Population genomics of helminth parasites.

Next generation sequencing technologies have facilitated a shift from a few targeted loci in population genetic studies to whole genome approaches. Here, we review the types of questions and inferences regarding the population biology and evolution of parasitic helminths being addressed within the field of population genomics. Topics include parabiome, hybridization, population structure, loci under selection and linkage mapping. We highlight various advances, and note the current trends in the field, particularly a focus on human-related parasites despite the inherent biodiversity of helminth species. We conclude by advocating for a broader application of population genomics to reflect the taxonomic and life history breadth displayed by helminth parasites. As such, our basic knowledge about helminth population biology and evolution would be enhanced while the diversity of helminths in itself would facilitate population genomic comparative studies to address broader ecological and evolutionary concepts.

The perioperative utility of 3D printed models in complex surgical care: feedback from 106 cases.

INTRODUCTION: 3D models are an emerging tool for surgical planning, providing an augmented method for the visualisation of a patient's anatomy. As their use increases, more data about the utility of these models is critical to inform budget allocation. This study provides the most comprehensive analysis to date for the use of 3D models in perioperative management. METHODS: 3D models for complex surgical cases in NHS hospitals were delivered alongside a surgeon feedback survey. The survey on the model's utility had been designed alongside the university data analytical team and focused on five areas: surgical planning and diagnosis, economic impact, impact on intraoperative and preoperative time, effect on communication and direct impact on the patient. RESULTS: There were 106 models used by 63 surgeons for complex surgical cases between May 2020 and March 2021, across multiple surgical specialties. The models were reported to have benefits in all perioperative areas, with 92.5% of responses agreeing that the 3D model was a better method for diagnosis and planning than traditional 2D techniques. Benefits were reported on preoperative planning (92.4%), economic savings due to equipment selection (54.4%), reduction in surgical time (41.5%) and surgeon-to-surgeon communication (92.6%). CONCLUSION: 3D models were shown to have a wide range of benefits in a surgical setting. The reduction in surgical time could have the potential to help alleviate surgical backlogs. With more widespread use and optimisation of costs the use of 3D models could become the standard for unusual and complex surgical cases.

Landspreading with co-digested cattle slurry, with or without pasteurisation, as a mitigation strategy against pathogen, nutrient and metal contamination associated with untreated slurry.

North Atlantic European grassland systems have a low nutrient use efficiency and high rainfall. This grassland is typically amended with unprocessed slurry, which counteracts soil organic matter depletion and provides essential plant micronutrients but can be mobilised during rainfall events thereby contributing to pathogen, nutrient and metal incidental losses. Co-digesting slurry with waste from food processing mitigates agriculture-associated environmental impacts but may alter microbial, nutrient and metal profiles and their transmission to watercourses, and/or soil persistence, grass yield and uptake. The impact of EU and alternative pasteurisation regimes on transmission potential of these various pollutants is not clearly understood, particularly in pasture-based agricultural systems. This study utilized simulated rainfall (Amsterdam drip-type) at a high intensity indicative of a worst-case scenario of ~11 mm hr-1 applied to plots 1, 2, 15 and 30 days after grassland application of slurry, unpasteurised digestate, pasteurised digestate (two conditions) and untreated controls. Runoff and soil samples were collected and analysed for a suite of potential pollutants including bacteria, nutrients and metals following rainfall simulation. Grass samples were collected for three months following application to assess yield as well as nutrient and metal uptake. For each environmental parameter tested: microbial, nutrient and metal runoff losses; accumulation in soil and uptake in grass, digestate from anaerobic co-digestion of slurry with food processing waste resulted in lower pollution potential than traditional landspreading of slurry without treatment. Reduced microbial runoff from digestate was the most prominent advantage of digestate application. Pasteurisation of the digestate further augmented those environmental benefits, without impacting grass output. Anaerobic co-digestion of slurry is therefore a multi-beneficial circular approach to reducing impacts of livestock production on the environment.

Muscarinic receptor subtype distribution in the central nervous system and relevance to aging and Alzheimer's disease.

Muscarinic acetylcholine receptors (mAChRs) are G proteincoupled receptors (GPCRs) that mediate the metabotropic actions of acetylcholine (ACh). There are five subtypes of mAChR, M1 - M5, which are expressed throughout the central nervous system (CNS) on numerous cell types and represent promising treatment targets for a number of different diseases, disorders, and conditions of the CNS. Although the present review will focus on Alzheimer's disease (AD) and amnestic mild cognitive impairment (aMCI), a number of conditions such as Parkinson's disease (PD), schizophrenia, and others represent significant unmet medical needs for which selective muscarinic agents could offer therapeutic benefits. Numerous advances have been made regarding mAChR localization through the use of subtype-selective antibodies and radioligand binding studies and these efforts have helped propel a number of mAChR therapeutics into clinical trials. However, much of what we know about mAChR localization in the healthy and diseased brain has come from studies employing radioligand binding with relatively modest selectivity. The development of subtype-selective small molecule radioligands suitable for in vitro and in vivo use, as well as robust, commercially-available antibodies remains a critical need for the field. Additionally, novel genetic tools should be developed and leveraged to help move the field increasingly towards a systems-level understanding of mAChR subtype action. Finally, functional, proteomic, and genetic data from ongoing human studies hold great promise for optimizing the design and interpretation of studies examining receptor levels by enabling patient stratification. This article is part of the Special Issue entitled 'Neuropharmacology on Muscarinic Receptors'.

Conversion of atrial dissociation with lidocaine in a dog.

A 3-year-old healthy dog was presented for abdominal surgery following ingestion of razor blades. An electrocardiogram revealed a regular sinus bradycardia with normal P waves at a heart rate of 45 bpm. In addition, low-amplitude positive deflections (p' waves) were visualized at a regular interval and rapid rate of 250 bpm, dissociated from the normal sinus P waves. A tentative diagnosis of atrial dissociation was proposed. Administration of lidocaine abolished the p' waves. This case describes atrial dissociation observed following premedication that was successfully terminated using lidocaine in a healthy dog.

Feasibility, safety, and tolerance of subcutaneous synthetic canine B-type natriuretic peptide (syncBNP) in healthy dogs and dogs with stage B1 mitral valve disease.

INTRODUCTION: An important aspect of heart failure is the progressive ineffectiveness of the salutary natriuretic peptide system and its secondary messenger, 3',5'-cyclic guanosine monophosphate (cGMP). In humans with acute heart failure, administration of exogenous natriuretic peptide is associated with improvement in clinical signs and reduction of cardiac filling pressures. This study aimed to determine the feasibility, tolerance, and safety of subcutaneous (SC) synthetic canine B-type natriuretic peptide (syncBNP) administration in dogs. ANIMALS: Six privately owned dogs. MATERIALS AND METHODS: Dogs were enrolled in a modified 3 + 3 phase I trial. Three dogs initially received doses of 2.5 and 5 µg/kg SC syncBNP followed by an additional three dogs dosed at 5 and 10 µg/kg. Hemodynamic monitoring was performed for 120 min after each injection. Blood and urine samples were collected at 45 and 120 min after injection of 5 µg/kg. Major adverse clinical events that would potentially halt testing were pre-defined. RESULTS: Four healthy dogs and two dogs with stage B1 mitral valve disease were recruited. Synthetic canine B-type natriuretic peptide was well tolerated at all doses. Synthetic canine B-type natriuretic peptide at 5 µg/kg significantly increased median plasma cGMP (baseline cGMP, 131.5 pmol/mL [range, 91.9-183.6 pmol/mL]; 45 min, 153.6 pmol/mL [140.3-214.3 pmol/mL]; 120 min, 192.7 pmol/mL [139.1-240.1 pmol/mL]; p=0.041). DISCUSSION AND CONCLUSIONS: We report for the first time administration of syncBNP in privately owned dogs. Administration of SC syncBNP was feasible, well tolerated, safe, and increased plasma cGMP concentration. Further studies using exogenous syncBNP for treatment of heart disease are warranted.

[Anaphylactic reactions to vaccines : Chicken egg allergy and the influenza H1N1 vaccination]. / Anaphylaktische Reaktionen auf Impfstoffe : Hühnereiweißallergie und Influenza-H1N1­Impfung.

BACKGROUND: Allergic reactions to influenza vaccinations are a well-known phenomenon; however, only a few published statistics give information on the risks. Patients with a chicken egg allergy must be particularly carefully handled during an influenza epidemic where vaccines produced using embryonated chicken eggs are primarily employed. METHODS: A selective literature review and analysis of the problem of allergic reactions to vaccinations was performed. RESULTS: The two most common relative contraindications among patients to be vaccinated are the presence of an egg allergy and a previous anaphylactic reaction to vaccination. These patients have a significantly increased risk of sustaining an adverse reaction. These high-risk patients should therefore only be vaccinated on the basis of thorough assessment of medical history, and then only with caution. The emergency routine must include sufficient precautionary measures, in case an anaphylactic reaction occurs. CONCLUSION: Current guidelines for the treatment of anaphylactic reactions are to be observed. Immediate treatment of the first symptoms of an anaphylactic reaction-i.v. administration of adrenalin, antihistamines, cortisone, and in some cases betamimetics-can usually prevent anaphylactic shock. Alternatively, a graded vaccination ("split protocol") and overnight surveillance can be considered in this group of patients.

Adipose tissue is influenced by hypoxia of obstructive sleep apnea syndrome independent of obesity.

AIMS: Obstructive sleep apnea syndrome (OSAS) is associated with increased cardiovascular risk and diabetes independent of obesity. We investigated whether adipose tissue dysfunction is exacerbated due to increased tissue hypoxia. METHODS: Adipose tissue (AT) oxygenation was measured with a Clarke-type electrode (pATO2) in 16 men with OSAS before and after 4 months of continuous positive airway pressure therapy (CPAP) and in BMI-matched controls. Oxygenation was simultaneously monitored in arterial blood by pulse oximetry (SaO2); mixed blood in AT microcirculation by reflectance spectroscopy (SATO2) along with blood flow. Markers of hypoxia, adipo- and angiogenesis, inflammation and fibrosis were analysed in AT and serum. RESULTS: OSAS subjects were more insulin resistant. Despite lower arterial SaO2 (95.4±1.3% vs. 97.1±1.6%, P=0.013) in subjects with OSAS, there was no difference in the oxygen content of AT microcirculation (61.6±18.4 vs. 72.2±7.0%, P=0.07) or pATO2 (49.2±7.5 vs. 50.4±14.7mmHg, P=0.83) between groups. Resting AT blood flow was higher in OSAS compared to controls (108.5±22.7 vs. 78.9±24.9au, P<0.005) and strongly associated with inflammation markers IL-6 and MCP-1. AT of OSAS subjects showed increased inflammation (TNFA P=0.049) and fibrosis (COL3A1 P=0.02), a trend of higher HIF1A expression (P=0.06) and reduced adipogenesis (PPARG P=0.006). After CPAP, only expression of the lipid deposition marker LPL increased (30%, P=0.047). CONCLUSIONS: Adipose tissue of awake OSAS subjects appears no more hypoxic than adipose tissue of BMI-matched controls despite daytime hypoxaemia. Increased adipose tissue blood flow may be explained by an increased inflammatory response. We observe features of adipose dysfunction in subjects with OSAS, which attribute to increased cardiometabolic risk associated with this condition.

Microstructure and mechanics of human resistance arteries.

Vascular diseases such as diabetes and hypertension cause changes to the vasculature that can lead to vessel stiffening and the loss of vasoactivity. The microstructural bases of these changes are not presently fully understood. We present a new methodology for stain-free visualization, at a microscopic scale, of the morphology of the main passive components of the walls of unfixed resistance arteries and their response to changes in transmural pressure. Human resistance arteries were dissected from subcutaneous fat biopsies, mounted on a perfusion myograph, and imaged at varying transmural pressures using a multimodal nonlinear microscope. High-resolution three-dimensional images of elastic fibers, collagen, and cell nuclei were constructed. The honeycomb structure of the elastic fibers comprising the internal elastic layer became visible at a transmural pressure of 30 mmHg. The adventitia, comprising wavy collagen fibers punctuated by straight elastic fibers, thinned under pressure as the collagen network straightened and pulled taut. Quantitative measurements of fiber orientation were made as a function of pressure. A multilayer analytical model was used to calculate the stiffness and stress in each layer. The adventitia was calculated to be up to 10 times as stiff as the media and experienced up to 8 times the stress, depending on lumen diameter. This work reveals that pressure-induced reorganization of fibrous proteins gives rise to very high local strain fields and highlights the unique mechanical roles of both fibrous networks. It thereby provides a basis for understanding the micromechanical significance of structural changes that occur with age and disease.

Anodal stimulation in two dogs with transvenous permanent bipolar pacemakers.

Management of symptomatic bradyarrhythmias such as complete atrioventricular block often involves permanent implantation of a transvenous pacemaker. Both during and after implantation, the operator can telemetrically assess and adjust a variety of electrical parameters associated with the pacemaker function in order to optimize the sensitivity, reliability, and power consumption of the device. Herein, we report an unexpected change in the paced electrocardiographic QRS complex morphology in two dogs undergoing bipolar pacing associated with changes in the pacemaker output amplitude settings first detected during threshold testing. The exclusivity of the electrocardiographic changes solely on pacemaker output settings, consistency between the surface electrocardiogram and ventricular endocardial electrogram, and resolution of this phenomenon when dogs were re-programmed to unipolar pacing is consistent with depolarization of the ventricular myocardium by the anodal electrode of the pacing lead at high pacemaker amplitudes. Anodal stimulation is a potential cause of varying QRS complex morphology witnessed during pacemaker evaluation and interrogation.

[Prophylactic antibiotic use in ENT surgery]. / Perioperative Antibiotikaprophylaxe in der HNO.

Surgical antibiotic prophylaxis (SAP) is defined as the administration of an antimicrobial agent prior to contamination in previously sterile spaces and fluid. SAP should not be confused with the therapeutic use of antibiotics. There are a growing number of studies with the goal of answering the question which patients benefit most from SAP during which specific surgical procedure. However, in the specific surgical field of head and neck surgery and otolaryngological surgery, there are only a few guidelines answering that question for specific procedures. The aim of this study was to analyze the evidence found in the literature and to develop a standard operating procedure, which specifically addresses head and neck and otolaryngeal surgical procedures.

[Perioperative antibiotic prophylaxis during standard interventions in ear, nose and throat medicine]. / Perioperative Antibiotikaprophylaxe bei Standardeingriffen in der HNO-Heilkunde.

BACKGROUND: The majority of standard interventions in otorhinolaryngology are classified as "clean contaminated" according to international classifications; correspondingly, no generally accepted recommendations regarding perioperative antibiotic prophylaxis (pAP) exist. The value of such pAP for these interventions remains unclear. Aim of the study was to assess the effects of pAP in selected standard otorhinolaryngologic procedures. MATERIALS AND METHODS: In August 2012 a standard operating procedure (SOP) was implemented, which lead to termination of routine pAP for the majority of standard operations. All patients included in this retrospective study had undergone a standard procedure (tonsil, septum or paranasal sinus surgery) during a period either 6 months before or 6 months after the inauguration of the SOP. The charts were reviewed for demographic factors, postoperative complications and length of hospital stay. RESULTS: The group before the inauguration of the SOP consisted of 316 patients (132 female, 184 male), aged 30±20 years. The group after the inauguration comprised 308 patients (128 female, 180 male), aged 31±19 years. For the entire patient collective, the termination of pAP led to a statistically significant increase in postoperative antibiotic treatment for all types of interventions tested. A statistically significant change in noninflammatory complications or the length of hospital stay was not detected. DISCUSSION: The termination of pAP during standard procedures in otorhinolaryngology is associated with an increase in postoperative antibiotic treatment but has no effect on other postoperative complications tested or the length of hospital stay.

Clinical Pharmacogenetics Implementation Consortium guidelines for dihydropyrimidine dehydrogenase genotype and fluoropyrimidine dosing.

The fluoropyrimidines are the mainstay chemotherapeutic agents for the treatment of many types of cancers. Detoxifying metabolism of fluoropyrimidines requires dihydropyrimidine dehydrogenase (DPD, encoded by the DPYD gene), and reduced or absent activity of this enzyme can result in severe, and sometimes fatal, toxicity. We summarize evidence from the published literature supporting this association and provide dosing recommendations for fluoropyrimidines based on DPYD genotype (updates at http://www.pharmgkb.org).

Clinical Pharmacogenetics Implementation Consortium guideline for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants.

Polymorphisms in CYP2D6 and CYP2C19 affect the efficacy and safety of tricyclics, with some drugs being affected by CYP2D6 only, and others by both polymorphic enzymes. Amitriptyline, clomipramine, doxepin, imipramine, and trimipramine are demethylated by CYP2C19 to pharmacologically active metabolites. These drugs and their metabolites, along with desipramine and nortriptyline, undergo hydroxylation by CYP2D6 to less active metabolites. Evidence from published literature is presented for CYP2D6 and CYP2C19 genotype-directed dosing of tricyclic antidepressants.

The Waterlow score for risk assessment in surgical patients.

INTRODUCTION: Perioperative scoring systems aim to predict outcome following surgery and are used in preoperative counselling to guide management and to facilitate internal or external audit. The Waterlow score is used prospectively in many UK hospitals to stratify the risk of decubitus ulcer development. The primary aim of this study was to assess the potential value of this existing scoring system in the prediction of mortality and morbidity in a general surgical and vascular cohort. METHODS: A total of 101 consecutive moderate to high risk emergency and elective surgical patients were identified through a single institution database. The preoperative Waterlow score and outcome data pertaining to that admission were collected. The discriminatory power of the Waterlow score was compared against that of the American Society of Anesthesiologists (ASA) grade and the Portsmouth Physiological and Operative Severity Score for the enUmeration of Mortality and morbidity (P-POSSUM). RESULTS: The inpatient mortality rate was 17% and the 30-day morbidity rate was 29%. A statistically significant association was demonstrated between the preoperative Waterlow score and inpatient mortality (p<0.0001) and 30-day morbidity (p=0.0002). Using a threshold Waterlow score of 20 to dichotomise risk, accuracies of 0.84 and 0.76 for prediction of mortality and morbidity were demonstrated. In comparison with P-POSSUM, the preoperative Waterlow score performed well on receiver operating characteristic analysis. With respect to mortality, the area under the curve was 0.81 (0.80-0.85) and for morbidity it was 0.72 (0.69-0.76). The ASA grade achieved a similar level of discrimination. CONCLUSIONS: The Waterlow score is collected routinely by nursing staff in many hospitals and might therefore be an attractive means of predicting postoperative morbidity and mortality. It might also function to stratify perioperative risk for comparison of surgical outcome data. A prospective study comparing these risk prediction scores is required to support these findings.

Clinical Pharmacogenetics Implementation Consortium guidelines for human leukocyte antigen-B genotype and allopurinol dosing.

Allopurinol is the most commonly used drug for the treatment of hyperuricemia and gout. However, allopurinol is also one of the most common causes of severe cutaneous adverse reactions (SCARs), which include drug hypersensitivity syndrome, Stevens­Johnson syndrome, and toxic epidermal necrolysis. A variant allele of the human leukocyte antigen (HLA)-B, HLA-B*58:01, associates strongly with allopurinolinduced SCAR. We have summarized the evidence from the published literature and developed peer-reviewed guidelines for allopurinol use based on HLA-B genotype.

Effect of an oxygen pressure injection (OPI) device on the oxygen saturation of patients during dermatological methyl aminolevulinate photodynamic therapy.

Methyl aminolevulinate photodynamic therapy (MAL-PDT) (a topical treatment used for a number of precancerous skin conditions) utilizes the combined interaction of a photosensitizer (protoporphyrin IX (PpIX)), light of the appropriate wavelength, and molecular oxygen to produce singlet oxygen and other reactive oxygen species which induce cell death. During treatment, localized oxygen depletion occurs and is thought to contribute to decreased efficacy. The aim of this study was to investigate whether an oxygen pressure injection (OPI) device had an effect on localized oxygen saturation levels and/or PpIX fluorescence of skin lesions during MAL-PDT. This study employed an OPI device to apply oxygen under pressure to the skin lesions of patients undergoing standard MAL-PDT. Optical reflectance spectrometry and fluorescence imaging were used to noninvasively monitor the localized oxygen saturation and PpIX fluorescence of the treatment area, respectively. No significant changes in oxygen saturation were observed when these data were combined for the group with OPI and compared to the group that received standard MAL-PDT without OPI. Additionally, no significant difference in PpIX photobleaching or clinical outcome at 3 months between the groups of patients was observed, although the group that received standard MAL-PDT demonstrated a significant increase (p<0.05) in PpIX fluorescence initially and both groups produced a significant decrease (p<0.05) after light irradiation. In conclusion, with this sample size, this OPI device was not found to be an effective method with which to improve tissue oxygenation during MAL-PDT. Further investigation is therefore required to find a more effective method of MAL-PDT enhancement.

Pharmacogenomics knowledge for personalized medicine.

The Pharmacogenomics Knowledgebase (PharmGKB) is a resource that collects, curates, and disseminates information about the impact of human genetic variation on drug responses. It provides clinically relevant information, including dosing guidelines, annotated drug labels, and potentially actionable gene-drug associations and genotype-phenotype relationships. Curators assign levels of evidence to variant-drug associations using well-defined criteria based on careful literature review. Thus, PharmGKB is a useful source of high-quality information supporting personalized medicine-implementation projects.

Complementary and alternative medications consumed by patients with head and neck carcinoma: a pilot study in Germany.

Complementary and alternative medicine (CAM) represents a wide range of treatment modalities. CAM products may interact with enzymes, transport proteins, and may therefore influence drug metabolism. The prevalence and patterns of CAM usage among patients with head and neck carcinoma (HNC) are largely unknown. This cross-sectional study was designed to document pattern of CAM consumption in patients with HNC. Statistical differences in a significantly higher prevalence of CAM consumption between tumor patients (n = 107) and the control group (n = 112) could be detected. Concerning the frequency of CAM usage, we could document a significant increased consumption of CAM among tumor patients (42.8% vs. 62.6%) especially for herbal teas (P < 0.05), phytotherapy (P < 0.001), supplement products (P < 0.05), and "other" supplements (P < 0.005) comparing the controls. Furthermore a significant influence of female gender and an increased CAM usage could be illustrated. Concerning the knowledge of potential interactions of CAM consumption, only 6.25% of the controls and 19.6% of tumor patients know about possible side effects but only 1.7% of the controls and 6.5% of the tumor patients informed their physician about the CAM usage. The frequency of CAM in head and neck tumor patients seems to be relevant in the supervision of anticancer therapies.

Chemotherapeutic alteration of ß-catenin and c-kit expression by imatinib in p16-positive squamous cell carcinoma compared to HPV-negative HNSCC cells in vitro.

The most common neoplasm arising in the upper aerodigestive tract is head and neck squamous cell carcinoma (HNSCC). Tumor growth, invasion and systemic dissemination is a multistep process of dysregulated cellular signaling pathways and an altered cell-cell and cell-matrix interaction. Aberrant Wnt/ß-catenin signaling is linked to tumor development and dissemination in several tumor entities. ß-catenin is a multifunctional protein within the canonical Wnt pathway, which is an important factor for reducing cell-cell adhesion in malignant tissue and for triggering cell cycle progression and unscheduled proliferation. Another pivotal factor in carcinogenesis is the tyrosine kinase receptor c-kit, which in the case of dysregulated expression is associated with neoplastic transformation in epithelial tissue. This study evaluates the expression pattern of secreted and nuclear ß-catenin and c-kit in p16-positive and HPV-negative squamous cell carcinomas (SCC) and the vulnerability of therapy with the tyrosine kinase inhibitor imatinib as a potential targeted treatment modality compared to platinum-based chemotherapeutic drugs. The different squamous tumor cell lines were incubated with increasing concentrations of carboplatin (3 or 7.5 µmol/ml) and imatinib (18 or 30 µmol/ml). ELISA and immunohistochemical methods were carried out after 48, 72, 120, 192 and 240 h. We detected a reliable trend towards significantly decreased cytosolic and nuclear ß-catenin and c-kit expression levels in p16-positive SCC and non-HPV HNSCC cells induced by imatinib exposure for an extended incubation period, whereas platinum-based agents had no or, at best, a slight influence. Virus-transformed squamous cell carcinoma (CERV196) cells were characterized by a reduced susceptibility to an imatinib-altered ß-catenin expression. Further studies are planned to investigate this observance in HPV-positive HNSCC in vitro. The implementation of a selective molecular therapy in established chemotherapeutic regimes may enhance the efficacy of platinum-based chemotherapy without increased toxicity and could thus improve the clinical outcome in HNSCC, irrespective of the HPV status.