Highly Enantiomerically Enriched Secondary Alcohols via Epoxide Hydrogenolysis.

In this article, we report the development of ruthenium-catalyzed hydrogenolysis of epoxides to selectively give the branched (Markovnikov) alcohol products. In contrast to previously reported catalysts, the use of Milstein's PNN-pincer-ruthenium complex at room temperature allows the conversion of enantiomerically enriched epoxides to secondary alcohols without racemization of the product. The catalyst is effective for a range of aryl epoxides, alkyl epoxides, and glycidyl ethers and is the first homogeneous system to selectively promote hydrogenolysis of glycidol to 1,2-propanediol, without loss of enantiomeric purity. A detailed mechanistic study was conducted, including experimental observations of catalyst speciation under catalytically relevant conditions, comprehensive kinetic characterization of the catalytic reaction, and computational analysis via density functional theory. Heterolytic hydrogen cleavage is mediated by the ruthenium center and exogenous alkoxide base. Epoxide ring opening occurs through an opposite-side attack of the ruthenium hydride on the less-hindered epoxide carbon, giving the branched alcohol product selectively.

Microfluidic electrochemical biosensors: tools for advancing the sustainable development goals.

New technologies can help to achieve the sustainable development goals (SDGs) of the United Nations. We discuss the contribution of microfluidic electrochemical biosensors to advancing the SDGs. These sensors can be applied in various fields given their low cost, self-powering ability, environmental compatibility, ease of use, and small sample volume requirements.

Art and Pediatric Orthopaedics: Repin and Inclusiveness.

A famous painting of the 19th century, by Ilia Repin, of a religious procession depicts the pageantry of the event but also draws the attention of the viewer to the exclusion of a disabled child from the festivities.

Massive bone destruction in a human proximal femur from ancient Nubia.

Massive bone destruction in a human right proximal femur is described and differentially discussed in this case study. The individual was an older adult female buried at the ancient Nubian site of Tombos (modern-day Sudan) dating to the early Napatan/Third Intermediate Period (c. 1069-750 BCE). The right femur displayed a pathologic fracture with extensive lytic destruction and resorption of the entire femoral neck, most of the femoral head, and trochanters. Macroscopic and radiographic analyses revealed cortical thinning of the proximal diaphysis with new bone formation enclosing the medullary cavity. The lesion is eccentrically located involving the anterior aspect of the neck. Numerous vascular channels are apparent in the underlying bone. Sclerotic bone marks the limit of the lesion, and osseous lucency is visible in the radiograph. The individual displayed no other lytic lesions; vertebral osteophytic growth, compression fractures, and Schmorl's nodes were observed along with dental disease typical for older individuals. A traumatic etiology is eliminated due to the extensive osteolysis. Vascular, congenital, and developmental conditions are also not consistent with the observed changes. Expansive osteolytic lesions may have been caused by a cyst. Neoplastic tumors resulting in lytic lesions with a high risk of pathologic fracture are also consistent. There have been few reports of such extensive lytic lesions of the proximal femur in the paleopathological and clinical literature; this case adds an example of this underreported condition.

Epidemiology, natural evolution, pathogenesis, clinical spectrum, and management of Legg-Calvé-Perthes.

Background: Legg-Calvé-Perthes disease is a self-limiting disorder that develops in children following interruption of the blood supply to the capital femoral epiphysis. This review outlines the current knowledge on the epidemiology, natural evolution, clinical spectrum, and management of the disease. Methods: The literature pertaining to these aspects of the disease were studied and summarized in this review. Results: Epidemiological studies suggest that environmental factors contribute to the causation of the disease. Incidence rates monitored over time indicate that the incidence of Legg-Calvé-Perthes disease is declining. The natural evolution followed on sequential plain radiographs enables division of the disease into Stages Ia, Ib, IIa, IIb, IIIa, IIIb, and IV. Reversible deformation of the capital occurs in Stages Ia-IIa simply on standing while irreversible deformation may occur in Stages IIb and IIIa. Treatment of Legg-Calvé-Perthes disease in Stages Ia-IIa aims to prevent the femoral head from getting deformed by containment and avoidance of weight-bearing. In Stages IIb and IIIa, treatment aims to remedy the effects of early irreversible deformation of the femoral head. In Stage IIIb and IV, treatment is directed to correcting the altered shape of the femoral head. The impression that these treatment methods are helpful is based on poor quality evidence. Conclusion: There is an urgent need to undertake Level I studies to establish the efficacy of currently treatment. Level of evidence: level V.

Low Molecular Weight Inhibitors Targeting the RNA-Binding Protein HuR.

The RNA-binding protein human antigen R (HuR) regulates stability, translation, and nucleus-to-cytoplasm shuttling of its target mRNAs. This protein has been progressively recognized as a relevant therapeutic target for several pathologies, like cancer, neurodegeneration, as well as inflammation. Inhibitors of mRNA binding to HuR might thus be beneficial against a variety of diseases. Here, we present the rational identification of structurally novel HuR inhibitors. In particular, by combining chemoinformatic approaches, high-throughput virtual screening, and RNA-protein pulldown assays, we demonstrate that the 4-(2-(2,4,6-trioxotetrahydropyrimidin-5(2H)-ylidene)hydrazineyl)benzoate ligand exhibits a dose-dependent HuR inhibition effect in binding experiments. Importantly, the chemical scaffold is new with respect to the currently known HuR inhibitors, opening up a new avenue for the design of pharmaceutical agents targeting this important protein.

On-chip modeling of tumor evolution: Advances, challenges and opportunities.

Tumor evolution is the accumulation of various tumor cell behaviors from tumorigenesis to tumor metastasis and is regulated by the tumor microenvironment (TME). However, the mechanism of solid tumor progression has not been completely elucidated, and thus, the development of tumor therapy is still limited. Recently, Tumor chips constructed by culturing tumor cells and stromal cells on microfluidic chips have demonstrated great potential in modeling solid tumors and visualizing tumor cell behaviors to exploit tumor progression. Herein, we review the methods of developing engineered solid tumors on microfluidic chips in terms of tumor types, cell resources and patterns, the extracellular matrix and the components of the TME, and summarize the recent advances of microfluidic chips in demonstrating tumor cell behaviors, including proliferation, epithelial-to-mesenchymal transition, migration, intravasation, extravasation and immune escape of tumor cells. We also outline the combination of tumor organoids and microfluidic chips to elaborate tumor organoid-on-a-chip platforms, as well as the practical limitations that must be overcome.

The Mechanism of Markovnikov-Selective Epoxide Hydrogenolysis Catalyzed by Ruthenium PNN and PNP Pincer Complexes.

The homogeneous catalysis of epoxide hydrogenolysis to give alcohols has recently received significant attention. Catalyst systems have been developed for the selective formation of either the Markovnikov (branched) or anti-Markovnikov (linear) alcohol product. Thus far, the reported catalysts exhibiting Markovnikov selectivity all feature the potential for Noyori/Shvo-type bifunctional catalysis, with either a RuH/NH or FeH/OH core structure. The proposed mechanisms of epoxide ring-opening have involved cooperative C-O bond hydrogenolysis involving the metal hydride and the acidic pendant group on the ligand, in analogy to the well-documented mechanism of polar double-bond hydrogenation exhibited by catalysts of this type. In this work, we present a combined computational/experimental study of the mechanism of epoxide hydrogenolysis catalyzed by Noyori-type PNP and PNN complexes of ruthenium. We find that, at least for these ruthenium systems, the previously proposed bifunctional pathway for epoxide ring-opening is energetically inaccessible; instead, the ring-opening proceeds through opposite-side nucleophilic attack of the ruthenium hydride on the epoxide carbon, without the involvement of the ligand N-H group. For both catalyst systems, the rate law and overall barrier predicted by density functional theory (DFT) are consistent with the results from kinetic studies.

Art and Pediatric Orthopaedics: "Arm-twisting" by Wyspianski, the Poet, Actor, and Artist.

Stanislaw Wyspianski, a multifaceted Polish artist painted "A Girl with a Red Hat", which portrays a young girl with an obviously deformed right upper limb. The pattern of deformities is suggestive of either athetoid hemiplegic cerebral palsy or Erb's palsy.

Does Prolonged Weight Relief Increase the Chances of a Favourable Outcome After Containment for Perthes Disease?

We have been treating children with Legg-Calvé-Perthes disease (LCPD) with a femoral varus osteotomy (PFVO) and weight relief till the disease evolves to the latter part of the stage of reconstitution (Stage IIIb). This entails weight relief for 18 to 24 months. We undertook this case-control study to test if a shorter period of weight relief would compromise the chance of retaining the spherical shape of the femoral head when the disease healed. Forty-one children diagnosed in the early stages of LCPD (Stages Ia, Ib, and IIa), were treated by PFVO and non-weight-bearing for a period of 6 months following surgery (6m group). Eighty-two children with LCPD matched for age, sex, and stage at surgery, who resumed weight-bearing only once they reached Stage IIIb, served as the control group (3b group). Both groups were followed up till the disease healed. The sphericity deviation score was calculated, and the height and width of the epiphysis were measured on the first radiograph designated as Stage IV. The median sphericity deviation score value at healing was 3 in the 3b group and 11 in the 6m group (P<0.001). The frequency of spherical heads was 76% in the 3b group and 49% in the 6m group (P<0.003). The Odds Ratio of the disease healing with an aspherical head in 6-month group was 3.05 (CI: 1.28 to 7.22) compared with the 3b group. The percentage increase in width of the femoral epiphysis at healing was greater in the 6 group (111.5±8.5% vs. 106.5±7.2%; P<0.001). The study confirms that containment by PFVO performed early in the course of LCPD combined with weight relief till the disease has evolved to Stage IIIb is likely to result in spherical hips in 75% of children. Reducing the period of weight relief to 6 months may yield significantly poorer results with only 49% spherical femoral heads.

Advances on microfluidic paper-based electroanalytical devices.

Since the inception of the first electrochemical devices on paper substrates, many different reports of microfluidic paper-based electroanalytical devices (µPEDs), innovative hydrophobic barriers and electrode fabrication processes have allowed the incorporation of diverse materials, resulting in different applications and a boost in performance. These advancements have led to the creation of paper-based devices with comparable performance to many standard conventional devices, with the added benefits of pumpless fluidic transport, component separation and reagent storage that can be exploited to automate and handle sample preprocessing. Herein, we review µPEDs, summarize the characteristics and functionalities of µPEDs, such as separation, fluid flow control and storage, and outline the conventional and emerging fabrication and modification approaches for µPEDs. We also examine the recent application of µPEDs in biomedicine, the environment, and food and water safety, as well as some limitations and challenges that must be addressed.

Piezoelectric micropump with integrated elastomeric check valves: design, performance characterization and primary application for 3D cell culture.

This paper reports on the study of a piezoelectric actuated micropump with integrated elastomeric check valves that can transport small amounts of fluid in a highly controllable manner. The proposed micropump consists of a piezoelectric actuated fluid chamber with two integrated elastomeric check valves for regulating input and output flow direction, while restricting backflows. The actuation, fluid dynamic response and fluid-structure interactions at various working cycles are studied through a fully coupled multiphysics simulation (solid mechanics, electrostatic and fluid flow). The pump bodies are manufactured by micromachining of PMMA sheets, while the middle elastomeric membrane and diaphragm are fabricated by spin-coating PDMS. The experimental results confirm that the micropump can provide sufficiently low-velocity outflow for biomedical applications between 3.4 - 41.8 µl/min. The performance of the micropump is improved significantly through a convenient geometric modification of an off-the-shelf piezoelectric brass disc. Furthermore, the combination of this micropump with the 3D cell-culture microfluidic chip realizes the dynamic culture of cells encapsulated in 3D hydrogels with a continuous flowing medium, which offers the potential for changing the traditional mode of 3D cell culture with a static supply of nutrition and factors.

Art and Pediatric Orthopaedics: Cot and the Crutch.

Pierre Auguste Cot's painting, "Mireille giving alms at the door of Saint-Trophime," depicts a wealthy lady giving alms to a crippled beggar boy. The beautiful painting portrays the striking contrast between the rich and the poor. The painting also draws attention to the crude crutch the boy was using. This type of crutch was used over the centuries; improvements in the design of the axillary crutch occurred only in the 20th century.

Back to Carracci.

Annibale Carracci's sketch of a boy with a hunchback conveys the boy's emotions remarkably well. The possibilities of the underlying cause of the spinal deformity and its neurologic complications are discussed.

Chemotherapy-Associated nausea and vomiting: A cross-sectional survey of occurrence and management patterns at jos university teaching hospital, Nigeria.

Background: The management patterns for chemotherapy-associated nausea and vomiting (CANV) in Sub-Saharan African settings have not been previously reported. The objectives of this study were to describe the prescribing pattern of antiemetics for CANV, to assess their adherence to guidelines, and to determine the occurrence of CANV. Subjects and Methods: This was a cross-sectional study, with data extracted from the records of adult patients who received chemotherapy from 2015 to 2018 at Jos University Teaching Hospital, Nigeria. The National Comprehensive Cancer Network Harmonized Guidelines™ for Sub-Saharan Africa for Antiemesis Version 3.2018 was used to determine the extent of guideline adherence. Results: Records of 165 patients were analyzed. Majority of the patients (76.4%, n = 126) received moderate-to-high emetic risk intravenous (IV) chemotherapy. Out of 129 antiemetic prescriptions for acute-phase prophylaxis, ondansetron (75.2%), corticosteroids (61.2%), and promethazine (24.8%) were the most prescribed agents. In the delayed phase, 50 patients received prophylactic antiemetics in the order of corticosteroids, ondansetron, and promethazine at 74%, 34%, and 26%, respectively. Guideline adherence was low for the acute-phase (23.6%), delayed-phase (20.6%), and overall period (17.6%). Among inpatients (n = 85), occurrences of nausea were negligible, whereas acute vomiting (9%) and delayed vomiting (15%) levels were considerable. Not receiving highly emetogenic IV chemotherapy was associated with significantly lower odds for nausea or vomiting occurrence, odds ratio 0.228 (95% confidence interval 0.054-0.967). Conclusions: Antiemetic guideline adherence was low due to antiemetic under-prescribing. A few nausea and vomiting events were recorded predominantly among patients who received highly emetogenic IV chemotherapy.

RésuméContexte: Les schémas de prise en charge des nausées et vomissements associés à la chimiothérapie (CANV) en Afrique subsaharienne n'ont pas Été signalée précédemment. Les objectifs de cette étude étaient de décrire le schéma de prescription des antiémétiques pour le CANV, d'évaluer leur adhésion Aux lignes directrices et pour déterminer l'occurrence du CANV. Subjets et méthodes: Il s'agissait d'une étude transversale, avec des données extraites de Les dossiers des patients adultes ayant reçu une chimiothérapie de 2015 à 2018 à l'hôpital universitaire de Jos, au Nigéria. Le global national Cancer Network Harmonized Guidelines™ for Sub-Saharan Africa for Antiemesis Version 3.2018 a été utilisé pour déterminer l'étendue de la directive Adhérence. Résultats: Les dossiers de 165 patients ont été analysés. La majorité des patients (76,4 %, n = 126) ont présenté un risque émétique modéré à élevé Chimiothérapie intraveineuse (IV). Sur 129 prescriptions d'antiémétiques en prophylaxie de phase aiguë, ondansétron (75,2 %), corticoïdes (61,2 %), Et la prométhazine (24,8 %) étaient les agents les plus prescrits. Dans la phase retardée, 50 patients ont reçu des antiémétiques prophylactiques de l'ordre de Corticostéroïdes, ondansétron et prométhazine à 74 %, 34 % et 26 %, respectivement. Le respect des lignes directrices était faible pour la phase aiguë (23,6 %), Phase retardée (20,6 %) et période globale (17,6 %). Parmi les patients hospitalisés (n = 85), les occurrences de nausées étaient négligeables, alors que Les taux de vomissements (9 %) et de vomissements retardés (15 %) étaient considérables. Le fait de ne pas recevoir de chimiothérapie IV hautement émétisante était associé àProbabilités significativement plus faibles de survenue de nausées ou de vomissements, rapport de cotes 0,228 (intervalle de confiance à 95 % 0,054-0,967). Conclusions : Antiémétique Le respect des lignes directrices était faible en raison de la sous-prescription des antiémétiques. Quelques nausées et vomissements ont été enregistrés principalement chez les Patients ayant reçu une chimiothérapie IV hautement émétisante. Mots-clés: Antiémétique, chimiothérapie, nausées, Nigéria, vomissements.

The Association Between Life Events and Incidence of Hypertension Among Government Employees in China: A Prospective Cohort Study.

Background: Hypertension (HTN) is a global public health concern. However, the association between life events (LEs) and HTN is complex. Thus, we conducted a prospective cohort study to explore this complex association. Methods: A total of 8,077 government employees without HTN were recruited through cluster sampling between 2018 and 2019 in Hunan Province, China. At baseline, information regarding sociodemographic characteristics, LEs, and behavioral factors was collected. After the 1-year follow-up, the participants were revisited to obtain the HTN diagnosis. Crude and adjusted Poisson regression models were constructed to calculate the incidence rate ratios (IRRs) and 95% confidence intervals (CIs). Cubic regression spline models were used to visualize the trends between LEs and HTN IRRs. Interactive and subgroup analyses were also performed. Results: The 1-year HTN incidence rate among government employees in Hunan province was 4.30% (95% CI: 3.86-4.74%). LEs were associated with a higher HTN risk (IRR, 1.02; 95% CI, 1.00-1.04). When calculating positive and negative LEs scores separately, only the latter was a risk factor for HTN incidence (IRR, 1.04; 95% CI, 1.03-1.06); conversely, positive LEs reduced the risk (IRR, 0.90; 95% CI, 0.85-0.96). Compared with patients in the lowest quartile of LEs score, those in quartiles two (IRR, 1.28; 95% CI, 0.96-1.71), three (IRR, 1.43; 95% CI, 1.04-1.96), and four (IRR, 1.73; 95% CI, 1.26-2.37) were at progressively higher risk. In restricted spline curves, a non-linear association was noted between LEs and HTN risk. Regarding the subcategories of LEs, work-related LEs, personal LEs, and all subcategories of negative LEs were associated with an increased risk of HTN. However, among positive LEs, only the family-related cases were associated with a lower risk of HTN. Conclusion: LEs had a non-linear association with an increased risk of HTN. Negative LEs were risk factors for HTN incidence, whereas positive LEs reduced the risk of HTN. Thus, the importance of LEs should be highlighted in the development of HTN prevention strategies and initiatives.

The Natural History of Non-operatively Managed Legg-Calvé-Perthes' Disease.

Background: The purpose of this study was to examine the evolution of Legg-Calvé-Perthes' disease (LCPD) among children from British Columbia (BC), Canada who were treated non-operatively and to compare the results to a previously conducted study in India. Methods: This was a retrospective review of patients treated non-operatively for LCPD in BC between 1990 and 2006 compared with a cohort from India. Demographic and treatment information were collected from medical records. Radiographs were assigned modified Waldenstrom, Catterall, Salter-Thompson and Herring classifications and intra- and interobserver reliability were assessed. We evaluated epiphyseal extrusion (EE) and metaphyseal width (MW), and assessed radiographs using the Mose and modified Stulberg classifications. Results: 102 hips (90 patients) had radiographs available for evaluation. 95% of the BC cohort presented as Waldenstrom stages I and II, whereas, 90% of the Indian cohort presented as IIIa. Final EE was similar for both groups (BC 26.8%, India 27.3%) and final MW was 119% in both groups. Modified Waldenstrom and Herring classifications had substantial intra- and interobserver reliability, while Salter-Thompson and Catterall classifications had moderate agreement at best. Most hips were Catterall IV (80%) and Herring C (89%) for the BC cohort compared to only 44% and 43% of Indian hips, respectively. Most hips were irregular according to the Mose classification (BC 43%, India 52%) and aspherical according to the Stulberg classification (BC 78%). Conclusions: We found similar radiographic progression and final radiographic appearances of LCPD in India and BC though differences in the distribution of the classification systems warrant further study. Supplementary Information: The online version contains supplementary material available at 10.1007/s43465-021-00543-x.

The "Discoid Epiphysis"-An Uncommon Presentation of Legg-Calvé-Perthes Disease.

BACKGROUND: Among a cohort of 402 children with Legg-Calvé-Perthes disease (LCPD), 32 children presented with sclerosis and severe collapse of the entire femoral epiphysis that closely resembled a discus.This study was undertaken to identify the characteristics of children with this form of a "discoid epiphysis," compare them with typical LCPD and ascertain the radiologic outcome of their hips when the disease healed. METHODS: Sequential radiographs of the children were studied to monitor disease evolution. Femoral epiphyseal extrusion was measured on the initial anteroposterior radiograph. Thirty-one of the 32 children were treated with a proximal femoral varus osteotomy and weight-bearing was deferred till the disease reached stage IIIb. The pattern of fragmentation of the epiphysis was noted and the Sphericity Deviation Score (SDS) was computed once the disease healed. RESULTS: The mean age of children with a discoid epiphysis was 6.81±1.57 years at onset of symptoms while that of children with the typical presentation was 7.54±1.64 years (P<0.017). Perfusion magnetic resonance imaging scans of three children with a discoid epiphysis done in stage Ib of the disease showed that over 95% of the epiphysis was avascular. Femoral head extrusion was frequently present on the initial radiographs (mean Reimer's migration index 27.08±8.7; range: 6.4 to 42.55).In operated children with a discoid epiphysis, the disease evolved typically with fragmentation of the epiphysis followed by reconstitution. The height of the epiphysis was never restored; when the disease healed the mean epiphyseal height was 51.31±10.44% of the normal contralateral epiphysis as compared with 82.46±11.24% in children with typical LCPD (P<0.001).The SDS at healing of operated children with a discoid epiphysis was 14.95±10.86 while the SDS for operated children without a discoid epiphysis was 9.77±11.7 (P<0.019). However, the SDS of children with typical onset LCPD who had Catterall IV involvement and Herring C collapse was 15.25±15.19 (P=0.49 NS). CONCLUSION: The outcome of treatment of children with a discoid epiphysis is comparable to that of children with typical onset LCPD with Catterall IV (whole-head involvement) and Herring C collapse of the lateral pillar. About a third of these children who undergo early surgical containment may have spherical heads when the disease heals.

Art and Paediatric Orthopaedics: A Sixteenth Century Lie-down Comedian.

This outstanding painting, by an unknown artist, of a man with multiple deformities compatible with a diagnosis of arthrogryposis multiplex congenita induces the viewer to think deeply about the artist's portrayal of the subject.