Herbicides and pesticides synergistically interact at low concentrations in complex mixtures.

Assessing a complex mixture of pesticides at the impacted sites has been challenging for risk assessors for 50 years. The default assumption is that at low concentrations, pesticides interact additively with one another; thus, the risk posed by each component of a complex mixture could be simply added up. The EPA interaction-based hazard index (HIInteraction) modifies this assumption using a binary weight-of-evidence (BINWOE). However, data gaps often preclude HIInteraction use at most sites. This study evaluated these assumptions using the BINWOE to estimate the hazard index (HI) of select pesticide mixtures. The lack of in vivo binary interaction data led us to use a cell line, SH-SY5Y, to obtain the data necessary for the BINWOE approach. In the risk assessment, we considered the most active exposure scenario inhaling a mixture of volatile pesticides from contaminated soil and groundwater. The potential interactions between pesticides in 15 binary mixtures were investigated using the MTT assay in SH-SY5Y cells. Our findings showed that 60% of the binary mixtures elicited synergism (in at least one concentration), 27% displayed antagonism, and 13% showed additive effects in SH-SY5Y cells. Combining human safety data with in vitro interaction data indicated that adults and toddlers were at the highest risk when considering industrial and commercial land use, respectively, compared to other subpopulations. Incorporating interaction data into the risk assessment either increased the risk by up to 20% or decreased the risk by 2%, depending on the mixture. Our results demonstrate the predominant synergistic interactions, even at low concentrations, altered risk characterization at the complex operating site. Most concerning, organochlorine pesticides with the same mechanism of action did not follow dose additivity when evaluated by SH-SY5Y cell lines. Based on our observations, we caution that current HI methods based on additivity assumptions may underestimate the risk of organochlorine mixtures.

Boomerang Modification of the Septal Extension Graft: Graft Design and Functional Outcomes.

Background: A "boomerang" graft is an end-to-end caudal septal extension graft (SEG) that conforms to the geometry of the anterior septal angle, and avoids septal overlap, unlike a side-to-side SEG. Objective: To compare breathing improvements in rhinoplasty patients receiving boomerang SEGs and patients receiving side-to-side SEGs. Methods: Retrospective cohort analysis of patients undergoing rhinoplasty with either end-to-end boomerang SEG or a side-to-side SEG. Functional outcomes were assessed through the Nasal Obstruction Symptom Evaluation (NOSE) survey. Results: The boomerang SEG cohort had a mean age of 34 years and were 68% female compared with 38 years and 67% female in the side-to-side SEG cohort (p > 0.05). The cohorts did not differ in the proportion of the lateral crural tensioning, spreader graft placement, or history of rhinoplasty. The boomerang cohort demonstrated a 67% reduction in NOSE scores compared with a 70% reduction among the side-to-side SEG cohort (p = 0.14). Men undergoing boomerang graft placement reported significantly less postoperative functional improvement than men undergoing placement of a side-to-side SEG (62% vs. 77%, p = 0.01). Conclusion: Use of a boomerang graft is not likely to negatively affect rhinoplasty functional outcomes when compared with a side-to-side SEG.

Validation of the CogDrisk Instrument as Predictive of Dementia in Four General Community-Dwelling Populations.

BACKGROUND: Lack of external validation of dementia risk tools is a major limitation for generalizability and translatability of prediction scores in clinical practice and research. OBJECTIVES: We aimed to validate a new dementia prediction risk tool called CogDrisk and a version, CogDrisk-AD for predicting Alzheimer's disease (AD) using cohort studies. DESIGN, SETTING, PARTICIPANTS AND MEASUREMENTS: Four cohort studies were identified that included majority of the dementia risk factors from the CogDrisk tool. Participants who were free of dementia at baseline were included. The predictors were component variables in the CogDrisk tool that include self-reported demographics, medical risk factors and lifestyle habits. Risk scores for Any Dementia and AD were computed and Area Under the Curve (AUC) was assessed. To examine modifiable risk factors for dementia, the CogDrisk tool was tested by excluding age and sex estimates from the model. RESULTS: The performance of the tool varied between studies. The overall AUC and 95% CI for predicting dementia was 0.77 (0.57, 0.97) for the Swedish National study on Aging and Care in Kungsholmen, 0.76 (0.70, 0.83) for the Health and Retirement Study - Aging, Demographics and Memory Study, 0.70 (0.67,0.72) for the Cardiovascular Health Study Cognition Study, and 0.66 (0.62,0.70) for the Rush Memory and Aging Project. CONCLUSIONS: The CogDrisk and CogDrisk-AD performed well in the four studies. Overall, this tool can be used to assess individualized risk factors of dementia and AD in various population settings.

Emergence of Canonical and Noncanonical Genomic Variants following In Vitro Exposure of Clinical Mycobacterium tuberculosis Strains to Bedaquiline or Clofazimine.

In Mycobacterium tuberculosis, bedaquiline and clofazimine resistance occurs primarily through Rv0678 variants, a gene encoding a repressor protein that regulates mmpS5/mmpL5 efflux pump gene expression. Despite the shared effect of both drugs on efflux, little else is known about other pathways affected. We hypothesized that in vitro generation of bedaquiline- or clofazimine-resistant mutants could provide insight into additional mechanisms of action. We performed whole-genome sequencing and determined phenotypic MICs for both drugs on progenitor and mutant progenies. Mutants were induced through serial passage on increasing concentrations of bedaquiline or clofazimine. Rv0678 variants were identified in both clofazimine- and bedaquiline-resistant mutants, with concurrent atpE SNPs occurring in the latter. Of concern was the acquisition of variants in the F420 biosynthesis pathway in clofazimine-resistant mutants obtained from either a fully susceptible (fbiD: del555GCT) or rifampicin mono-resistant (fbiA: 283delTG and T862C) progenitor. The acquisition of these variants possibly implicates a shared pathway between clofazimine and nitroimidazoles. Pathways associated with drug tolerance and persistence, F420 biosynthesis, glycerol uptake and metabolism, efflux, and NADH homeostasis appear to be affected following exposure to these drugs. Shared genes affected by both drugs include Rv0678, glpK, nuoG, and uvrD1. Genes with variants in the bedaquiline resistant mutants included atpE, fadE28, truA, mmpL5, glnH, and pks8, while clofazimine-resistant mutants displayed ppsD, fbiA, fbiD, mutT3, fadE18, Rv0988, and Rv2082 variants. These results show the importance of epistatic mechanisms as a means of responding to drug pressure and highlight the complexity of resistance acquisition in M. tuberculosis.

Target Organ Toxicity in Rats After Subchronic Oral Exposure to Soil Extracts Containing a Complex Mixture of Contaminants.

Complex mixtures of unknown contaminants present a challenge to identify toxicological risks without using large numbers of animals and labor-intensive screens of all organs. This study examined soil extracts from a legacy-contaminated pesticide packaging and blending site. HepG2 cytotoxicity was used as an initial screen of 18 soil samples; then, three extracts (A, B and C) from different locations at the study site were used for testing in animals. The first two extracts were identified as the most toxic in vitro, and the latter extract obtained from a location further from these two toxic sampling sites. Then, target organ toxicities were identified following biweekly oral gavage for one month of three soil extracts (0.1% in polyethylene glycol or PEG) compared to vehicle control in male Sprague-Dawley rats (n = 9-10/group). Exposure to extract A significantly increased neutrophils and lymphocytes compared to control. In contrast, all extracts increased plasma α-2 macroglobulin and caused mild-to-moderate lymphocytic proliferation within the spleen white pulp, all indicative of inflammation. Rats exposed to all soil extracts exhibited acute tubular necrosis. Cholinesterase activity was significantly reduced in plasma, but not brain, after exposure to extract A compared to control. Increased hepatic ethoxyresorufin-o-deethylase activity compared to control was observed following exposure to extracts A and B. Exposure to soil extract C in rats showed a prolonged QTc interval in electrocardiography as well as increased brain lipid peroxidation. Candidate contaminants are organochlorine, organophosphate/carbamate pesticides or metabolites. Overall, HepG2 cytotoxicity did not successfully predict the neurotoxicity and cardiotoxicity observed with extract C but was more successful with suspected hydrocarbon toxicities in extracts A and B. Caution should be taken when extrapolating the observation of no effects from in vitro cell culture to in vivo toxicity, and better cell culture lines or assays should be explored.

Spinal anesthesia in the percutaneous fixation of fragility fractures of the pelvis.

Introduction: The number of geriatric patients with a pelvic ring fracture is rising and minimal invasive fixation techniques are increasingly popular. The patient characteristics of these fragile patients are similar to those of patients with a proximal femur fracture. In the field of proximal femur fracture surgery spinal anesthesia is a very commonly used anesthetic technique in this more fragile patient population. Methods: All patients were treated between January 2022 and May 2022 in the Amsterdam UMC location AMC in The Netherlands. The operations were performed by a surgeon who specialized in pelvic and acetabular fracture surgery in a hybrid operating theatre. All patient in this case series received spinal anesthesia using 2-2.5 ml glucosated bupivacaine 5 mg/ml. Results: We describe, for the first time, four cases of percutaneous pelvic ring fracture fixation using spinal anesthesia. There were no perioperative or direct postoperative complications. Patients quickly regained the ability to mobilize, reported little pain complaints, and could be safely discharged to either a rehabilitation center or home. Conclusion: We believe spinal anesthesia could be a safe alternative to general anesthesia for the percutaneous fixation of pelvic ring injuries in a selected group of frail elderly patients. A proper assessment should determine whether or not spinal anesthesia is an option in pelvic fracture fixation, taking patient preference, the advice of the anesthetist, the choice of operative technique, and fracture pattern into consideration.

Charge-neutral fermions and magnetic field-driven instability in insulating YbIr3Si7.

Kondo lattice materials, where localized magnetic moments couple to itinerant electrons, provide a very rich backdrop for strong electron correlations. They are known to realize many exotic phenomena, with a dramatic example being recent observations of quantum oscillations and metallic thermal conduction in insulators, implying the emergence of enigmatic charge-neutral fermions. Here, we show that thermal conductivity and specific heat measurements in insulating YbIr3Si7 reveal emergent neutral excitations, whose properties are sensitively changed by a field-driven transition between two antiferromagnetic phases. In the low-field phase, a significant violation of the Wiedemann-Franz law demonstrates that YbIr3Si7 is a charge insulator but a thermal metal. In the high-field phase, thermal conductivity exhibits a sharp drop below 300 mK, indicating a transition from a thermal metal into an insulator/semimetal driven by the magnetic transition. These results suggest that spin degrees of freedom directly couple to the neutral fermions, whose emergent Fermi surface undergoes a field-driven instability at low temperatures.

An appeal to our government for nationwide policies in the prevention of cardiovascular disease.

The high prevalence and burden of cardiovascular diseases (CVD) is largely attributable to unhealthy lifestyle factors such as smoking, alcohol consumption, physical inactivity and unhealthy food habits. Prevention of CVD, through the promotion of healthy lifestyles, appears to be a Sisyphean task for healthcare professionals, as the root causes of an unhealthy lifestyle lie largely outside their scope. Since most lifestyle choices are habitual and a response to environmental cues, rather than rational and deliberate choices, nationwide policies targeting the context in which lifestyle behaviours occur may be highly effective in the prevention of CVD. In this point-of-view article, we emphasise the need for government policies beyond those mentioned in the National Prevention Agreement in the Netherlands to effectively reduce the CVD risk, and we address the commonly raised concerns regarding 'paternalism'.

The challenge of choosing in cardiovascular risk management.

Cardiovascular disease (CVD) is a major cause of morbidity and mortality worldwide. For many years guidelines have listed optimal preventive therapy. More recently, novel therapeutic options have broadened the options for state-of-the-art CV risk management (CVRM). In the majority of patients with CVD, risk lowering can be achieved by utilising standard preventive medication combined with lifestyle modifications. In a minority of patients, add-on therapies should be considered to further reduce the large residual CV risk. However, the choice of which drug combination to prescribe and in which patients has become increasingly complicated, and is dependent on both the absolute CV risk and the reason for the high risk. In this review, we discuss therapeutic decisions in CVRM, focusing on (1) the absolute CV risk of the patient and (2) the pros and cons of novel treatment options.

Lifestyle management to prevent atherosclerotic cardiovascular disease: evidence and challenges.

Lifestyle management is the cornerstone of both primary and secondary prevention of atherosclerotic cardiovascular disease (ASCVD) and the importance of lifestyle management is emphasised by all major guidelines. Despite this, actual implementation of lifestyle management is poor. Lifestyle modification includes smoking cessation, weight loss, dietary change, increasing physical inactivity, and stress management. This review summarises evidence-based opportunities and challenges for healthcare professionals to promote healthy lifestyles at an individual level for the prevention of ASCVD.

In-depth assessment of health-related quality of life after in-hospital cardiac arrest.

INTRODUCTION: Evidence on physical and psychological well-being of in-hospital cardiac arrest (IHCA) survivors is scarce. The aim of this study is to describe long-term health-related quality of life (HRQoL), functional independence and psychological distress 3 and 12 months post-IHCA. METHODS: A multicenter prospective cohort study in 25 hospitals between January 2017 - May 2018. Adult IHCA survivors were included. HRQoL (EQ-5D-5L, SF-12), psychological distress (HADS, CSI) and functional independence (mRS) were assessed at 3 and 12 months post-IHCA. RESULTS: At 3-month follow-up 136 of 212 survivors responded to the questionnaire and at 12 months 110 of 198 responded. The median (IQR) EQ-utility Index score was 0.77 (0.65-0.87) at 3 months and 0.81 (0.70-0.91) at 12 months. At 3 months, patients reported a median SF-12 (IQR) physical component scale (PCS) of 38.9 (32.8-46.5) and mental component scale (MCS) of 43.5 (34.0-39.7) and at 12 months a PCS of 43.1 (34.6-52.3) and MCS 46.9 (38.5-54.5). DISCUSSION: Using various tools most IHCA survivors report an acceptable HRQoL and a substantial part experiences lower HRQoL compared to population norms. Our data suggest that younger (male) patients and those with poor functional status prior to admission are at highest risk of impaired HRQoL.

Antimicrobial resistance in Neisseria gonorrhoeae and Mycoplasma genitalium isolates from the private healthcare sector in South Africa: A pilot study.

BACKGROUND: Reports have emerged globally of antimicrobial resistance (AMR) in Neisseria gonorrhoeae and Mycoplasma genitalium infections. In South Africa (SA), there are substantial differences between private and public healthcare with regard to antimicrobial drug prescribing practice, which could affect AMR patterns of private and public healthcare patients. OBJECTIVES: To perform a pilot study to determine the frequency of AMR of N. gonorrhoeae and M. genitalium in patients accessing SA's private healthcare sector. METHODS: In this cross-sectional study, N. gonorrhoeae-positive cultures and M. genitalium DNA samples were collected from a private healthcare reference laboratory from August 2018 to August 2019. In N. gonorrhoeae-positive cultures, antimicrobial susceptibility testing was performed, followed by N. gonorrhoeae multiantigen sequence typing (NG-MAST) to determine genetic relatedness of the isolates. To determine macrolide and fluoroquinolone resistance rates, M. genitalium-positive samples were analysed by sequencing the 23S rRNA, gyrA and parC genes. RESULTS: Twenty-one N. gonorrhoeae- and 27 M. genitalium-positive specimens were included in this analysis. High rates of resistance were detected among gonococcal isolates, with 90% resistance to tetracycline, 86% to penicillin and 62% to ciprofloxacin, but no resistance to azithromycin, cefixime and ceftriaxone. NG-MAST revealed genetically diverse isolates with 83% novel NG-MAST sequence types. Macrolide and fluoroquinolone resistance-associated mutations were detected in 18.5% (n=5/27) and 7.4% (n=2/27) of M. genitalium strains, respectively. CONCLUSIONS: We observed high frequencies of ciprofloxacin, penicillin and tetracycline resistance in N. gonorrhoeae and macrolide resistance-associated mutations in M. genitalium in private healthcare sector patients in SA. This finding highlights the need to use diagnostics for sexually transmitted infections and to include the private healthcare sector in antimicrobial surveillance and stewardship programmes.

Lung microbiome of stable and exacerbated COPD patients in Tshwane, South Africa.

Chronic obstructive pulmonary disease (COPD) is characterised by the occurrence of exacerbations triggered by infections. The aim of this study was to determine the composition of the lung microbiome and lung virome in patients with COPD in an African setting and to compare their composition between the stable and exacerbated states. Twenty-four adult COPD patients were recruited from three hospitals. Sputum was collected and bacterial DNA was extracted. Targeted metagenomics was performed to determine the microbiome composition. Viral DNA and RNA were extracted from selected samples followed by cDNA conversion. Shotgun metagenomics sequencing was performed on pooled DNA and RNA. The most abundant phyla across all samples were Firmicutes and Proteobacteria. The following genera were most prevalent: Haemophilus and Streptococcus. There were no considerable differences for alpha and beta diversity measures between the disease states. However, a difference in the abundances between disease states was observed for: (i) Serratia (3% lower abundance in exacerbated state), (ii) Granulicatella (2.2% higher abundance in exacerbated state), (iii) Haemophilus (5.7% higher abundance in exacerbated state) and (iv) Veillonella (2.5% higher abundance in exacerbated state). Virome analysis showed a high abundance of the BeAn 58058 virus, a member of the Poxviridae family, in all six samples (90% to 94%). This study is among the first to report lung microbiome composition in COPD patients from Africa. In this small sample set, no differences in alpha or beta diversity between stable and exacerbated disease state was observed, but an unexpectedly high frequency of BeAn 58058 virus was observed. These observations highlight the need for further research of the lung microbiome of COPD patients in African settings.

The Prevalence of Frailty Using Three Different Frailty Measurements in Two Finnish Cohorts Born Before and After the Second World War.

OBJECTIVES: To study the prevalence of frailty and its relationship to mortality in cohorts born before and after the Second World War using three different frailty measures. METHODS: Cross-sectional data from two cohorts born in 1935 (n=593) and 1945 (n=714) were studied for frailty at the mean age of 70.7 (SD 1.8) years. Frailty was measured using the Frailty Phenotype (FP), the Frail Scale (FS) and the 74-item Frailty Index (FI>0.21 denoted frailty). Information on socioeconomic factors was obtained via a study questionnaire and the data on mortality were obtained from the Population Information System. RESULTS: The prevalence of frailty by FI was more common in the older 1935 cohort than in the 1945 cohort (p<0.001). The percentage of robust subjects was higher in both sexes in the 1945 cohort using both FI and FS. After adjusting for sociodemographic factors, the difference in the prevalence of frailty between the cohorts remained significant in women only (OR 1.9 (95% CI 1.3-2.9), p=0.001). The FI classified people as frail more often (30.2% in the 1935 cohort and 17.5% in the 1945 cohort) than the FS (13.1% and 8.8%) or FP (1.8% and 1.6%). Low financial satisfaction was associated significantly with frailty in both sexes. Low level of education was associated with frailty in women and being unmarried or divorced in men. Frailty was associated to increased mortality using all frailty definitions in the 1935 cohort with a longer follow-up time. CONCLUSIONS: Improved living conditions and health care may have resulted in the lower prevalence of frailty in the 1945 cohort. The present study further strengthens the association between frailty and mortality and poor economic status and frailty. Frailty definitions are in need of further study.

Microbial and physicochemical assessment of irrigation water treatment methods.

AIMS: The presence of foodborne pathogens in preharvest agricultural water has been identified as a potential contamination source in outbreak investigations, driving markets and auditing bodies to begin requiring water treatment for high-risk produce. Therefore, it is essential that we identify water treatment methods which are effective as well as practical in their application on farm. METHODS AND RESULTS: In this work, we evaluated two sanitizers which are most prominent in preharvest agricultural water treatment (calcium hypochlorite (free chlorine: 3-5 ppm) and peracetic acid (PAA: 5 ppm)), an EPA registered antimicrobial device (ultraviolet light (UV)), in addition to a combination approach (chlorine + UV, PAA + UV). Treatments were evaluated for their ability to inactivate total coliforms and generic Escherichia coli and consistency in treatment efficacy over 1 h of operation. Physicochemical variables were measured along with microbial populations at 0, 5, 15, 30, 45 and 60 min of operation. Escherichia coli and coliform counts showed a significant (P < 0·05) reduction after treatment, with combination and singular treatments equally effective at inactivating E. coli and coliforms. A significant increase (P < 0·05) in oxidation-reduction potential was seen during water treatment (Chlorine; UV + Chlorine), and a significant reduction (P < 0·05) in pH was seen after PAA and PAA + UV treatments (60 min). CONCLUSION: Overall, the results indicate that all treatments evaluated are equally efficacious for inactivating E. coli and coliforms present in surface agricultural water. SIGNIFICANCE AND IMPACT OF THE STUDY: This information when paired with challenge studies targeting foodborne pathogens of interest can be used to support grower decisions when selecting and validating a preharvest agricultural water treatment programme.

Recovery expectations of neck pain patients do not predict treatments outcome in manual therapy.

Patient recovery expectations can predict treatment outcome. Little is known about the association of patient recovery expectations on treatment outcome in patients with neck pain consulting a manual therapist. This study evaluates the predictive value of recovery expectations in neck pain patients consulting manual therapists in the Netherlands. The primary outcome measure 'recovery' is defined as 'reduction in pain and perceived improvement'. A prospective cohort study a total of 1195 neck pain patients. Patients completed the Patient Expectancies List (PEL) at baseline (3 item questionnaire, score range from 3 to 12), functional status (NDI), the Global Perceived Effect (GPE) for recovery (7-points Likert scale) post treatment and pain scores (NRS) at baseline and post treatment. The relationship between recovery expectancy and recovery (dichotomized GPE scores) was assessed by logistic regression analysis. Patients generally reported high recovery expectations on all three questions of the PEL (mean sumscores ranging from 11.3 to 11.6). When adjusted for covariates the PEL sum-score did not predict recovery (explained variance was 0.10 for the total PEL). Separately, the first question of the PEL showed predictive potential (OR 3.7; 95%CI 0.19-73.74) for recovery, but failed to reach statistical significance. In this study patient recovery expectations did not predict treatment outcome. Variables predicting recovery were recurrence and duration of pain. The precise relationship between patient recovery expectations and outcome is complex and still inconclusive. Research on patient expectancy would benefit from more consistent use of theoretical expectancy and outcome models.

The scientific basis for secondary prevention of coronary artery disease: recent contributions from the Netherlands.

While the beneficial effects of secondary prevention of cardiovascular disease are undisputed, implementation remains challenging. A gap between guideline-mandated risk factor targets and clinical reality was documented as early as the 1990s. To address this issue, research groups in the Netherlands have performed several major projects. These projects address innovative, multidisciplinary strategies to improve medication adherence and to stimulate healthy lifestyles, both in the setting of cardiac rehabilitation and at dedicated outpatient clinics. The findings of these projects have led to changes in prevention and rehabilitation guidelines.