highest when MR provides evidence suggesting that a biomarker is not causal. In contrast, there are many examples of clinical trials that still failed despite targeting confirmed causal biomarkers. We discuss why such trials may not succeed, despite evidence for causality in MR studies, and outline important limitations when using MR for biomarker validation in drug development. Nonetheless, given the current inefficiencies in drug development, MR methods have potential to improve the success rate of drug development and ultimately the delivery of new molecules to clinical care.

Vitamin D and Risk of Multiple Sclerosis: A Mendelian Randomization Study.

BACKGROUND: Observational studies have demonstrated an association between decreased vitamin D level and risk of multiple sclerosis (MS); however, it remains unclear whether this relationship is causal. We undertook a Mendelian randomization (MR) study to evaluate whether genetically lowered vitamin D level influences the risk of MS. METHODS AND FINDINGS: We identified single nucleotide polymorphisms (SNPs) associated with 25-hydroxyvitamin D (25OHD) level from SUNLIGHT, the largest (n = 33,996) genome-wide association study to date for vitamin D. Four SNPs were genome-wide significant for 25OHD level (p-values ranging from 6 × 10-10 to 2 × 10-109), and all four SNPs lay in, or near, genes strongly implicated in separate mechanisms influencing 25OHD. We then ascertained their effect on 25OHD level in 2,347 participants from a population-based cohort, the Canadian Multicentre Osteoporosis Study, and tested the extent to which the 25OHD-decreasing alleles explained variation in 25OHD level. We found that the count of 25OHD-decreasing alleles across these four SNPs was strongly associated with lower 25OHD level (n = 2,347, F-test statistic = 49.7, p = 2.4 × 10-12). Next, we conducted an MR study to describe the effect of genetically lowered 25OHD on the odds of MS in the International Multiple Sclerosis Genetics Consortium study, the largest genetic association study to date for MS (including up to 14,498 cases and 24,091 healthy controls). Alleles were weighted by their relative effect on 25OHD level, and sensitivity analyses were performed to test MR assumptions. MR analyses found that each genetically determined one-standard-deviation decrease in log-transformed 25OHD level conferred a 2.0-fold increase in the odds of MS (95% CI: 1.7-2.5; p = 7.7 × 10-12; I2 = 63%, 95% CI: 0%-88%). This result persisted in sensitivity analyses excluding SNPs possibly influenced by population stratification or pleiotropy (odds ratio [OR] = 1.7, 95% CI: 1.3-2.2; p = 2.3 × 10-5; I2 = 47%, 95% CI: 0%-85%) and including only SNPs involved in 25OHD synthesis or metabolism (ORsynthesis = 2.1, 95% CI: 1.6-2.6, p = 1 × 10-9; ORmetabolism = 1.9, 95% CI: 1.3-2.7, p = 0.002). While these sensitivity analyses decreased the possibility that pleiotropy may have biased the results, residual pleiotropy is difficult to exclude entirely. CONCLUSIONS: A genetically lowered 25OHD level is strongly associated with increased susceptibility to MS. Whether vitamin D sufficiency can delay, or prevent, MS onset merits further investigation in long-term randomized controlled trials.

Adult-onset Alexander's disease mimicking degenerative disease.

Adult-onset Alexander's disease is a rare leukodystrophy that can present later in life in a variety of ways, often mimicking more common neurodegenerative conditions. We present two cases with novel mutations, diagnosed from their characteristic MR scan findings. Even in much older people, clinicians should have a high clinical suspicion if there are typical imaging findings.

Urinary Biomarkers for Lupus Nephritis: A Systems Biology Approach.

Systemic lupus erythematosus (SLE) is the prototypical systemic autoimmune disorder. Kidney involvement, termed lupus nephritis (LN), is seen in 40-60% of patients with systemic lupus erythematosus (SLE). After the diagnosis, serial measurement of proteinuria is the most common method of monitoring treatment response and progression. However, present treatments for LN-corticosteroids and immunosuppressants-target inflammation, not proteinuria. Furthermore, subclinical renal inflammation can persist despite improving proteinuria. Serial kidney biopsies-the gold standard for disease monitoring-are also not feasible due to their inherent risk of complications. Biomarkers that reflect the underlying renal inflammatory process and better predict LN progression and treatment response are urgently needed. Urinary biomarkers are particularly relevant as they can be measured non-invasively and may better reflect the compartmentalized renal response in LN, unlike serum studies that are non-specific to the kidney. The past decade has overseen a boom in applying cutting-edge technologies to dissect the pathogenesis of diseases at the molecular and cellular levels. Using these technologies in LN is beginning to reveal novel disease biomarkers and therapeutic targets for LN, potentially improving patient outcomes if successfully translated to clinical practice.

Physical functioning in patients with end-stage knee osteoarthritis: A cross-sectional study in Jordan using self-reported questionnaire and performance-based tests.

BACKGROUND: Knee osteoarthritis (OA) is a debilitating condition that leads to functional limitations. Self-reported questionnaires and performance-based tests are tools commonly used for measuring physical function. OBJECTIVES: (1) To evaluate the impact of end-stage knee OA on functional outcomes and examine the association between self-reported and performance-based measures of function in patients with end-stage knee osteoarthritis awaiting total knee arthroplasty (2) To explore the interrelationships among pain, strength, and overall physical function in this patient population. METHODS: In this cross-sectional analysis, 33 patients with end-stage knee OA were recruited and completed the knee Outcome Survey-Activities of Daily Living Scale (KOS-ADLS) and executed performance-based tests including the Timed Up and Go, the 30-second chair stand test, and the Stair Climbing Test. Knee pain, and isometric hip and knee strength were evaluated. RESULTS: Patients perceived deficits in their physical functionwith a score of 35/100 on the KOS-ADLS and demonstrated functional limitations in all performed tasks. KOS-ADLs was weakly associated with TUG and 30s-CST (r=-0.301, p= 0.047, and r= 0.39, p= 0.014. respectively). Knee pain was linked with the KOS-ADL score and GRS score (r=-0.406, p= 0.010; r=-0.343, p= 0.027; respectively), while the strength of the affected side was correlated with the performed (p=< 0.001) and reported function outcomes (p= 0.007). CONCLUSION: Participants exhibit declines in both perceived and executed functional abilities. Self-reported and performance-based functional measures are weakly correlated within our study group, highlighting the importance of incorporating both measures in clinical practice for a comprehensive evaluation of physical function. Pain was linked to subjective aspect of physical function, while strength was connected to perceived and performed functional capacity. Implementing a tailored rehabilitation program targeting muscle weakness and pain holds the potential to mitigate functional decline in individuals awaiting total knee arthroplasty (TKA).

Tailoring magnetic Sn-MOFs for efficient amoxicillin antibiotic removal through process optimization.

This study investigated the efficacy of magnetic Sn metal-organic frameworks (MSn-MOFs) in removing the insecticide amoxicillin (AMX) from aqueous solutions. Our thorough experimental investigation showed that MSn-MOFs were an incredibly effective adsorbent for removing AMX. Several methods were used to characterize the material. BET investigation of the data displayed a significant surface area of 880 m2 g-1 and a strong magnetic force of 89.26 emu g-1. To identify the point of zero charge, surface characterization was carried out and the value was 7.5. This shows that the adsorbent carries a positive and negative charge below and above this position, respectively. Moreover, the impact of pH on adsorption equilibrium was explored. The results of kinetic models to explore the adsorption of AMX on MSn-MOFs supported the pseudo-second-order, and the adsorption complied well with the Langmuir isotherm. The results revealed that the overall adsorption mechanism may entail chemisorption via an endothermic spontaneous process with MSn-MOFs. The precise modes by which MSn-MOFs and AMX interacted may involve pore filling, H-bonding, π-π interaction, or electrostatic interaction. Determining the nature of this interaction is essential in understanding the adsorption behavior of the MOFs and optimize the adsorbent design for real-world applications. The use of the MSn-MOF adsorbent provides a straightforward yet efficient method for the filtration of water and treatment of industrial effluents. The results showed 2.75 mmol g-1 as the maximum capacity for adsorption at pH = 6. Additional tests were conducted to assess the adsorbent regeneration, and even after more than six cycles, the results demonstrated a high level of efficiency. The adsorption results were enhanced by the application of the Box-Behnken design.

Intravenous fluid rate of 250 mL/h versus 125 mL/h in nulliparous women: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Evidence regarding the type and rate of intravenous (IV) fluid administration during labor is still inconclusive and the studies assessing the impact of IV fluids had mixed results. OBJECTIVES: To evaluate the effects of IV fluids at an infusion rate of 250 mL/h as compared with 125 mL/h on labor outcomes in nulliparous women. SEARCH STRATEGY: We searched six databases for relevant studies through a search strategy containing the relevant keywords "IV hydration", "IV fluids", and "labor" from the inception of these databases to May 1, 2023, without any applied restrictions. SELECTION CRITERIA: Search results were imported to Covidence for screening of eligible articles for this review. Randomized controlled trials (RCTs) assessing the impact of IV fluids at 250 mL/h on the outcomes of labor in nulliparous women at term (>37 weeks) as compared with 125 mL/h were included only. DATA COLLECTION AND ANALYSIS: Data regarding the characteristics of included studies, participant's baseline characteristics, and concerned outcomes were collected in an Excel spreadsheet and all the concerned outcomes were pooled as risk ratios (RR) or mean difference (MD) with 95% confidence interval (CI) in the meta-analysis models using RevMan 5.4. MAIN RESULTS: Pooled data from 11 RCTs with 1815 patients showed that 250 mL/h infusion rate had a significant reduction in cesarean section rate (RR 0.70, 95% CI 0.56-0.88, P = 0.002), the first stage of labor duration (MD -46.97, 95% CI -81.79 to -12.14, P = 0.008), the second stage of labor duration (MD -2.69, 95% CI -4.34 to -1.05, P = 0.001), prolonged labor incidence (RR 0.72, 95% CI 0.58-0.89, P = 0.003), as compared with 125 mL/h. Also, the vaginal delivery rate (RR 1.07, 95% CI 1.02-1.12, P = 0.009) was higher with a 250 mL/h infusion rate. CONCLUSION: IV fluids at an infusion rate of 250 mL/h during labor in nulliparous women decreased the cesarean delivery rate, increased the vaginal delivery rate, shortened the first and second-stage labor duration, decreased the incidence of prolonged labor as compared with 125 mL/h. These findings suggest enhanced labor progression and a lower risk of labor complications with higher infusion rates. However, future research involving a more diverse population and exploring the potential benefits of combining IV infusion rates with other interventions, such as adding dextrose or less restrictive oral intake during labor, is needed.

The Long and Winding Road: 25 Years of the National Advanced Driving Simulator.

The National Advanced Driving Simulator is a high-fidelity motion-base simulator owned by the National Highway Transportation Safety Administration and managed and operated by the University of Iowa. Its 25-year history has intersected with some of the most significant developments in automotive history, such as advanced driver assistance systems like stability control and collision warning systems, and highly automated vehicles. The simulator is an application of immersive virtual reality that uses multiprojection instead of head-mounted displays. A large-excursion motion system provides realistic acceleration and rotation cues to the driver. Due to its level of immersion and realism, drivers respond to events in the simulator the same way they would in their own vehicle. We document the history and technology behind this national facility.

Bispecific Antibodies in Hematological Malignancies: A Scoping Review.

Bispecific T-cell engagers (BiTEs) and bispecific antibodies (BiAbs) have revolutionized the treatment landscape of hematological malignancies. By directing T cells towards specific tumor antigens, BiTEs and BiAbs facilitate the T-cell-mediated lysis of neoplastic cells. The success of blinatumomab, a CD19xCD3 BiTE, in acute lymphoblastic leukemia spearheaded the expansive development of BiTEs/BiAbs in the context of hematological neoplasms. Nearly a decade later, numerous BiTEs/BiAbs targeting a range of tumor-associated antigens have transpired in the treatment of multiple myeloma, non-Hodgkin's lymphoma, acute myelogenous leukemia, and acute lymphoblastic leukemia. However, despite their generally favorable safety profiles, particular toxicities such as infections, cytokine release syndrome, myelosuppression, and neurotoxicity after BiAb/BiTE therapy raise valid concerns. Moreover, target antigen loss and the immunosuppressive microenvironment of hematological neoplasms facilitate resistance towards BiTEs/BiAbs. This review aims to highlight the most recent evidence from clinical trials evaluating the safety and efficacy of BiAbs/BiTEs. Additionally, the review will provide mechanistic insights into the limitations of BiAbs whilst outlining practical applications and strategies to overcome these limitations.

Bringing High-Dose Neurorestorative Behavioral Training Into the Acute Stroke Unit.

ABSTRACT: Stroke remains common and is a leading cause of adult disability. While there have been enormous system changes for the diagnosis and delivery of hyperacute stroke treatments at comprehensive stroke centers, few advances have been made in those same centers for treatments focused on behavioral recovery and brain repair. Specifically, during the early hospital period, there is a paucity of approaches available for reduction of impairment beyond what is expected from spontaneous biological recovery. Thus, patients in the early stroke recovery period are not receiving the kind of training needed, at the requisite intensity and dose, to exploit a potential critical period of heightened brain plasticity that could maximize true recovery instead of just compensation. Here, we describe an ongoing pilot program to reconfigure the acute stroke unit experience to allow for a new emphasis on brain repair. More specifically, we have introduced a novel room-based video-gaming intervention; restorative neuroanimation, into the acute stroke hospital setting. This new intervention provides the opportunity for an extra hour(s) of high-intensity neurorestorative behavioral treatment that is complementary to conventional rehabilitation. To accomplish this, system redesign was required to insert this new treatment into the patient day, to properly stratify patients behaviorally and physiologically for the treatment, to optimize the digital therapeutic approach itself, and to maintain the impairment reduction after discharge.

Older Adults and Three-Dimensional Exergaming: Motivators and Barriers to Participation and Retention.

Background: Cognitive and physical activity are important for daily functioning. However, limited research exists on the motivators and barriers associated with older adults participating and adhering to exergame studies that promote physical and cognitive activity. Our objective was to examine older adults' motivators and barriers to joining and completing a three-dimensional exergame study. Methods: Fourteen older adults who participated in the exergame study contributed to one of three focus group discussions. Inductive and deductive methods were used to analyze the qualitative data. Results: Motivators for joining were generativity, peer referrals, self-improvement, and curiosity. Accomplishment, immersion, and exercise were motivators for retention. Participants also cited the structured schedule and adaptive difficulty features as motivators for retention. Barriers to participation included frustration due to lack of level advancement and fatigue/pain during gameplay. Some (n = 3) reported camera tracking issues as a barrier. Unanticipated gender-based trends arose when examining perceptions of the study team's role and motivators for retention. Conclusion: These findings will inform future research strategies for participant recruitment, enrollment, and retention, in addition to providing insights into the design of motivating, enjoyable, and sustainable exergames for older adults.

Clinical Impact of CDK4/6 Inhibitors in De Novo or PR- or Very Elderly Post-Menopausal ER+/HER2- Advanced Breast Cancers.

The CDK4/6 inhibitors significantly increase progression-free survival (PFS) in ER+/HER2- advanced breast cancer patients. In clinical trials, overall survival (OS) improvement has been demonstrated for ribociclib and abemaciclib but not for palbociclib. We undertook a real-world evaluation of PFS and OS in 227 post-menopausal patients who received first-line CDK4/6 inhibitors. There is no significant difference in median PFS (27.5 months vs. 25.7 months, p = 0.3) or median OS (49.5 months vs. 50.2 months, p = 0.67) in patients who received either palbociclib or ribociclib, respectively. De novo disease is significantly associated with prolonged median PFS and median OS compared with recurrence disease (47.1 months vs. 20.3 months (p = 0.0002) and 77.4 months vs. 37.3 months (p = 0.0003), respectively). PR- tumours have significantly reduced median PFS and OS compared with PR+ disease (19.2 months vs. 38 months (p = 0.003) and 34.3 months vs. 62.6 months (p = 0.02), respectively). In the very elderly (>80 years), median PFS and OS are significantly shorter compared with patients who are 65 years or below (14.5 months vs. 30.2 months (p = 0.01), and 77.4 months vs. 29.6 months (p = 0.009), respectively) in the palbociclib group. Our data suggest that the benefit in the very elderly is limited, and PR+/de novo disease obtains the maximum survival benefit.

Three-dimensional catheter tip force sensing using multi-core fiber Bragg gratings.

Awareness of catheter tip interaction forces is a crucial aspect during cardiac ablation procedures. The most important contact forces are the ones that originate between the catheter tip and the beating cardiac tissue. Clinical studies have shown that effective ablation occurs when contact forces are in the proximity of 0.2 N. Lower contact forces lead to ineffective ablation, while higher contact forces may result in complications such as cardiac perforation. Accurate and high resolution force sensing is therefore indispensable in such critical situations. Accordingly, this work presents the development of a unique and novel catheter tip force sensor utilizing a multi-core fiber with inscribed fiber Bragg gratings. A customizable helical compression spring is designed to serve as the flexural component relaying external forces to the multi-core fiber. The limited number of components, simple construction, and compact nature of the sensor makes it an appealing solution towards clinical translation. An elaborated approach is proposed for the design and dimensioning of the necessary sensor components. The approach also presents a unique method to decouple longitudinal and lateral force measurements. A force sensor prototype and a dedicated calibration setup are developed to experimentally validate the theoretical performance. Results show that the proposed force sensor exhibits 7.4 mN longitudinal resolution, 0.8 mN lateral resolution, 0.72 mN mean longitudinal error, 0.96 mN mean lateral error, a high repeatability, and excellent decoupling between longitudinal and lateral forces.

OLDER ADULTS' SUBJECTIVE WELL-BEING EXPERIENCING THE EXERGAME "I AM DOLPHIN".

The objective of this study was to understand older adults' perceptions of the connections between an exergame intervention, "I Am Dolphin," and their subjective well-being. Researchers conducted three focus groups with 14 older adults who participated in the exergame feasibility study. The semi-structured focus groups were transcribed, coded, and analysed using deductive and inductive techniques. Three themes were constructed related to playing the exergame and participants' subjective well-being: 1) elevated mood (through scheduled activity, immersion, and socialization), 2) feelings of achievement (especially following frustration and competition), and 3) perceived cognitive or physical changes. These findings will help researchers better understand how exergames may relate to the well-being of older adults. Future investigators could use these findings to create and implement new exergame interventions.

Discovery of novel (N-aryl-4-methylpiperidinyl)pyrazoles: a new class of potent lepidopteran insecticides.

BACKGROUND: Insects of the order Lepidoptera are among the most destructive global pests, causing billions of dollars in damage annually. A new class of N-arylpyrazole-4-methylpiperidines with potent activity on lepidopteran species has been discovered. RESULTS: In a high-throughput insecticide screen compound 1 was identified to possess modest activity on the lepidopteran insect Plutella xylostella. Optimization of 1 to compound 42 resulted in a compound with excellent activity on Spodoptera exigua, Spodoptera frugiperda, and Helicoverpa zea with median lethal concentrations values of 2.8, 1.4, and 12.5 ppm respectively. Although the mode of action remains unknown, these compounds do not appear to work by many of the known biochemical mechanisms of insect control. CONCLUSION: N-Arylpyrazole-4-methylpiperidines represent a new class of insecticides with excellent activity on a broad spectrum of lepidopteran pests. Studies to date indicate the potential for a novel mode of action; however, the target site is unknown at present. © 2023 Society of Chemical Industry.