To form or not to form a reaction complex: exploring ion-molecule reactions between C3H4 isomers and Xe+ and O2.

Ion-molecule reactions are an essential contributor to the chemistry of a diverse range of environments. While a great deal of work has been done to understand the fundamental mechanisms driving these reactions, there is still much more to discover. Here, we expand upon prior studies on ion-molecule reactions involving two isomers of C3H4, allene (H2C3H2) and propyne (H3C3H). Specifically, we probe the previously observed isomeric dependent reactivity of these molecules by reacting them with two ions with nearly identical ionization potentials, Xe+ and O2+. Our goal is to determine if the isomer-dependent reaction mechanisms previously observed are universal for C3H4 or if they depend on the ion character as well. Through the combination of experimental measurements and theoretical calculations, we found that both isomeric structure and identity of the ion contribute to the propensity of a reaction complex forming or for only long-range charge transfer to occur.

Snakebite in South Africa: A retrospective review May 2015-June 2020.

Snakebite envenoming in Sub-Saharan Africa present a significant public health problem. An investigation into how often species responsible for envenomation were correctly identified, as well as which venomous species caused the most frequent and problematic envenomation symptomatology were conducted to establish severity of this problem from a South African context. Descriptive statistics were used to quantitatively describe the variables in snakebite related Telelog call records reported to the Poison Information Helpline of the Western Cape (PIHWC) over a five-year period. A total of 1411 snakebite related calls were received. In 44% of all snakebite calls the bite was inflicted by an unidentified snake specie. The most snakebites occurred during the summer months from December-March. The most bites occurred in males (20-39 years). The incidence of snakebite in South Africa was 2.39 per 100 000 population, with the highest incidence of snakebite in North-West province of South Africa. In sub-Saharan Africa there is a major underestimation of the incidence of snakebite due to under reporting and absence of physical attendance to health care facilities. The PIHWC provides an invaluable service in assisting and in-forming medical personnel and the public on the management of snakebites. Data collected by centers provides a source of information on the prevalence of snakebites and medically important species that research should be aimed towards.

[Dermatological conditions requiring intensive care]. / Intensivpflichtige Hauterkrankungen.

Some skin conditions may require treatment in intensive care units. The early diagnosis of life-threatening dermatoses is a considerable challenge. We review skin diseases which may require intensive care. In addition to Stevens-Johnson syndrome and toxic epidermal necrolysis, representing adverse skin reactions, we discuss staphylococcal scalded skin syndrome and necrotizing fasciitis as infection-associated dermatoses, as well as angioedema. We focus on the course of disease describing clinical presentations, diagnostics and therapeutic strategies with respect to critical medical conditions.

Ivermectin exposures reported to the Poisons Information Helpline in South Africa during the COVID-19 pandemic.

BACKGROUND: Ivermectin is an antiparasitic drug that has shown in vitro activity against COVID­19. Clinical studies supporting ivermectin for COVID­19 prevention and treatment are conflicting, with important limitations. Public support for ivermectin is significant, with extensive off-label use despite the conflicting views on its efficacy. Ivermectin tablets and injectable formulations are not registered in South Africa for human use by the South African Health Products Regulatory Authority. The National Department of Health does not currently recommend the use of ivermectin for COVID­19. OBJECTIVES: To describe cases of ivermectin exposure reported to the Poisons Information Helpline of the Western Cape (PIHWC) before and after publication of the drug's in vitro activity against SARS-CoV-2. METHODS: In a retrospective review, ivermectin-related calls reported to the PIHWC from 1 June 2015 to 30 June 2020 (period 1) were compared with calls received from 1 July 2020 to 31 July 2021 (period 2), dichotomised according to the first publication indicating ivermectin activity against SARS-CoV-2. RESULTS: Seventy-one cases were screened, and 65 were included for analysis; 19 cases were reported during period 1 and 46 during period 2. During period 2, 25 ivermectin cases (54.3%) were related to COVID­19 use. Of these, 24 cases (52.2%) involved veterinary preparations, 3 (6.5%) human preparations and 19 (41.3%) unknown preparations. Fourteen cases (73.7%) during period 1 and 30 (65.2%) during period 2 were reported to be symptomatic. The most common organ systems involved were the central nervous (n=26 cases; 40.0%), gastrointestinal (n=18; 27.7%), ocular (n=9; 13.8%) and dermatological (n=5; 7.7%) systems. CONCLUSION: Ivermectin-related exposure calls increased during study period 2, probably as a result of ivermectin being used as preventive and definitive therapy for COVID­19 in the absence of robust evidence on efficacy, dosing recommendations or appropriate formulations.

German-Austrian-Swiss Consensus Conference on clinical practice in chronic graft-versus-host disease (GVHD): guidance for supportive therapy of chronic cutaneous and musculoskeletal GVHD.

Supportive therapy plays a central role in the management of cutaneous and musculoskeletal manifestations of chronic graft-versus-host disease (cGVHD), either alone or in combination with systemic approaches. We present results from the German-Austrian-Swiss Consensus Conference on clinical practice in cGVHD, held in Regensburg, Germany, in November 2009. The intention was to achieve a consensus on current evidence-based treatment options as well as to provide guidelines for daily clinical practice. Skin is the most common organ involved in cGVHD. Its clinical presentation varies considerably. Patients may have pruritus, rash, pain, dyspigmentation and fibrotic or sclerodermatous lesions, often leading to contractures. Treatment options for supportive therapy in cutaneous cGVHD include topical therapies such as topical steroids and topical calcineurin inhibitors, as well as phototherapy and physiotherapy. The most relevant manifestation in musculoskeletal cGVHD is fasciitis which must be distinguished from sclerodermatous skin cGVHD. Physiotherapy is the mainstay of supportive treatment in fasciitis in cGVHD. Successful therapy of cutaneous and musculoskeletal cGVHD depends on interdisciplinary management to improve patients' quality of life.

Marker-less online MR-guided stereotactic body radiotherapy of liver metastases at a 1.5 T MR-Linac - Feasibility, workflow data and patient acceptance.

INTRODUCTION: Stereotactic body radiotherapy (SBRT) is an established ablative treatment for liver tumors with excellent local control rates. Magnetic resonance imaging guided radiotherapy (MRgRT) provides superior soft tissue contrast and may therefore facilitate a marker-less liver SBRT workflow. The goal of the present study was to investigate feasibility, workflow parameters, toxicity and patient acceptance of MRgSBRT on a 1.5 T MR-Linac. METHODS: Ten consecutive patients with liver metastases treated on a 1.5 T MR-Linac were included in this prospective trial. Tumor delineation was performed on four-dimensional computed tomography scans and both exhale triggered and free-breathing T2 MRI scans from the MR-Linac. An internal target volume based approach was applied. Organ at risk constraints were based on the UKSABR guidelines (Version 6.1). Patient acceptance regarding device specific aspects was assessed and toxicity was scored according to the common toxicity criteria of adverse events, version 5. RESULTS: Nine of ten tumors were clearly visible on the 1.5 T MR-Linac. No patient had fiducial markers placed for treatment. All patients were treated with three or five fractions. Median dose to 98% of the gross tumor volume was 38.5 Gy. The median time from "patient identity check" until "beam-off" was 31 min. Median beam on time was 9.6 min. Online MRgRT was well accepted in general and no treatment had to be interrupted on patient request. No event of symptomatic radiation induced liver disease was observed after a median follow-up of ten month (range 3-17 months). CONCLUSION: Our early experience suggests that online 1.5 T MRgSBRT of liver metastases represents a promising new non-invasive marker-free treatment modality based on high image quality, clinically reasonable in-room times and high patient acceptance. Further studies are necessary to assess clinical outcome, to validate advanced motion management and to explore the benefit of online response adaptive liver SBRT.

Core competencies required by toxicology graduates in order to function effectively in a Poisons Information Centre: A Delphi study.

INTRODUCTION: The availability of trained Medical Toxicologists in developing countries is limited and education in Medical Toxicology remains inadequate. The lack of toxicology services contributes to a knowledge gap in the management of poisonings. A need existed to investigate the core competencies required by toxicology graduates to effectively operate in a Poisons Information Centre. The aim of this study was to obtain consensus from an expert group of health care workers on these core competencies. This was done by making use of the Delphi technique. METHODOLOGY: The Delphi survey started with a set of carefully selected questions drawn from various sources including a literature review and exploration of existing curricula. To capture the collective opinion of experts in South Africa, Africa and also globally, three different groups were invited to participate in the study. To build and manage the questionnaire, the secure Research Electronic Data Capture (REDCap) web platform was used. RESULTS: A total of 134 competencies were selected for the three rounds and in the end consensus was reached on 118 (88%) items. Panel members agreed that 113 (96%) of these items should be incorporated in a Medical Toxicology curriculum and five (4%) should be excluded. DISCUSSION: All participants agreed that effective communication is an essential skill for toxicology graduates. The curriculum can address this problem by including effective pedagogy to enhance oral and written communication skills.Feedback from panellists indicated that the questionnaires were country-specific and not necessarily representative of all geographical locations. This is an example of the 'battle of curriculum design' where the context in which the curriculum will be used, will determine the content. CONCLUSION: The Delphi method, based on three iterative rounds and feedback from experts, was effective in reaching consensus on the learning outcomes of a Medical Toxicology curriculum. The study results will ultimately improve education in Medical Toxicology.

Mutants of bovine pancreatic trypsin inhibitor lacking cysteines 14 and 38 can fold properly.

It is a generally accepted principle of biology that a protein's primary sequence is the main determinant of its tertiary structure. However, the mechanism by which a protein proceeds from an unfolded, disordered state to a folded, relatively well-ordered, native conformation is obscure. Studies have been initiated to examine the "genetics" of protein folding, with mutants of bovine pancreatic trypsin inhibitor (BPTI) being used to explore the nature of the specific intramolecular interactions that direct this process. Previous work with BPTI chemically modified at cysteines 14 and 38 indicated that transient disulfide bond formation by these residues contributed to efficient folding at 25 degrees C. In the present work, mutants of BPTI in which these cysteines were replaced by alanines or threonines were made and the mutant proteins were produced by a heterologous Escherichia coli expression system. At 25 degrees C in vitro, the refolding behavior of these mutants was characterized by a pronounced lag. However, when expressed at 37 degrees C in E. coli, or when refolded at 37 degrees or 52 degrees C in vitro, the mutant proteins folded readily into the native conformation, albeit at a rate somewhat slower than that exhibited by wild-type BPTI. These results indicate that, at physiological temperatures, BPTI lacking cysteines 14 and 38 can refold quantitatively.

Production of 2-Keto-L-Gulonate, an Intermediate in L-Ascorbate Synthesis, by a Genetically Modified Erwinia herbicola.

A new metabolic pathway has been created in the microorganism Erwinia herbicola that gives it the ability to produce 2-keto-L-gulonic acid, an important intermediate in the synthesis of L-ascorbic acid. Initially, a Corynebacterium enzyme that could stereoselectively reduce 2,5-diketo-D-gluconic acid to 2-keto-L-gulonic acid was identified and purified. DNA probes based on amino acid sequence information from 2,5-diketo-D-gluconic acid reductase were then used to isolate the gene for this enzyme from a Corynebacterium genomic library. The 2,5-diketo-D-gluconic acid reductase coding region was fused to the Escherichia coli trp promoter and a synthetic ribosome binding site and was then introduced into E. herbicola on a multicopy plasmid. Erwinia herbicola naturally produces 2,5-diketo-D-gluconic acid via glucose oxidation, and when recombinant cells expressing the plasmid-encoded reductase were grown in the presence of glucose, 2-keto-L-gulonic acid was made and released into the culture medium. The data demonstrate the feasibility of creating novel in vivo routes for the synthesis of important specialty chemicals by combining useful metabolic traits from diverse sources in a single organism.

The immunological evolution of catalysis.

The germline genes used by the mouse to generate the esterolytic antibody 48G7 were cloned and expressed in an effort to increase our understanding of the detailed molecular mechanisms by which the immune system evolves catalytic function. The nine replacement mutations that were fixed during affinity maturation increased affinity for the transition state analogue by a factor of 10(4), primarily the result of a decrease in the dissociation rate of the hapten-antibody complex. There was a corresponding increase in the rate of reaction of antibody with substrate, k(cat)/k(m), from 1.7 x 10(2)M(-1) min(-1) to 1.4 x 10(4)M(-1) min(-1). The three-dimensional crystal structure of the 48G7-transition state analogue complex at 2.0 angstroms resolution indicates that one of the nine residues in which somatic mutations have been fixed directly contact the hapten. Thus, in the case of 48G7, affinity maturation appears to play a conformational role, either in reorganizing the active site geometry of limiting side-chain and backbone flexibility of the germline antibody. The crystal structure and analysis of somatic and directed active site mutants underscore the role of transition state stabilization in the evolution of this catalytic antibody.

The uptake of laparoscopic colorectal surgery in Great Britain and Ireland: a questionnaire survey of consultant members of the ACPGBI.

OBJECTIVE: The National Institute for Clinical Excellence (NICE) has recommended laparoscopic resection as an alternative to open surgery for patients with colorectal cancer. The aim of this study was to evaluate the current uptake of laparoscopic colorectal surgery in Great Britain and Ireland. METHOD: A questionnaire was distributed to members of the Association of Coloproctology of Great Britain and Ireland (ACPGBI) regarding their current surgical practice. Results were analysed individually, by region, and nationwide. RESULTS: Information was received on 436 consultants (in 155 replies), of whom 233 (53%) perform laparoscopic colorectal procedures. During the previous year, 25% of colorectal resections were performed laparoscopically by the respondents. However, of those surgeons who were performing laparoscopic resections, only 30% performed more than half of all their resections laparoscopically. Right hemicolectomy, left-sided resections, and rectopexy were the most frequently performed laparoscopic resections. There was an even distribution throughout the country of consultants performing laparoscopic resections (regional IQR 48-60%). The main reason for consultants not performing laparoscopic procedures was a lack of training or funding. CONCLUSION: Laparoscopic colorectal surgery is being performed by more than half (53%) of colorectal consultants nationwide, although only a quarter of all procedures are being undertaken laparoscopically.

Development of a Children's Trust in General Physicians Scale.

BACKGROUND: Researchers have developed scales assessing adults' trust beliefs in physicians and found that those are associated with measures of health behaviour and physical health. The purpose of the research was to develop a Children's Trust in General Physicians Scale (CTGPS) and examine its relation to health behaviour: adherence to medical regimes. METHODS: The participants were 128 children (68 girls and 60 boys) in Study 1 and 198 children (105 girls and 93 boys) in Study 2 who attended years 5 and 6 of elementary school in UK (mean ages = 10 years and 10 months and 10 years and 7 months respectively). The children completed the nine-item CTGPS and reported their trust in doctors and (in Study 2) adherence to medical regimes. Parents also reported those behaviours. RESULTS: Principal components analysis and confirmatory factor analysis of the CTGPS yielded the expected three factors: Honesty, Emotional and Reliability. The CTGPS had acceptable internal consistency and, as evidence for its validity, was associated with reported trust in doctors. The results from Study 2 confirmed that the CTGPS was associated with adherence to medical regimes. CONCLUSION: A CTGPS was developed that is associated with adherence to medical regimes.

A role for myelography in assessing paraparesis.

Imaging of the spine is a fundamental part of assessment of paraparesis. Since the advent of MRI the indications for myelograms have diminished. However, a myelogram, although an invasive test, should still be considered a useful investigation for localising lesions in the spinal cord and for identifying rare causes of myelopathy. This case illustrates how a CT myelogram identified an arachnoid cyst, which is a potentially treatable cause of paraparesis.

Propofol increased the interleukin-6 to interleukin-10 ratio more than isoflurane after surgery in long-term alcoholic patients.

This study investigated the effect of an anaesthetic regimen on the immune response in 40 long-term alcoholic patients undergoing surgery. Patients were randomly allocated to receive either propofol or isoflurane during surgery. Plasma cytokines interleukin (IL)-6 and IL-10 were measured at defined times and rates of post-operative infections were documented. The IL-6/IL-10 ratio significantly increased with propofol compared with isoflurane on day 1 after surgery and the IL-10 level significantly increased with isoflurane on day 1 after surgery. The overall post-operative infection rate was significantly higher in isoflurane-treated patients. Our findings indicate that propofol anaesthesia might be the more favourable regimen, with the IL-6/IL-10 ratio indicating an attenuation of the immune imbalance after surgery in long-term alcoholic patients. These results support the undertaking of a properly powered clinical trial to determine if propofol anaesthesia can reduce the postoperative infection rate in this special patient population.

Antibody H3 Structure Prediction.

Antibodies are proteins of the immune system that are able to bind to a huge variety of different substances, making them attractive candidates for therapeutic applications. Antibody structures have the potential to be useful during drug development, allowing the implementation of rational design procedures. The most challenging part of the antibody structure to experimentally determine or model is the H3 loop, which in addition is often the most important region in an antibody's binding site. This review summarises the approaches used so far in the pursuit of accurate computational H3 structure prediction.

Berg adder (Bitis atropos): An unusual case of acute poisoning.

A 5-year-old boy presented to hospital with mild local cytotoxic and severe neurotoxic symptoms. The neurotoxic symptoms included ptosis, fixed dilated pupils and flaccid paralysis with respiratory failure. Mild hyponatraemia was also a clinical feature. After various unsuccessful treatment options were followed, the Tygerberg Poison Information Centre was contacted and a diagnosis of berg adder bite was made. Berg adder bites are uncommon and therefore not usually considered in the differential diagnosis of a patient presenting with an unexplained clinical picture. A timeous poison information helpline consultation is recommended in this situation.

Sex work practices and condom use in female sex workers in Sydney.

The aim of this study was to determine sex work practices and predictors of condom use among female sex workers (SWs) in Sydney. SWs from two centres completed a self-administered questionnaire covering demographic and sexual characteristics and sex work practices. One hundred and forty-eight international (born in Asia) and 141 local SWs (born in Australia, New Zealand or the UK) were recruited. Local SWs saw more clients per shift than international SWs (P = 0.002), but international SWs worked more shifts per week than local SWs (P = 0.001). International SWs used condoms less consistently at work than local SWs (P = 0.001). About 37% of international SWs never used condoms with non-paying partners, compared with 14% of local SWs (P = 0.01). Speaking Thai (odds ratio [OR] 8.9, 95% confidence interval [CI]; 3.19-24.87) or Chinese (OR 17.4; 95% CI 4.98-60.89) (both P < 0.001) and previous sex work in Thailand (OR 10.0 95% CI 2.31-43.52; P = 0.02) were associated with inconsistent condom use. Strategies to improve condom use need to be evaluated.