Synthesis of Chiral 1,2-Amino Alcohol-Containing Compounds Utilizing Ruthenium-Catalyzed Asymmetric Transfer Hydrogenation of Unprotected α-Ketoamines.

Herein, we disclose a facile synthetic strategy to access an important class of drug molecules that contain chiral 1,2-amino alcohol functionality utilizing highly effective ruthenium-catalyzed asymmetric transfer hydrogenation of unprotected α-ketoamines. Recently, the COVID-19 pandemic has caused a crisis of shortage of many important drugs, especially norepinephrine and epinephrine, for the treatment of anaphylaxis and hypotension because of the increased demand. Unfortunately, the existing technologies are not fulfilling the worldwide requirement due to the existing lengthy synthetic protocols that require additional protection and deprotection steps. We identified a facile synthetic protocol via a highly enantioselective one-step process for epinephrine and a two-step process for norepinephrine starting from unprotected α-ketoamines 1b and 1a, respectively. This newly developed enantioselective ruthenium-catalyzed asymmetric transfer hydrogenation was extended to the synthesis of many 1,2-amino alcohol-containing drug molecules such as phenylephrine, denopamine, norbudrine, and levisoprenaline, with enantioselectivities of >99% ee and high isolated yields.

Management of isolated volar lunate facet fractures of the distal radius.

Distal radius fractures are among the most common fractures treated globally. Consideration of the mechanism of injury and careful radiographic assessment contributes to appropriate management of these injuries in isolation or jointly with other fractures or injuries affecting the wrist joint. Treatment options can range from non-operative management to a variety of fixation techniques. Interest in the distal radius fractures was renewed as open reduction and monoblock volar locking plate fixation became the preferred contemporary treatment in the last few decades. Isolated volar lunate facet (VLF) fractures are uncommon. However, the stability of the entire carpus may be compromised with fractures of the volar marginal rim. Inadequately or improperly treated fractures of the VLF can lead to significant long-term complications. A critical approach to this unique fracture pattern's evaluation, management, and surgical fixation is paramount for successful and reproducible outcomes in stability and durability.

Effects of time spent in pregnancy or brooding on immunocompetence.

Sexes of a species may show different characteristics beyond the differences in their sexual organs and such sexual dimorphism often occurs in the level of immune response when exposed to pathogens (immunocompetence). In general, females have increased longevity relative to males, which is associated with higher immunocompetence. However, males have higher immunocompetence in some species, such as pipefishes and seahorses. Experimental evidence suggests that this could be because males, rather than females, carry fertilized eggs to birth in these species. This observation suggests that an increase in immunocompetence may be related to the level of parental investment and not to a particular sex. We use state-dependent life-history theory to study optimal investment in offspring production relative to parent immunocompetence, varying the relative time that a parent spends in brooding or pregnancy within a breeding cycle. When offspring is dependent on a parent's survival for a large part of the breeding cycle, we predict higher investments in immunity and longer life expectancies.

The "Bag of Bones" Treatment of Comminuted Intra-articular Distal Humerus Fractures in the Elderly.

BACKGROUND: Extensively comminuted intra-articular distal humerus fractures in the elderly present a challenging therapeutic dilemma. The purpose of this study was to investigate the results of nonoperative treatment of these fractures in a select subset of patients. METHODS: Patients treated with nonoperative management for a comminuted intra-articular distal humerus fracture between 2007 and 2018 were reviewed. Patients were administered 3 elbow-specific functional outcomes instruments. RESULTS: A total of 8 patients (2 men, 6 women) were treated with brief immobilization followed by early range of motion. All had fractures with extensive comminution of the articular surface such that open reduction and internal fixation was not feasible. Average age was 70 years. At an average of 33 months postinjury, average flexion was 124°, and extension was -27°, with full forearm rotation. No patients required pain medications at the latest follow-up. At 33 months of follow-up, the average Mayo Elbow Performance Score was 92/100 (100 optimal), Oxford Elbow Score was 43/48 (48 optimal), and Quick Disabilities of the Arm, Shoulder, and Hand Score was 10/100 (0 optimal). All patients were satisfied with the nonsurgical treatment that they received. CONCLUSIONS: Nonoperative treatment for comminuted intra-articular distal humerus fractures results in acceptable functional outcome in elderly patients and should be considered when the fracture is not amenable to internal fixation and in lower-demand patients with higher surgical risk.

Design and Discovery of Water-Soluble Benzooxaphosphole-Based Ligands for Hindered Suzuki-Miyaura Coupling Reactions with Low Catalyst Load.

We report a new class of highly effective, benzooxaphosphole-based, water-soluble ligands in the application of Suzuki-Miyaura cross-coupling reactions for sterically hindered substrates in aqueous media. The catalytic activities of the coupling reactions were greatly enhanced by the addition of catalytic amounts of organic phase transfer reagents, such as tetraglyme and tetrabutylammonium bromide. The optimized general protocol can be conducted with a low catalyst load, thereby providing a practical solution for these reactions. The viability of this new Suzuki-Miyaura protocol was demonstrated with various substrates to generate important building blocks, including heterocycles, for the synthesis of biologically active compounds.

Bibliometric Analysis of Context, Trends, and Contents of Digital Health Technology Used in Dental Health.

Digital tools and apps are revolutionizing healthcare and provide creative answers to urgent problems. Through teamwork and the incorporation of digital technologies, dentistry has experienced a remarkable revolution. A large body of scholarly research backs up this trend. The context, trends, and content of digital health technology in oral and dental health are examined in our bibliometric analysis. Using targeted keywords and synonyms, an organized searching technique was used in the Scopus database, yielding 1942 articles that were extracted into a CSV file. To acquire insights into the content, trends, and context, visualization using VOSviewer 1.6.18 and a variety of analyses-including coauthorship, citation, cooccurrence of author keywords, bibliographic coupling, and cocitation-were executed. The analysis revealed that the USA and the UK contributed to a significant quantity of the literature, with newer contributions coming from nations like India. Cone Beam Computed Tomography, Dental Caries, and Artificial Intelligence were prominent keywords. It is important to note that BMC Oral Health was associated with a sizable number of the papers. This bibliometric analysis provides insightful information about the context, content, and trends of digital health in the field of oral and dental health. By implementing the right technology, policymakers can use this information to increase oral health, encourage dental literacy, and improve access to dental treatment. It is vital to take into account the wide variety of technologies and their classifications based on dental services and contextual variables.

A Simplified Risk Score to Estimate the Risk of Contrast-Induced Nephropathy after Contrast Exposure.

Introduction: Scores are available to predict the probability of contrast-induced nephropathy (CIN) after cardiac interventions, but not many scores are available for non-cardiac interventions and there are none for intravenous exposure to contrast. We designed this study to develop a simplified score to determine the probability of developing CIN in patients exposed to the parenteral contrast medium. Methods: This was a prospective study of patients who received parenteral contrast. Of 1300 patients, the first 1000 comprised the derivation cohort and the next 300 comprised the validation cohort. The patient variables in the development cohort were studied using univariate analysis. Statistically significant individual variables were used as independent variables, and CIN was used as the dependent variable in the final multivariate logistic regression model. Then, the risk score was obtained and validated. Results: The incidence of CIN was 3.8%. The risk factors, namely the presence of diabetes mellitus, e-GFR, and route and volume of contrast material were significantly associated with the risk of CIN (P < 0.05). The developed risk score had a sensitivity of 90.4% and specificity of 98.78%. The overall accuracy was 97.8%. The values of AUC of ROC in the development and validation datasets were high. This indicated that the predicted CIN risk score correlated well with the calibration and discriminative characteristics. Conclusions: The route and volume of contrast administered, low e-GFR, and diabetes mellitus were the significant risk factors. The developed risk score exhibited very good sensitivity and specificity and excellent accuracy in predicting the probability of CIN.

Muscle Belly Repair: Biomechanical Assessment of the Anchor Suture and the Modified Kessler Techniques.

Background: Treatment of muscle belly lacerations remains a problem for surgeons. Inadequate repair of lacerations can cause functional disability. To date, there is no consensus on the method of repair for these injuries. We have previously described a technique of repairing mid-substance muscle belly lacerations. The aim of this study was to determine the ultimate strength of an intact muscle belly and to compare the anchor suture (AS) technique with the modified Kessler (MK) technique. Methods: Fifteen fresh frozen hind-legs from adolescent pigs were divided into three groups and used for the testing. Each group consisted of five specimens. Group one was the intact control group, group two was repaired with the MK technique and group three was repaired with the AS technique. Following repair, the muscles were secured in a custom-made fixation apparatus and underwent linear tensioning at a rate of 25 mm/min, generating a load-displacement curve for each specimen. The data regarding ultimate strength, modes of failure and number of intact suture/anchor constructs (for groups 2 and 3) was calculated. Results: The ultimate strength of the intact muscle group of was found to be 608.1 ± 107.9  N. This was significantly (p < 0.05) higher than the pull-out strength of the MK and AS groups. The pull-out strength of the AS group was 143.1 ± 36.7 N, nearly twice that of the MK group 69.8 ± 16.4 N (p = 0.11). Suture pull-out was the most common mode of failure. Conclusions: The AS technique was found to have both higher strain and nearly twice the ultimate pull-out strength compared to the MK repair group. We suggest the AS technique as a viable technique for mid-substance muscle belly repairs.

Direct Path from Turbulence to Time-Periodic Solutions.

Viscous flows through pipes and channels are steady and ordered until, with increasing velocity, the laminar motion catastrophically breaks down and gives way to turbulence. How this apparently discontinuous change from low- to high-dimensional motion can be rationalized within the framework of the Navier-Stokes equations is not well understood. Exploiting geometrical properties of transitional channel flow we trace turbulence to far lower Reynolds numbers (Re) than previously possible and identify the complete path that reversibly links fully turbulent motion to an invariant solution. This precursor of turbulence destabilizes rapidly with Re, and the accompanying explosive increase in attractor dimension effectively marks the transition between deterministic and de facto stochastic dynamics.

Theoretical assessment of persistence and adaptation in weeds with complex life cycles.

Herbicide-resistant weeds pose a substantial threat to global food security. Perennial weed species are particularly troublesome. Such perennials as Sorghum halepense spread quickly and are difficult to manage due to their ability to reproduce sexually via seeds and asexually through rhizomes. Our theoretical study of S. halepense incorporates this complex life cycle with control measures of herbicide application and tillage. Rooted in the biology and experimental data of S. halepense, our population-based model predicts population dynamics and target-site resistance evolution in this perennial weed. We found that the resistance cost determines the standing genetic variation for herbicide resistance. The sexual phase of the life cycle, including self-pollination and seed bank dynamics, contributes substantially to the persistence and rapid adaptation of S. halepense. While self-pollination accelerates target-site resistance evolution, seed banks considerably increase the probability of escape from control strategies and maintain genetic variation. Combining tillage and herbicide application effectively reduces weed densities and the risk of control failure without delaying resistance adaptation. We also show how mixtures of different herbicide classes are superior to rotations and mono-treatment in controlling perennial weeds and resistance evolution. Thus, by integrating experimental data and agronomic views, our theoretical study synergistically contributes to understanding and tackling the global threat to food security from resistant weeds.

Using Teriparatide to Augment Healing in a Humeral Shaft Nonunion: A Case Report.

The occurrence of complications of fracture healing, such as delayed union and nonunion, is well known, but the use of pharmacotherapy for these delayed unions and nonunions has not been explored in detail. The authors describe a case of traumatic humeral shaft fracture successfully treated with once-daily administration of 20mcg of teriparatide for six months. The patient was a 22-year-old male who had been through a road traffic accident. The radiograph of the humerus shaft showed a fracture line and the displaced distal portion of the shaft of the humerus. Based on these features, the patient was diagnosed with a humeral shaft fracture. The patient underwent internal fixation with a dynamic compression plate. However, there were no signs of callus formation even after 12 weeks from the time of internal fixation. The patient was initiated with teriparatide administration and union was achieved after six months of a once-daily administration of teriparatide. Once-daily teriparatide treatment is shown to be beneficial for improving the healing of humeral shaft fractures showing delayed union.

Advancement of targeted protein degradation strategies as therapeutics for undruggable disease targets.

Targeted protein degradation (TPD) aids in developing novel bifunctional small-molecule degraders and eliminates proteins of interest. The TPD approach shows promising results in oncological, neurogenerative, cardiovascular and gynecological drug development. We provide an overview of technology advancements in TPD, including molecular glues, proteolysis-targeting chimeras (PROTACs), lysosome-targeting chimeras, antibody-based PROTAC, GlueBody PROTAC, autophagy-targeting chimera, autophagosome-tethering compound, autophagy-targeting chimera and chaperone-mediated autophagy-based degraders. Here we discuss the development and evolution of the TPD field, the variety of proteins that PROTACs target and the biological repercussions of their degradation. We particularly highlight the recent improvements in TPD research that utilize autophagy or the endolysosomal pathway, which enables the targeting of undruggable targets.

Optimizing crop rotations via Parrondo's paradox for sustainable agriculture.

Crop rotation, a sustainable agricultural technique, has been at humanity's disposal since time immemorial and is practised globally. Switching between cover crops and cash crops helps avoid the adverse effects of intensive farming. Determining the optimum cash-cover rotation schedule for maximizing yield has been tackled on multiple fronts by agricultural scientists, economists, biologists and computer scientists, to name a few. However, considering the uncertainty due to diseases, pests, droughts, floods and impending effects of climate change is essential when designing rotation strategies. Analysing this time-tested technique of crop rotations with a new lens of Parrondo's paradox allows us to optimally use the rotation technique in synchrony with uncertainty. While previous approaches are reactive to the diversity of crop types and environmental uncertainties, we make use of the said uncertainties to enhance crop rotation schedules. We calculate optimum switching probabilities in a randomized cropping sequence and suggest optimum deterministic sequences and judicious use of fertilizers. Our methods demonstrate strategies to enhance crop yield and the eventual profit margins for farmers. Conforming to translational biology, we extend Parrondo's paradox, where two losing situations can be combined eventually into a winning scenario, to agriculture.

Efficacy and Safety of Teriparatide in Improving Fracture Healing and Callus Formation: A Systematic Review.

Fracture nonunion remains a great challenge for orthopedic surgeons. Some bone fractures don't heal promptly, resulting in delayed unions and nonunions, and there is a need for an additional surgical procedure. Previous research has shown that teriparatide, a type of synthetic parathyroid hormone, can promote the formation of callus and lead to healing in individuals with delayed or non-healing bone fractures. Limited systematic reviews exist that examine the use of teriparatide in cases of delayed healing or non-healing bone fractures, which have their limitations. In this review, we overcome those limitations by including prospective studies, retrospective studies, case reports, and case series together. A systematic search of the literature was conducted in both PubMed and Google Scholar up to September of the year 2022. The studies included in our research included adult patients (over the age of 16) diagnosed with delayed union or nonunion of any bone in the body (flat bone, long bone, short bone, or irregular bone). The studies were limited to those written in English. The outcomes that were tracked and recorded include the healing of the fracture and any negative side effects or adverse events. The initial search yielded 504 abstracts and titles. After reviewing these, 32 articles were selected for further analysis, which included 19 case reports, five case series, two retrospective studies, and six prospective studies. Studies included daily (20 micrograms) or weekly (56.5 micrograms) subcutaneous administration of teriparatide. The duration of follow-up for these studies varied from three to 24 months. Based on the available research, it appears that administering teriparatide subcutaneously is a safe treatment option for delayed healing and non-healing bone fractures, with very few to no reported negative side effects. Using teriparatide for induction of callus formation and treating delayed and nonunions is highly safe and effective.

A Systematic Review of Cystic Fibrosis in Children: Can Non-Medical Therapy Options Lead to a Better Mental Health Outcome?

Cystic fibrosis (CF) is a chronic disorder that begins at an early age, so it is crucial to be aware of the physical and emotional burden placed on individuals suffering from it and their families. It significantly impacts an individual's life; therefore, it is essential to acknowledge the effects of the disease on physical and mental health. Our systematic review aims to highlight the areas of life affected by cystic fibrosis and evaluate various non-medical treatment options that may support the mental health of CF patients. We selected PubMed, Google Scholar, and MEDLINE (Medical Literature Analysis and Retrieval System Online) as our databases. We initially found 146,095 articles and narrowed the number of articles down using filters, exclusion and inclusion criteria, and various combinations of Medical Subheadings (MeSH) and key terms. We decided to use a final count of nine articles for our systematic review. The studies we included highlighted the negative impact of cystic fibrosis on mental health, like depression and anxiety, as well as on sleep, physical health, and overall quality of life. Several non-medical interventions, such as logotherapy, psychological interventions, complementary and alternative medicine, and many more, have been shown to enhance the mental health of many participants. Studies suggested that such therapy options may greatly benefit individuals with cystic fibrosis and their current treatment plan. This review indicates that non-medical therapy options can enhance the mental health of individuals suffering from cystic fibrosis and that it is crucial to bring more attention to preventing and treating mental health issues in cystic fibrosis patients. However, as current data is limited, more research with a larger number of participants over an extended period of time is necessary to better evaluate the efficacy of non-medical interventions on mental health.

A Systematic Review of the Efficacy of Early Initiation of Speech Therapy and Its Positive Impact on Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is a condition that consists predominantly of an apparent early delay in communication and social skills. Among the multiple identified etiologies, genetics play a key role. The implementation of early interventional therapy for children with ASD is starting to show promising results. A few medical databases were used to collect multiple published types of research, which were thoroughly screened. Ultimately, a small amount was selected according to the defined eligibility criteria. The 12 articles that were reviewed involved a more significant number of boys than girls, and most clinical trials displayed the importance of starting early therapy. Astonishingly, the overwhelming effects of the COVID-19 pandemic did not affect the continuation of speech therapy in certain areas. In addition, studies emphasize knowledge scarcity, insufficient resources in certain areas, and the demand to educate the community. Conversely, no difference in the level of severity was noted with the implementation of early therapy. Early therapy, chiefly speech therapy used to treat children with ASD, demonstrated favorable outcomes. Communities require awareness about the condition on a broader scale to educate caregivers on early alarming symptoms. All in all, additional exploration needs to be done.

The sphingolipids ceramide and inositol phosphorylceramide protect the Leishmania major membrane from sterol-specific toxins.

The accessibility of sterols in mammalian cells to exogenous sterol-binding agents has been well-described previously, but sterol accessibility in distantly related protozoa is unclear. The human pathogen Leishmania major uses sterols and sphingolipids distinct from those used in mammals. Sterols in mammalian cells can be sheltered from sterol-binding agents by membrane components, including sphingolipids, but the surface exposure of ergosterol in Leishmania remains unknown. Here, we used flow cytometry to test the ability of the L. major sphingolipids inositol phosphorylceramide (IPC) and ceramide to shelter ergosterol by preventing binding of the sterol-specific toxins streptolysin O and perfringolysin O and subsequent cytotoxicity. In contrast to mammalian systems, we found that Leishmania sphingolipids did not preclude toxin binding to sterols in the membrane. However, we show that IPC reduced cytotoxicity and that ceramide reduced perfringolysin O- but not streptolysin O-mediated cytotoxicity in cells. Furthermore, we demonstrate ceramide sensing was controlled by the toxin L3 loop, and that ceramide was sufficient to protect L. major promastigotes from the anti-leishmaniasis drug amphotericin B. Based on these results, we propose a mechanism whereby pore-forming toxins engage additional lipids like ceramide to determine the optimal environment to sustain pore formation. Thus, L. major could serve as a genetically tractable protozoan model organism for understanding toxin-membrane interactions.

Machine learning aided near-field acoustic holography based on equivalent source method.

In recent times, equivalent source method-based near-field acoustic holography methods have been extensively applied in sound source localization and characterization. The most commonly used equivalent sources are spherical harmonics. In a non-reverberant environment with no reflections, these equivalent sources could be the best choice since spherical harmonics are derived for the Sommerfeld boundary condition. However, these methods are not the best fit for reverberating environments. In such cases, a new relationship can be calculated between the field weights and the measured pressure with enough training examples. The proposed machine learning models include linear regression (LR) with adaptive moment estimation (Adam), LR with limited-memory Broyden-Fletcher-Goldfarb-Shanno (L-BFGS), and multi-layer perceptron with one and two hidden layers. These methods are tested for multiple monopoles and vibrating plate simulations in a room with different wall absorption coefficients. The data-driven methods are also studied on loudspeakers numerically and experimentally in a free field environment. The results from these methods are compared with the results of one norm convex optimization (L1CVX). LR with L-BFGS performed the best among all the methods studied and performed better than L1CVX for less absorption coefficient for geometrically separable sources. LR with L-BFGS also has much faster inference times.

Osteonecrosis of Trapezium Occurring in Patient with History of Recurrent Carpometacarpal Corticosteroid Injection.

Osteonecrosis affecting the carpal bones is rare and is mostly seen in the lunate (Kienböck's disease). Osteonecrosis of the scaphoid (Preiser disease) is even rarer. There are only four individual case reports published on patients presenting with trapezium necrosis, none with previous history of corticosteroid injection. This case report is the first presentation of isolated trapezial necrosis in the setting of prior corticosteroid injection for thumb basilar arthritis. Level of Evidence: Level V (Therapeutic).

Ecological Drivers of Community Cohesion.

From protocellular to societal, networks of living systems are complex and multiscale. Discerning the factors that facilitate assembly of these intricate interdependencies using pairwise interactions can be nearly impossible. To facilitate a greater understanding, we developed a mathematical and computational model based on a synthetic four-strain Saccharomyces cerevisiae interdependent system. Specifically, we aimed to provide a greater understanding of how ecological factors influence community dynamics. By leveraging transiently structured ecologies, we were able to drive community cohesion. We show how ecological interventions could reverse or slow the extinction rate of a cohesive community. An interconnected system first needs to persist long enough to be a subject of natural selection. Our emulation of Darwin's "warm little ponds" with an ecology governed by transient compartmentalization provided the necessary persistence. Our results reveal utility across scales of organization, stressing the importance of cyclic processes in major evolutionary transitions, engineering of synthetic microbial consortia, and conservation biology. IMPORTANCE We are facing unprecedented disruption and collapse of ecosystems across the globe. To have any hope of mitigating this phenomenon, a much greater understanding of ecosystem dynamics is required. However, ecosystems are typically composed of highly dynamic networks of individual species. These interactions are further modulated by abiotic and biotic factors that vary temporally and spatially. Thus, ecological dynamics are obfuscated by this complexity. Here, we developed a theoretical model, informed by a synthetic experimental system, of Darwin's "warm little ponds." This cycling four-species system seeks to elucidate the ecological factors that drive or inhibit interaction. We show that these factors could provide an essential tool for avoiding the accelerating ecological collapse. Our study also provides a starting point to develop a more encompassing model to inform conservation efforts.