Thinking about inequalities in physical activity as an emergent feature of complex systems.

Inequalities in physical activity are well documented, especially between socioeconomic groups. However, progress on reducing these inequalities is proving challenging. In this commentary, we argue that a complex system perspective is needed, specifically to reorient our thinking of inequalities in physical activity to be emergent features of complex systems. Operationalising this perspective involves acknowledging the multiple dynamic and non-linear interactions which take place between system parts and, over time aggregate to become macro patterns such as physical activity inequalities. We argue that this framing will enhance our understanding of the emergence of inequalities in physical activity and, therefore, provide interventions better suited to the subgroups of the population they are designed to help.

Sentinel lymph node biopsy for melanoma in the older population: A prospective analysis of outcomes.

BACKGROUND: The use of sentinel lymph node biopsy (SLNB) in the older population, defined as those over 70 years old, has been debated since the adoption of SLNB into routine practice. Interestingly, there remains a paucity of evidence, especially regarding the rates of SLNB positivity, complications, and subsequent adjuvant therapy in those with node positivity. METHOD: Data on patient's comorbidities, positivity rates, complication rates, and subsequent adjuvant treatments were collected prospectively from 998 patients (644 patients < 70 and 354 patients ≥ 70 years old) between 2016 and 2022. RESULTS: Patients aged ≥ 70 were found to have a higher prevalence of comorbidities, including hypertension, diabetes and hyperlipidaemia. The mean Breslow thickness was 2.2 and 2.5 in the under and over 70 groups respectively (p = 0.03). The mean mitotic rate was found to be 3.3 in the under 70 s and 4.1 in the over 70 s (p = 0.02). Despite these results, no significant differences were observed in the positivity rates of sentinel lymph node biopsies or in the treatment options selected for positive results. The under 70 s were more likely to experience loss of sensation (p < 0.01), but no difference was found in the total number of complications between the two groups. CONCLUSION: Although patients aged 70 and above had a greater incidence of comorbidities, the study revealed that they had lower complications rates and there was no significant variation in the SLNB positivity rate or chosen treatment options between the two age groups. This study supports the move to physiological rather than chronological age assessments in SLNB of the elderly.

The prevalence of Mycoplasma genitalium (MG) and Trichomonas vaginalis (TV) at testing centers in Belgium, Germany, Spain, and the UK using the cobas TV/MG molecular assay.

Mycoplasma genitalium (MG) and Trichomonas vaginalis (TV) can lead to long-term sequelae in males and females; however, global prevalence data vary between geographical regions, as these sexually transmitted infections are not included in routine screening. The objective of this study was to use the cobas® TV/MG assay to assess the point prevalence of TV and MG in specimens from men and women over a broad European geographical area. Urine, vaginal, endocervical, and rectal samples were collected from patients aged ≥ 18 years receiving Chlamydia trachomatis (CT) and/or Neisseria gonorrhoeae (NG) screening as per local standard of care at sites in Belgium, Germany, Spain, and the UK (Wales). Remnant samples were assessed using the cobas TV/MG assay. Analysis of 2795 samples showed that MG prevalence varied slightly across female sample types (range: 1.7-5.8%; p = 0.0042). MG prevalence was higher in male rectal samples (12.5%) than in male urine samples (3.9%; p < 0.0001). TV prevalence was low in male (0.8%; 12/1535) and female (1.3%; 16/1260) samples across all sites. Co-infection of TV/MG with CT or NG was 10.0% (19/190) and 9.6% (7/73), respectively, in both male and female samples. MG and TV prevalence rates were comparable to the published literature in Europe. MG prevalence was highest in male rectal samples; as rectal testing is an off-label use of the cobas TV/MG assay, the clinical utility of this assay for rectal testing should be further investigated.

Ethnicity as a predictor of outcomes of psychological therapies for anxiety and depression: a retrospective cohort analysis.

BACKGROUND: Studies on predictors of outcomes of treatment for common mental health disorders (CMDs) in community mental health settings are scarce, and sample sizes are often small. Research on the impact of identifying as a member of an ethnic minority group on treatment outcomes is limited. AIMS: To ascertain whether ethnicity is an independent predictor of outcome and the extent to which any association is mediated by other sociodemographic factors. METHOD: Retrospective observational study of anonymised treatment data collected for routine clinical purposes. Data were analysed from nine Improving Access to Psychological Therapy (IAPT) services from 2009 to 2016. Social functioning, ethnic group, age, gender, occupation and baseline severity of the mental health disorder were analysed as predictors of outcome. RESULTS: Outcomes varied with ethnic group. Levels of occupation, social deprivation, initial morbidity and social functioning varied between ethnic groups at baseline. After adjustment for these factors the impact of ethnicity was attenuated and only some ethnic groups remained as significant independent predictors of treatment outcome. CONCLUSIONS: Ethnic minority status is a marker for multiple disadvantages. Some of the differences in outcome seen between ethnic groups may be the result of more general factors present in all ethnic groups but at greater intensity in some ethnic minority groups.

Plasmodium falciparum pfhrp2 and pfhrp3 Gene Deletions and Relatedness to Other Global Isolates, Djibouti, 2019-2020.

Deletions of pfhrp2 and paralogue pfhrp3 (pfhrp2/3) genes threaten Plasmodium falciparum diagnosis by rapid diagnostic test. We examined 1,002 samples from suspected malaria patients in Djibouti City, Djibouti, to investigate pfhrp2/3 deletions. We performed assays for Plasmodium antigen carriage, pfhrp2/3 genotyping, and sequencing for 7 neutral microsatellites to assess relatedness. By PCR assay, 311 (31.0%) samples tested positive for P. falciparum infection, and 296 (95.2%) were successfully genotyped; 37 (12.5%) samples were pfhrp2+/pfhrp3+, 51 (17.2%) were pfhrp2+/pfhrp3-, 5 (1.7%) were pfhrp2-/pfhrp3+, and 203 (68.6%) were pfhrp2-/pfhrp3-. Histidine-rich protein 2/3 antigen concentrations were reduced with corresponding gene deletions. Djibouti P. falciparum is closely related to Ethiopia and Eritrea parasites (pairwise GST 0.68 [Ethiopia] and 0.77 [Eritrea]). P. falciparum with deletions in pfhrp2/3 genes were highly prevalent in Djibouti City in 2019-2020; they appear to have arisen de novo within the Horn of Africa and have not been imported.

Detecting asymptomatic carriage of Plasmodium falciparum in southern Ghana: utility of molecular and serological diagnostic tools.

BACKGROUND: Asymptomatic malaria infections can serve as potential reservoirs for malaria transmission. The density of parasites contained in these infections range from microscopic to submicroscopic densities, making the accurate detection of asymptomatic parasite carriage highly dependent on the sensitivity of the tools used for the diagnosis. This study sought to evaluate the sensitivities of a variety of molecular and serological diagnostic tools at determining the prevalence of asymptomatic Plasmodium falciparum parasite infections in two communities with varying malaria parasite prevalence. METHODS: Whole blood was collected from 194 afebrile participants aged between 6 and 70 years old living in a high (Obom) and a low (Asutsuare) malaria transmission setting of Ghana. Thick and thin blood smears, HRP2 based malaria rapid diagnostic test (RDT) and filter paper dried blood spots (DBS) were prepared from each blood sample. Genomic DNA was extracted from the remaining blood and used in Plasmodium specific photo-induced electron transfer polymerase chain reaction (PET-PCR) and Nested PCR, whilst the HRP2 antigen content of the DBS was estimated using a bead immunoassay. A comparison of malaria parasite prevalence as determined by each method was performed. RESULTS: Parasite prevalence in the high transmission site of Obom was estimated at 71.4%, 61.9%, 60%, 37.8% and 19.1% by Nested PCR, the HRP2 bead assay, PET-PCR, HRP2-RDT and microscopy respectively. Parasite prevalence in the low transmission site of Asutsuare was estimated at 50.1%, 11.2%, 5.6%, 0% and 2.2% by Nested PCR, the HRP2 bead assay, PET-PCR, RDT and microscopy, respectively. The diagnostic performance of Nested PCR, PET-PCR and the HRP2 bead assay was similar in Obom but in Asutsuare, Nested PCR had a significantly higher sensitivity than PET-PCR and the HRP2 bead assay, which had similar sensitivity. CONCLUSIONS: Nested PCR exhibited the highest sensitivity by identifying the highest prevalence of asymptomatic P. falciparum in both the high and low parasite prevalence settings. However, parasite prevalence estimated by the HRP2 bead assay and PET-PCR had the highest level of inter-rater agreement relative to all the other tools tested and have the advantage of requiring fewer processing steps relative to Nested PCR and producing quantitative results.

The natural history of asymptomatic central venous catheter-related thrombosis in critically ill children.

Asymptomatic central venous catheter (CVC)-related thrombosis in children varies in incidence from 5% to 69%. The rate of acute and long-term complications, such as postthrombotic syndrome (PTS), from asymptomatic CVC-related thrombosis is unknown. This article reports the outcomes of a prospective study of 189 children in pediatric intensive care that aimed to determine the frequency of asymptomatic CVC-related thrombosis during hospital admission, and the incidence of residual CVC-related thrombosis and clinically significant PTS 2 years later. Risk factors associated with CVC-related thrombosis were also identified. This study is distinct from previous work as children identified to have asymptomatic CVC-related thrombosis were not treated (clinical team kept blinded) and the entire cohort was followed for 2 years to determine the natural history of asymptomatic thrombosis. Ultrasounds of 146 children determined a 21.9% incidence of acute CVC-related thrombosis. Two children were symptomatic. No radiological thrombosis extension or clinical embolization occurred in the 126 children assessed at follow-up. Using 2 recognized PTS scales, clinically significant PTS was reported in 2 children (1 symptomatic, 1 asymptomatic CVC-related thrombosis), however, neither had functional impairment. Cardiac arrest was a risk factor for CVC-related thrombosis during admission and femoral CVC placement was predictive of residual thrombosis 2 years later. This study challenges the notion that critically ill children with asymptomatic CVC-related thrombosis require anticoagulant treatment, as the results demonstrate that the incidence of acute or long-term complications is low. A larger confirmatory study of nontreatment of CVC-related thrombosis in critically ill children is justified.

Guiding principles for rewilding.

There has been much recent interest in the concept of rewilding as a tool for nature conservation, but also confusion over the idea, which has limited its utility. We developed a unifying definition and 10 guiding principles for rewilding through a survey of 59 rewilding experts, a summary of key organizations' rewilding visions, and workshops involving over 100 participants from around the world. The guiding principles convey that rewilding exits on a continuum of scale, connectivity, and level of human influence and aims to restore ecosystem structure and functions to achieve a self-sustaining autonomous nature. These principles clarify the concept of rewilding and improve its effectiveness as a tool to achieve global conservation targets, including those of the UN Decade on Ecosystem Restoration and post-2020 Global Biodiversity Framework. Finally, we suggest differences in rewilding perspectives lie largely in the extent to which it is seen as achievable and in specific interventions. An understanding of the context of rewilding projects is the key to success, and careful site-specific interpretations will help achieve the aims of rewilding.

Recientemente ha habido mucho interés por el concepto de retorno a la vida silvestre como herramienta para la conservación de la naturaleza, pero también ha habido confusión por la idea que ha limitado su utilidad. Desarrollamos una definición unificadora y diez principios básicos para el retorno a la vida silvestre por medio de encuestas a 59 expertos en retorno a la vida silvestre, un resumen de las visiones de las organizaciones más importantes para el retorno a la vida silvestre y talleres que involucraron a más de 100 participantes de todo el mundo. Los principios básicos transmiten que el retorno a la vida silvestre existe en un continuo de escala, conectividad y nivel de influencia humana y que su objetivo es restaurar la estructura y las funciones del ecosistema para lograr una naturaleza autónoma autosustentable. Estos principios aclaran el concepto del retorno a la vida silvestre e incrementan su efectividad como herramienta para lograr los objetivos mundiales de conservación, incluyendo aquellos de la Década de la ONU para la Restauración de Ecosistemas y el Marco de Trabajo de la Biodiversidad Global post 2020. Finalmente, sugerimos que las diferencias en las perspectivas del retorno a la vida silvestre yacen principalmente en el grado al que es visto como factible y en intervenciones específicas. Un entendimiento del contexto de los proyectos de retorno a la vida silvestre es importante para el éxito, y las interpretaciones específicas de sitio ayudarán a lograr las metas del retorno a la vida silvestre. Principios Básicos para el Retorno a la Vida Silvestre.

Community-based surveys for Plasmodium falciparum pfhrp2 and pfhrp3 gene deletions in selected regions of mainland Tanzania.

BACKGROUND: Histidine-rich protein 2 (HRP2)-based malaria rapid diagnostic tests (RDTs) are effective and widely used for the detection of wild-type Plasmodium falciparum infections. Although recent studies have reported false negative HRP2 RDT results due to pfhrp2 and pfhrp3 gene deletions in different countries, there is a paucity of data on the deletions of these genes in Tanzania. METHODS: A community-based cross-sectional survey was conducted between July and November 2017 in four regions: Geita, Kigoma, Mtwara and Ruvuma. All participants had microscopy and RDT performed in the field and provided a blood sample for laboratory multiplex antigen detection (for Plasmodium lactate dehydrogenase, aldolase, and P. falciparum HRP2). Samples showing RDT false negativity or aberrant relationship of HRP2 to pan-Plasmodium antigens were genotyped to detect the presence/absence of pfhrp2/3 genes. RESULTS: Of all samples screened by the multiplex antigen assay (n = 7543), 2417 (32.0%) were positive for any Plasmodium antigens while 5126 (68.0%) were negative for all antigens. The vast majority of the antigen positive samples contained HRP2 (2411, 99.8%), but 6 (0.2%) had only pLDH and/or aldolase without HRP2. Overall, 13 samples had an atypical relationship between a pan-Plasmodium antigen and HRP2, but were positive by PCR. An additional 16 samples with negative HRP2 RDT results but P. falciparum positive by microscopy were also chosen for pfhrp2/3 genotyping. The summation of false negative RDT results and laboratory antigen results provided 35 total samples with confirmed P. falciparum DNA for pfhrp2/3 genotyping. Of the 35 samples, 4 (11.4%) failed to consistently amplify positive control genes; pfmsp1 and pfmsp2 and were excluded from the analysis. The pfhrp2 and pfhrp3 genes were successfully amplified in the remaining 31 (88.6%) samples, confirming an absence of deletions in these genes. CONCLUSIONS: This study provides evidence that P. falciparum parasites in the study area have no deletions of both pfhrp2 and pfhrp3 genes. Although single gene deletions could have been missed by the multiplex antigen assay, the findings support the continued use of HRP2-based RDTs in Tanzania for routine malaria diagnosis. There is a need for the surveillance to monitor the status of pfhrp2 and/or pfhrp3 deletions in the future.

Screening for Pfhrp2/3-Deleted Plasmodium falciparum, Non-falciparum, and Low-Density Malaria Infections by a Multiplex Antigen Assay.

Background: Detection of Plasmodium antigens provides evidence of malaria infection status and is the basis for most malaria diagnosis. Methods: We developed a sensitive bead-based multiplex assay for laboratory use, which simultaneously detects pan-Plasmodium aldolase (pAldo), pan-Plasmodium lactate dehydrogenase (pLDH), and P. falciparum histidine-rich protein 2 (PfHRP2) antigens. The assay was validated against purified recombinant antigens, monospecies malaria infections, and noninfected blood samples. To test against samples collected in an endemic setting, Angolan outpatient samples (n = 1267) were assayed. Results: Of 466 Angolan samples positive for at least 1 antigen, the most common antigen profiles were PfHRP2+/pAldo+/pLDH+ (167, 36%), PfHRP2+/pAldo-/pLDH- (163, 35%), and PfHRP2+/pAldo+/pLDH- (129, 28%). Antigen profile was predictive of polymerase chain reaction (PCR) positivity and parasite density. Eight Angolan samples (1.7%) had no or very low PfHRP2 but were positive for 1 or both of the other antigens. PCR analysis confirmed 3 (0.6%) were P. ovale infections and 2 (0.4%) represented P. falciparum parasites lacking Pfhrp2 and/or Pfhrp3. Conclusions: These are the first reports of Pfhrp2/3 deletion mutants in Angola. High-throughput multiplex antigen detection can inexpensively screen for low-density P. falciparum, non-falciparum, and Pfhrp2/3-deleted parasites to provide population-level antigen estimates and identify specimens requiring further molecular characterization.

WGS to determine the extent of Clostridioides difficile transmission in a high incidence setting in North Wales in 2015.

OBJECTIVES: Rates of Clostridioides (Clostridium) difficile infection (CDI) are higher in North Wales than elsewhere in the UK. We used WGS to investigate if this is due to increased healthcare-associated transmission from other cases. METHODS: Healthcare and community C. difficile isolates from patients across North Wales (February-July 2015) from glutamate dehydrogenase (GDH)-positive faecal samples underwent WGS. Data from patient records, hospital management systems and national antimicrobial use surveillance were used. RESULTS: Of the 499 GDH-positive samples, 338 (68%) were sequenced and 299 distinct infections/colonizations were identified, 229/299 (77%) with toxin genes. Only 39/229 (17%) toxigenic isolates were related within ≤2 SNPs to ≥1 infections/colonizations from a previously sampled patient, i.e. demonstrated evidence of possible transmission. Independent predictors of possible transmission included healthcare exposure in the last 12 weeks (P = 0.002, with rates varying by hospital), infection with MLST types ST-1 (ribotype 027) and ST-11 (predominantly ribotype 078) compared with all other toxigenic STs (P < 0.001), and cephalosporin exposure in the potential transmission recipient (P = 0.02). Adjusting for all these factors, there was no additional effect of ward workload (P = 0.54) or failure to meet cleaning targets (P = 0.25). Use of antimicrobials is higher in North Wales compared with England and the rest of Wales. CONCLUSIONS: Levels of transmission detected by WGS were comparable to previously described rates in endemic settings; other explanations, such as variations in antimicrobial use, are required to explain the high levels of CDI. Cephalosporins are a risk factor for infection with C. difficile from another infected or colonized case.

Multiplex malaria antigen detection by bead-based assay and molecular confirmation by PCR shows no evidence of Pfhrp2 and Pfhrp3 deletion in Haiti.

BACKGROUND: The Plasmodium falciparum parasite is the only human malaria that produces the histidine-rich protein 2 and 3 (HRP2/3) antigens. Currently, HRP2/3 are widely used in malaria rapid diagnostic tests (RDTs), but several global reports have recently emerged showing genetic deletion of one or both of these antigens in parasites. Deletion of these antigens could pose a major concern for P. falciparum diagnosis in Haiti which currently uses RDTs based solely on the detection of the HRP2/3 antigens. METHODS: From September 2012 through February 2014, dried blood spots (DBS) were collected in Haiti from 9317 febrile patients presenting to 17 health facilities in 5 departments throughout the country as part of a bed net intervention study. All DBS from RDT positive persons and a random sampling of DBS from RDT negative persons were assayed for P. falciparum DNA by nested and PET-PCR (n = 2695 total). All PCR positive samples (n = 331) and a subset of PCR negative samples (n = 95) were assayed for three malaria antigens by a multiplex bead assay: pan-Plasmodium aldolase (pAldo), pan-Plasmodium lactate dehydrogenase (pLDH), and HRP2/3. Any samples positive for P. falciparum DNA, but negative for HRP2/3 antigens were tested by nested PCR for Pfhrp2 and Pfhrp3 gene deletions. RESULTS: Of 2695 DBS tested for Plasmodium DNA, 345 (12.8%) were originally found to be positive for P. falciparum DNA; 331 of these had DBS available for antigen detection. Of these, 266 (80.4%) were positive for pAldo, 221 (66.8%) positive for pLDH, and 324 (97.9%) were positive for HRP2/3 antigens. Seven samples (2.1%) positive for P. falciparum DNA were not positive for any of the three antigens by the bead assay, and were investigated for potential Pfhrp2/3 gene deletion by PCR. These samples either successfully amplified Pfhrp2/3 genes or were at an estimated parasite density too low for sufficient DNA to perform successful genotyping. CONCLUSIONS: Malaria positive samples in multiple Haitian sites were found to contain the HRP2/3 antigens, and no evidence was found of Pfhrp2/3 deletions. Malaria RDTs based on the detection of the HRP2/3 antigens remain a reliable P. falciparum diagnostic tool as Haiti works towards malaria elimination.

A review of the WHO malaria rapid diagnostic test product testing programme (2008-2018): performance, procurement and policy.

Malaria rapid diagnostic tests (RDTs) emerged in the early 1990s into largely unregulated markets, and uncertain field performance was a major concern for the acceptance of tests for malaria case management. This, combined with the need to guide procurement decisions of UN agencies and WHO Member States, led to the creation of an independent, internationally coordinated RDT evaluation programme aiming to provide comparative performance data of commercially available RDTs. Products were assessed against Plasmodium falciparum and Plasmodium vivax samples diluted to two densities, along with malaria-negative samples from healthy individuals, and from people with immunological abnormalities or non-malarial infections. Three measures were established as indicators of performance, (i) panel detection score (PDS) determined against low density panels prepared from P. falciparum and P. vivax wild-type samples, (ii) false positive rate, and (iii) invalid rate, and minimum criteria defined. Over eight rounds of the programme, 332 products were tested. Between Rounds 1 and 8, substantial improvements were seen in all performance measures. The number of products meeting all criteria increased from 26.8% (11/41) in Round 1, to 79.4% (27/34) in Round 8. While products submitted to further evaluation rounds under compulsory re-testing did not show improvement, those voluntarily resubmitted showed significant increases in P. falciparum (p = 0.002) and P. vivax PDS (p < 0.001), with more products meeting the criteria upon re-testing. Through this programme, the differentiation of products based on comparative performance, combined with policy changes has been influential in the acceptance of malaria RDTs as a case-management tool, enabling a policy of parasite-based diagnosis prior to treatment. Publication of product testing results has produced a transparent market allowing users and procurers to clearly identify appropriate products for their situation, and could form a model for introduction of other, broad-scale diagnostics.

Unsymmetrical Organotrisulfide Formation via Low-Temperature Disulfanyl Anion Transfer to an Organothiosulfonate.

New methodology is presented for the formation of unsymmetrical organotrisulfides in a high yield and purity, relatively free of polysulfide byproducts. The highlight of the method is the low-temperature (-78 °C) deprotection of a disulfanyl acetate with sodium methoxide in THF to form a disulfanyl anion, which reacts rapidly in situ with an organothiosulfonate ( S-aryl or S-alkyl) within 30 seconds followed by quenching. The discovery of these new reaction conditions together with the relative greenness of the chemistry overall makes for an efficient protocol, from which a range of organotrisulfides covering aliphatic, aromatic, as well as cysteine and sugar groups can be accessed in a high yield and purity.

Method for Tuneable Homeotropic Anchoring at Microstructures in Liquid Crystal Devices.

A simple method for vapour-phase deposition of a silane surfactant is presented, which produces tuneable homeotropic anchoring in liquid crystals. Both the zenithal anchoring energy and surface slip are measured by fitting to the latching threshold versus pulse width characteristic of a zenithal bistable nematic liquid crystal device based on a deep, submicron grating. The method is shown to give microscopic anchoring strength between 5 × 10-5 and 2 × 10-4 J/m2, with a surface slip of about 100 nm. The silanated surfaces are characterized using atomic force microscopy and X-ray photoelectron spectroscopy, which show a direct relationship between the surface coverage of silane groups and the resulting anchoring energy.

The effects of kisspeptin on ß-cell function, serum metabolites and appetite in humans.

AIMS: To investigate the effect of kisspeptin on glucose-stimulated insulin secretion and appetite in humans. MATERIALS AND METHODS: In 15 healthy men (age: 25.2 ± 1.1 years; BMI: 22.3 ± 0.5 kg m-2 ), we compared the effects of 1 nmol kg-1 h-1 kisspeptin versus vehicle administration on glucose-stimulated insulin secretion, metabolites, gut hormones, appetite and food intake. In addition, we assessed the effect of kisspeptin on glucose-stimulated insulin secretion in vitro in human pancreatic islets and a human ß-cell line (EndoC-ßH1 cells). RESULTS: Kisspeptin administration to healthy men enhanced insulin secretion following an intravenous glucose load, and modulated serum metabolites. In keeping with this, kisspeptin increased glucose-stimulated insulin secretion from human islets and a human pancreatic cell line in vitro. In addition, kisspeptin administration did not alter gut hormones, appetite or food intake in healthy men. CONCLUSIONS: Collectively, these data demonstrate for the first time a beneficial role for kisspeptin in insulin secretion in humans in vivo. This has important implications for our understanding of the links between reproduction and metabolism in humans, as well as for the ongoing translational development of kisspeptin-based therapies for reproductive and potentially metabolic conditions.

Quaternized α,α'-Amino Acids via Curtius Rearrangement of Substituted Malonate-Imidazolidinones.

An efficient synthesis protocol is presented for accessing quaternized α-amino acids in chiral, nonracemic form via diastereoselective malonate alkylation followed by C- to N-transposition. The key stereodifferentiating step involves a diastereoselective alkylation of an α-monosubstituted malonate-imidazolidinone, which is followed first by a chemoselective malonate PMB ester removal and then a Curtius rearrangement to provide the transposition. The method demonstrates a high product ee (89-99% for eight cases) for quaternizing a range of proteinogenic α-amino acids. The stereogenicity in targets 5a-i supports previous conclusions that the diastereoselective alkylation step proceeds via an α-substituted malonate-imidazolidinone enolate in its Z-configuration, with the auxiliary in an s-transC-N conformation.

Six Weeks Versus 3 Months of Anticoagulant Treatment for Pediatric Central Venous Catheter-related Venous Thromboembolism.

OBJECTIVE: Central venous catheters (CVCs) are the single most important predisposing factor for the development of pediatric venous thromboembolism (VTE). Treatment recommendations suggest anticoagulation for the duration of 6 weeks to 3 months. This project investigated clinical outcomes associated with 6 weeks compared with 3 months of enoxaparin therapy following diagnosis of a CVC-related VTE. METHODS: This retrospective cohort study enrolled patients aged 18 years and below treated with enoxaparin with/without unfractionated heparin for a radiologically confirmed CVC-related VTE. Patients were identified using the pharmacy database, radiologic imaging, and medical records. Patients were divided into 2 groups based on the duration of anticoagulation (6+1 or 12±2 wk) and data were analyzed using descriptive statistics. RESULTS: Seventy-four patients were included. Higher rates of complete thrombosis resolution were observed in children treated for 6 weeks at treatment cessation (39.4%) and long-term follow-up (61.5%), compared with 3 months (11.8% and 9.0%, respectively). CONCLUSIONS: Six weeks of treatment for CVC-related VTE may provide noninferior clinical outcomes compared with 3 months of anticoagulation. An international randomized-controlled trial (Kids-DOTT) is underway to explore the optimal duration of anticoagulation for acute-provoked VTE in children. This manuscript highlights that data from such studies is urgently needed.