A Quality Improvement Project to Measure and Improve the Quality of Below-Knee Ankle Cast Application in Emergency Departments.

Background Ankle fractures are very common injuries seen in an emergency setting. Initial management involves the application of below-knee plaster casts. At our local trauma meetings, we have observed that below-knee casts are often applied incorrectly which can result in suboptimal outcomes for patients and increase the burden on plaster room services if re-application is required. This quality improvement project aimed to assess the quality of below-knee cast applications for ankle fractures in two local district general hospitals (DGHs). Methodology We performed a closed-loop audit utilising a retrospective analysis of patients who underwent casting for unstable ankle fractures. Two audit cycles were completed over a 90-day period across two DGHs. Working within our local orthopaedic unit, we created a targeted, multi-disciplinary educational programme led by experienced plaster technicians. Between audit cycles, we organised a single interactive session with specialist nurses in the urgent treatment centre (UTC) of our DGH while a second DGH did the same with junior doctors working in the emergency department. Both sessions demonstrated correct casting techniques and discussed the importance of a neutral ankle position for optimal patient recovery. Our audit criteria were based on AO Foundation guidance, which states that the ankle should be immobilised in a neutral plantigrade position. All patients with an unstable ankle fracture requiring immobilisation in a below-knee cast were included in the audit. We measured the angle of plantarflexion from neutral, with 90° representing a neutral angle. The angle between the axis of the tibia and the sole of the foot was measured and judged to be within an acceptable range if it was between 80° and 100°, representing a stable ankle position. The audit findings were presented in our local audit meeting. Results In our first audit cycle, we collected data from 65 patients across both sites (N = 32 for DGH 1 and N = 33 for DGH 2). The mean angle was 108.5° and 18 of the 65 (27.7%) patients had angles of ankle plantarflexion that were in the acceptable range (80°-100°). Following the intervention, we again collected data from 61 patients across both sites (N = 28 for DGH 1 and N = 33 for DGH 2). The mean angle was 106.2° and 23 of the 61 (37.7%) patients had an acceptable angle of ankle plantarflexion (80°-100°). Both of our outcome measures showed an improvement but were not statistically significant. The hospital that provided an educational session for the doctors showed an improvement in acceptable ankle casts of 3% while the hospital which provided an educational session for the UTC team improved by 22%. Conclusions We demonstrated a quantifiable approach to assess and improve the quality of below-knee cast application for ankle fractures via a single intervention that would be easily reproducible in other hospitals. We suggest further studies to investigate below-knee cast application quality and its association with patient outcomes as our data and other preliminary sources suggest that current standards are unsatisfactory.

Atypical case of coexistent vascular compression syndromes: median arcuate ligament syndrome and nutcracker syndrome.

Vascular compression syndromes, including median arcuate ligament syndrome (MALS) and nutcracker syndrome (NCS), are poorly understood and frequently delayed diagnoses. This case describes a young adult female presenting with chronic vomiting, abdominal pain and weight loss, with dependence on nasogastric feeding. Subsequent to her gastrointestinal symptoms, she developed haematuria and orthostatic intolerance. Investigations confirmed NCS and possible MALS, with superadded gastroparesis and bradygastria. Under the joint care of general and vascular surgeons, she underwent a gastrojejunostomy and panelled renocaval bypass which led to partial resolution of her symptoms. It is hypothesised that gastroparesis may have been caused by MALS via a neurogenic mechanism, or coexistent compression of the duodenum by the superior mesenteric artery. This case highlights the difficulty in diagnosis of vascular compression syndromes, the overlap between the conditions and the potential for multiple coexistent conditions which complicate diagnosis and lead to increased lead-time and morbidity for patients.

Is Capitate Shift Reliable as a Single Indicator for Failure of Non-operative Management in Distal Radius Fractures?

Background Distal radius fractures (DRFs) are the most commonly treated fracture; however, their treatment remains controversial. There is significant variation in the rate of surgical intervention related to a lack of consensus regarding the displacement threshold for surgery. Although studies have advocated that carpal malalignment is the most important radiographic parameter for surgical correction, it is rarely considered in general clinical practice and remains poorly studied. Recently, capitate shift was identified as the most useful measure of carpal malalignment, and a capitate shift threshold of -5.98 mm was proposed to indicate surgical intervention. This study aimed to investigate if this threshold is associated with the failure of non-operatively managed DRFs and should be used as a threshold for primary surgical intervention. Methodology A retrospective analysis was performed of all adult patients who underwent closed manipulation and cast immobilisation for DRFs in a UK district general hospital between September 2021 and February 2022. Capitate shift was measured on initial post-casting radiographs using the validated capitate-to-axis-of-radius distance (CARD) by a junior surgeon. The outcome measure was the failure of conservative management, which was defined as the need for repeat intervention (i.e., cast reapplication or surgical fixation) following closed reduction and cast immobilisation. Results A total of 64 patients with 65 DRFs (16 (25%) male, 49 (75%) female) were included in the study. The mean age was 66.6 years (SD = 17.9, 95% CI = 62.2 to 70.9). The mean capitate shift was -1.51 mm (SD = 5.05, 95% CI = -0.28 to -2.73) in all cases (n = 65). The failure rate of DRFs with an 'unacceptable' capitate shift (i.e., equal or less than -5.98 mm) compared to those with an 'acceptable' capitate shift (i.e., greater than -5.98 mm) was 16.7% versus 3.8% (p = 0.09). Conclusions The study concluded that there was no significant association between a capitate shift threshold of -5.98 mm and failure of non-operatively managed DRFs. Given the ease of use and reliability of capitate shift, we advocate for multicentre large cohort studies to identify a threshold for surgical intervention and establish its association with functional outcomes.

Selective Reduction of Secondary Amides to Imines Catalysed by Schwartz's Reagent.

The partial reduction of amides is a challenging transformation that must overcome the intrinsic stability of the amide bond and exhibit high chemoselective control to avoid overreduction to amine products. To address this challenge, we describe a zirconium-catalysed synthesis of imines by the reductive deoxygenation of secondary amides. This reaction exploits the excellent chemoselectivity of Schwartz's reagent (Cp2 Zr(H)Cl) and utilises (EtO)3 SiH as a mild stoichiometric reductant to enable catalyst turnover. The reaction generally proceeds with high yields (19 examples, 51 to 95 % yield) and tolerates a variety of functional groups (alkene, ester, nitro, etc.). Stoichiometric mechanistic investigations suggest the regeneration of the active [Zr]-H catalyst is achieved through the metathesis of Si-H and Zr-OR σ-bonds.

Acute compartment syndrome of the thigh in a body builder following open reduction and internal fixation for proximal femur fracture.

Acute compartment syndrome (ACS) of the thigh following femoral fracture has been rarely reported in previous literature. This condition must be diagnosed quickly to prevent the affected limb becoming ischaemic. We document the management of ACS of the thigh in a healthy male patient who suffered a proximal femur fracture following a high-speed road traffic accident. Early identification of characteristic clinical signs allowed for a diagnosis of ACS to be made and then managed with an emergency fasciotomy. The patient is a bodybuilder with an exceptionally large muscle mass. This made ACS more difficult to identify and wound closure a complex process over a period of 13 days. We aimed to highlight the importance of maintaining a high index of suspicion for ACS following traumatic injuries, recognising that ACS in larger patients can be mistaken for an increased analgesia requirement and closing fasciotomies slowly using mass tension sutures.

Functional assessment of somatic STK11 variants identified in primary human non-small cell lung cancers.

Serine/Threonine Kinase 11 (STK11) encodes an important tumor suppressor that is frequently mutated in lung adenocarcinoma. Clinical studies have shown that mutations in STK11 resulting in loss of function correlate with resistance to anti-PD-1 monoclonal antibody therapy in KRAS-driven non-small cell lung cancer (NSCLC), but the molecular mechanisms responsible remain unclear. Despite this uncertainty, STK11 functional status is emerging as a reliable biomarker for predicting non-response to anti-PD-1 therapy in NSCLC patients. The clinical utility of this biomarker ultimately depends upon accurate classification of STK11 variants. For nonsense variants occurring early in the STK11 coding region, this assessment is straightforward. However, rigorously demonstrating the functional impact of missense variants remains an unmet challenge. Here we present data characterizing four STK11 splice-site variants by analyzing tumor mRNA, and 28 STK11 missense variants using an in vitro kinase assay combined with a cell-based p53-dependent luciferase reporter assay. The variants we report were identified in primary human NSCLC biopsies in collaboration with the University of Vermont Genomic Medicine group. Additionally, we compare our experimental results with data from 22 in silico predictive algorithms. Our work highlights the power, utility and necessity of functional variant assessment and will aid STK11 variant curation, provide a platform to assess novel STK11 variants and help guide anti-PD-1 therapy utilization in KRAS-driven NSCLCs.

Acute Myeloid Leukemia with t(8;16)(p11.2;p13.3)/ KAT6A-CREBBP in a Patient with an NF1 Germline Mutation and Clinical Presentation Mimicking Acute Promyelocytic Leukemia.

OBJECTIVES: Acute myeloid leukemia (AML) with t(8;16)(p11.2;p13.3)/KAT6A-CREBBP is an uncommon subtype of AML accounting for less than 0.5% of AML cases. AML with t(8;16)/KAT6A-CREBBP has characteristic clinical and pathologic features including disseminated intravascular coagulation (DIC), leukemia cutis, hemophagocytosis, monocytic or myelomonocytic differentiation, is frequently associated with therapy-related AML and has a poor prognosis. We present a classic case of AML with t(8;16)/KAT6A-CREBBP occurring in a patient with both a germline NF1 mutation and recent cytotoxic therapy for embryonal rhabdomyosarcoma.

Arylboronic Acid Catalyzed C-Alkylation and Allylation Reactions Using Benzylic Alcohols.

The arylboronic acid catalyzed dehydrative C-alkylation of 1,3-diketones and 1,3-ketoesters using secondary benzylic alcohols as the electrophile is reported, forming new C-C bonds (19 examples, up to 98% yield) with the release of water as the only byproduct. The process is also applicable to the allylation of benzylic alcohols using allyltrimethylsilane as the nucleophile (12 examples, up to 96% yield).

Acute Myeloid Leukemia with t(6;9)(p23;q34.1); DEK-NUP214: The Pathogenesis and Potential.

OBJECTIVES: Acute myeloid leukemia (AML) is caused by the arrested differentiation and dysregulated proliferation of myeloid precursors. Many AMLs harbor genetic abnormalities which determine the molecular mechanisms of the disease and are associated with distinct clinical and pathological features, prognosis, and targeted therapies. We present a case of acute myeloid leukemia with t(6;9)(p23;q34.1) and review the classic clinical presentations and underlying pathogenesis of the disease.

Synthesis and structures of anionic rhenium polyhydride complexes of boron-hydride ligands and their application in catalysis.

The rhenium complex, [K(DME)(18-c-6)][ReH4(Bpin)(η2-HBpin)(κ2-H2Bpin)] 1, comprising hydride and boron ligands only, has been synthesized by exhaustive deoxygenation of the commercially available perrhenate anion (ReO4 -) with pinacol borane (HBpin). The structure of 1 was analysed by X-ray crystallography, NMR spectroscopy, and DFT calculations. While no hydrides were located in the X-ray crystal structure, it revealed a trigonal arrangement of pinacol boron ligands. Variable-temperature NMR spectroscopy supported the presence of seven hydride ligands but further insight was hindered by the fluxionality of both hydride and boron ligands at low temperature. Further evaluation of the structure by Ab Initio Random Structure Searching (AIRSS) identified the presence of hydride, boryl, σ-borane, and dihydroborate ligands. This complex, either isolated or prepared in situ, is a catalyst for the 1,4-hydroboration of N-heteroaromatic substrates under simple operating procedures. It also acts as a reagent for the stoichiometric C-H borylation of toluene, displaying high meta regioselectivity in the borylated products. Reaction of 1 with 9-BBN resulted in HBpin substitution to form the new anionic tetra(dihydroborate) complex [K(DME)(18-c-6)][Re(κ2-H-9-BBN)4] 4 for which the hydride positions were clearly identified by X-ray crystallography. The method used to generate these isolable yet reactive boron-hydride complexes is direct and straightforward and has potential utility for the exploitation of other metal oxo compounds in operationally simple catalytic reactions.

The Ups and Downs When TLX-1 and Other Transcriptional Modulators Abound: A Case of T-ALL with a Transcriptionally Complex Set of Mutations.

OBJECTIVES: Acute T-lymphoblastic leukemia (T-ALL) is a malignancy of immature T-cells in children and adults and although it occurs less frequently than B-ALL, it carries a worse prognosis, especially after relapse. Molecular characterization and subtyping of T-ALL has begun to reveal vital insights into the complex biology of T-ALL and has prognostic and therapeutic implications. We present a case of a 19-year-old male who was found to have an early cortical phenotype T-ALL with multiple cytogenetic and somatic mutations including t(10;14) TLX-1 translocation, 9p22 CDKN2A deletion and missense mutations in PHF6, NOTCH-1, and FBXW7. Characterization of the significance of these mutations reveals that PHF6 mutations occur more frequently in adult males in association with TLX-1 translocations and early cortical phenotypes with NOTCH-1 activating mutations. We show mechanistically that these alterations occur in concert with one another to drive cell growth, cell survival and cell cycle progression. While still in development, further characterization of T-ALL is essential to provide more prognostic and therapeutically useful information.

Recent Advances in the Deoxydehydration of Vicinal Diols and Polyols.

Deoxydehydration (DODH) is one of the most promising tools to reduce the oxygen content of biomass (sugars and polyols) and provide analogues of platform chemicals that are derived from fossil resources. This reaction converts a vicinal diol into an alkene and is typically catalyzed by high-oxidation-state metal-oxo compounds in the presence of a stoichiometric reductant, with examples of both homogeneous and heterogeneous systems. This minireview will highlight the developments in this field over the past 5 years and focus on efforts to solve the problems that currently prevent DODH being performed on a commercial scale, including the nature of the reductant, substrate scope and selectivity, and catalyst recovery and expense.

A suite of phenotypic assays to ensure pipeline diversity when prioritizing drug-like Cryptosporidium growth inhibitors.

Cryptosporidiosis is a leading cause of life-threatening diarrhea in children, and the only currently approved drug is ineffective in malnourished children and immunocompromised people. Large-scale phenotypic screens are ongoing to identify anticryptosporidial compounds, but optimal approaches to prioritize inhibitors and establish a mechanistically diverse drug development pipeline are unknown. Here, we present a panel of medium-throughput mode of action assays that enable testing of compounds in several stages of the Cryptosporidium life cycle. Phenotypic profiles are given for thirty-nine anticryptosporidials. Using a clustering algorithm, the compounds sort by phenotypic profile into distinct groups of inhibitors that are either chemical analogs (i.e. same molecular mechanism of action (MMOA)) or known to have similar MMOA. Furthermore, compounds belonging to multiple phenotypic clusters are efficacious in a chronic mouse model of cryptosporidiosis. This suite of phenotypic assays should ensure a drug development pipeline with diverse MMOA without the need to identify underlying mechanisms.

Aryl Boronic Acid Catalysed Dehydrative Substitution of Benzylic Alcohols for C-O Bond Formation.

A combination of pentafluorophenylboronic acid and oxalic acid catalyses the dehydrative substitution of benzylic alcohols with a second alcohol to form new C-O bonds. This method has been applied to the intermolecular substitution of benzylic alcohols to form symmetrical ethers, intramolecular cyclisations of diols to form aryl-substituted tetrahydrofuran and tetrahydropyran derivatives, and intermolecular crossed-etherification reactions between two different alcohols. Mechanistic control experiments have identified a potential catalytic intermediate formed between the aryl boronic acid and oxalic acid.

Exploiting the Bis-Nucleophilicity of α-Aminoboronates: Copper-Catalyzed, Intramolecular Aminoalkylations of Bromobenzoyl Chlorides.

α-Aminoboronate salts are interesting examples of heteroatomic species containing adjacent nucleophilic centers. We have developed an acylation/arylation reaction using 2-bromobenzoyl chlorides as bis-electrophiles that harnesses the nucleophilicity of both positions, leading to isoindolinones. The reactions proceed under mild conditions via an intramolecular, Cu-catalyzed sp(3)-sp(2) coupling, giving products in up to 95% yield. These conditions enable arylation of α,α-disubstituted aminoboronates, which are difficult to accomplish using methods based on less abundant and more expensive transition metals.

Catalytic reductive N-alkylation of amines using carboxylic acids.

We report a catalytic reductive alkylation reaction of primary or secondary amines with carboxylic acids. The two-phase process involves silane mediated direct amidation followed by catalytic reduction.

HIV treatments reduce malaria liver stage burden in a non-human primate model of malaria infection at clinically relevant concentrations in vivo.

We have previously shown that the HIV protease inhibitor lopinavir-ritonavir (LPV-RTV) and the antibiotic trimethoprim sulfamethoxazole (TMP-SMX) inhibit Plasmodium liver stages in rodent malarias and in vitro in P. falciparum. Since clinically relevant levels are better achieved in the non-human-primate model, and since Plasmodium knowlesi is an accepted animal model for the study of liver stages of malaria as a surrogate for P. falciparum infection, we investigated the antimalarial activity of these drugs on Plasmodium knowlesi liver stages in rhesus macaques. We demonstrate that TMP-SMX and TMP-SMX+LPV-RTV (in combination), but not LPV-RTV alone, inhibit liver stage parasite development. Because drugs that inhibit the clinically silent liver stages target parasites when they are present in lower numbers, these results may have implications for eradication efforts.

Feed-forward regulation of phagocytosis by Entamoeba histolytica.

The parasitic protozoan Entamoeba histolytica is aptly named for its capacity to destroy host tissue. When E. histolytica trophozoites invade the lamina propria of a host colon, extracellular matrices are degraded while host cells are killed and phagocytosed. The ability of E. histolytica to phagocytose host cells correlates with virulence in vivo. In order to better understand the mechanism of phagocytosis, we used an E. histolytica Affymetrix microarray chip to measure the total gene expression of phagocytic and nonphagocytic subpopulations. Using paramagnetic beads coated with a known host ligand that stimulates phagocytosis, phagocytic and nonphagocytic amoebae from a single culture were purified. Microarray analysis of the subpopulations identified 121 genes with >2-fold higher expression in phagocytic than in nonphagocytic amoebae. Functional annotation identified genes encoding proteins involved in actin binding and cytoskeletal organization as highly enriched gene clusters. Post hoc analyses of selected genes showed that the gene expression profile identified in the microarray experiment did not exist prior to cell sorting but rather was stimulated through phagocytosis. Further, these expression profiles correlated with an increase in phagocytic ability, as E. histolytica cultures exposed to an initial stimulus of phagocytosis showed increased phagocytic ability upon a second stimulus. To our knowledge, this is the first description of such feed-forward regulation of gene expression and phagocytic ability in a phagocyte.

Ultrasonic analysis of rennet-induced pre-gelation and gelation processes in milk.

Dynamics of micro-structural changes in milk during the renneting process were analysed using high-resolution ultrasonic spectroscopy in combination with dynamic rheology and NIR transmission measurements. Two independent ultrasonic parameters, velocity and attenuation were measured in the frequency range 2 to 15 MHz, as a function of time after addition of rennet to milk. The results show an initial decrease of 20 nm for the average diameter of micelles caused by hydrolysis of the kappa-casein 'hairy' layer followed by an aggregation of the micelles into small clusters (effective aggregation number of 3) and then formation of the gel structure. It was found that evolution of ultrasonic attenuation in the renneting process could well be described by the scattering of the ultrasonic waves on aggregates. The evolution of ultrasonic velocity is well described by the scattering theory but deviates from the predicted curve at the gelation stage of the process, which shows the difference in propagation of ultrasonic waves in a gel structure compared with dispersions. Overall, we found high-resolution ultrasonic spectroscopy to be a powerful tool for analysis of microscopic processes in the formation of milk gel. It allows the characterisation of the pre-gelation processes, such as hydrolysis and aggregation, and the initial stages in the formation of the gel network as well as monitoring of the microscopic evolution in the gel at the post-gelation stage.