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Chemical contamination of drinking water is of great concern for public health. Chemical analyses are used for monitoring of selected chemicals, however, no information on unknown chemicals or potential toxicity of the mixture of chemicals in a water sample is obtained. Effect‐based methods in cells are new high throughput tools, to evaluate the hazard of the whole mixture of chemicals present in drinking water. These methods can be used together with chemical analysis for assessment of the chemical safety of drinking water. This article will review the principle of effect‐based methods in cells and how they compare to traditionally used chemical analysis and effect‐based methods in whole organisms. Further, this article will give examples from the literature, highlighting how cellular effect‐based methods can be used in different practical applications to improve drinking water safety; for example, for monitoring of drinking water quality and evaluation of treatment efficiency in drinking water processing. Finally, this article will review the current regulatory and water sector acceptance of these methods and discuss future expectations on the role of effect‐based methods for improved drinking water safety. This article is categorized under:Engineering Water > Water, Health, and SanitationScience of Water > Water Quality [ABSTRACT FROM AUTHOR]

Introduction/Aims: Most persons with amyotrophic lateral sclerosis (ALS) live at home with support of family caregivers, with escalating complexity of care over the trajectory of the disease requiring resources and support to mitigate negative physical, social, and emotional outcomes. Methods: This scoping review identifies the home health/home care needs of persons with ALS and their caregivers as a basis for creating a home health medical standard. We used the PRISMA Extension for Scoping Reviews (PRISMA‐ScR) to examine studies describing home care needs published between 2011 and 2021. Results: Our search yielded 481 articles, of which 44 were included with a total of 3592 (9–273) participants. Most studies used a cross‐sectional design and 20 (45%) were rated as high quality. We grouped the needs identified as emotional/psychological, assistive devices and technology, information and education, and human resources and professional services. Most studies demonstrated persistent unmet needs and that available interventions were helpful while needs generally were not met proactively, despite the predictable trajectory. Discussion: This review describes biopsychosocial and equipment interventions over the trajectory of ALS with implications for anticipatory planning by clinicians, as well as policy for coverage of necessary services and supports. Interdisciplinary expert teams could develop consensus around needs across the trajectory and recommended services and supports. To make knowledge more accessible, encourage availability of services, and clarify the need for coverage of services, we aim to develop an expert consensus‐based ALS home health medical standard guidance document in collaboration with the American Association of Neuromuscular and Electrodiagnostic Medicine. [ABSTRACT FROM AUTHOR]

Introduction: Use of antipsychotic drugs, especially second‐generation agents, has been suggested to cause acute pancreatitis in multiple case reports; however, such an association has not been corroborated by larger studies. This study examined the association of antipsychotic drugs with risk of acute pancreatitis. Methods: Nationwide case–control study, based on data from several Swedish registers and including all 52,006 cases of acute pancreatitis diagnosed in Sweden between 2006 and 2019 (with up to 10 controls per case; n = 518,081). Conditional logistic regression models were used to calculate odds ratios (ORs) in current and past users of first‐generation and second‐generation antipsychotic drugs (dispensed prescription <91 and ≥91 days of the index date, respectively) compared with never users of such drugs. Results: In the crude model, first‐generation and second‐generation antipsychotic drugs were associated with increased risk of acute pancreatitis, with slightly higher ORs for past use (1.58 [95% confidence interval 1.48–1.69] and 1.39 [1.29–1.49], respectively) than for current use (1.34 [1.21–1.48] and 1.24 [1.15–1.34], respectively). The ORs were largely attenuated in the multivariable model—which included, among others, alcohol abuse and the Charlson comorbidity index—up to the point where only a statistically significant association remained for past use of first‐generation agents (OR 1.18 [1.10–1.26]). Conclusion: There was no clear association between use of antipsychotic drugs and risk of acute pancreatitis in this very large case–control study, indicating that previous case report data are most likely explained by confounding. [ABSTRACT FROM AUTHOR]

This article explores how domestic NGOs responded to new opportunities that emerged during the 2015–2020 'modern slavery' labour reforms in Thailand's seafood sector. The analysis takes place against the background of civil society transitions in a 'post‐aid' setting. Like NGOs in other middle‐income countries, the Thai NGO sector has struggled to remain relevant and financially viable in recent decades, as international donors have withdrawn from countries with steadily declining poverty rates. As a result of the 'developmental successes' of Thailand, the NGO sector needed to rethink its strategies. Examining the modern slavery labour reform process provides an opportunity to understand the strategic choices available to NGOs in the face of several important phenomena: the emergence of new actors such as international philanthropic donors; the growing influence of the private sector in governance matters; and the need for NGOs to balance multiple strategic alliances. The article draws on in‐depth interviews to explore narratives of Thai labour NGO adjustments during the period of the modern slavery reform. The study contributes to a better understanding of how NGOs in post‐aid countries transition and adapt to changing circumstances by embracing new roles as 'sub‐contractors' for emerging global philanthropic donors and as 'partners' of private corporations. [ABSTRACT FROM AUTHOR]

Objectives: Mutations in VCP, HNRNPA2B1, HNRNPA1, and SQSTM1, encoding RNA‐binding proteins or proteins in quality‐control pathways, cause multisystem proteinopathies (MSP). They share pathological findings of protein aggregation and clinical combinations of inclusion body myopathy (IBM), neurodegeneration [motor neuron disorder (MND)/frontotemporal dementia (FTD)], and Paget disease of bone (PDB). Subsequently, additional genes were linked to similar but not full clinical‐pathological spectrum (MSP‐like disorders). We aimed to define the phenotypic‐genotypic spectrum of MSP and MSP‐like disorders at our institution, including long‐term follow‐up features. Methods: We searched the Mayo Clinic database (January 2010–June 2022) to identify patients with mutations in MSP and MSP‐like disorders causative genes. Medical records were reviewed. Results: Thirty‐one individuals (27 families) had pathogenic mutations in: VCP (n = 17), SQSTM1 + TIA1 (n = 5), TIA1 (n = 5), MATR3, HNRNPA1, HSPB8, and TFG (n = 1, each). Myopathy occurred in all but 2 VCP‐MSP patients with disease onset at age 52 (median). Weakness pattern was limb‐girdle in 12/15 VCP‐MSP and HSPB8 patient, and distal‐predominant in other MSP and MSP‐like disorders. Twenty/24 muscle biopsies showed rimmed vacuolar myopathy. MND and FTD occurred in 5 (4 VCP, 1 TFG) and 4 (3 VCP, 1 SQSTM1 + TIA1) patients, respectively. PDB manifested in 4 VCP‐MSP. Diastolic dysfunction occurred in 2 VCP‐MSP. After 11.5 years (median) from symptom onset, 15 patients ambulated without gait‐aids; loss of ambulation (n = 5) and death (n = 3) were recorded only in VCP‐MSP. Interpretation: VCP‐MSP was the most common disorder; rimmed vacuolar myopathy was the most frequent manifestation; distal‐predominant weakness occurred frequently in non‐VCP‐MSP; and cardiac involvement was observed only in VCP‐MSP. [ABSTRACT FROM AUTHOR]

This study aimed to assess and compare the burden of transactive response DNA‐binding protein of 43 kDa (TDP‐43) pathology and clinical features of amyotrophic lateral sclerosis (ALS) in three age groups. All cases were from the Mayo Clinic brain bank for neurodegenerative disorders and most were followed longitudinally in the ALS Clinic. Cases with moderate‐to‐severe Alzheimer's disease neuropathological change were excluded. The 55 cases included in the study were divided into three groups by age at death: 75 years or older (old‐ALS, n = 8), 64–74 years (middle‐ALS, n = 23), and 63 years or younger (young‐ALS, n = 24). Clinical features, including disease duration, initial symptoms, and ALS Cognitive Behavior Score (ALS‐CBS), were summarized. Sections of paraffin‐embedded tissue from the motor cortex, basal forebrain, medial temporal lobe, and middle frontal gyrus were processed for phospho‐TDP‐43 immunohistochemistry. The burden of TDP‐43 pathology was analyzed using digital image analysis. The TDP‐43 burden in the limbic system (i.e., amygdala, dentate gyrus and CA1 sector of the hippocampus, subiculum, and entorhinal cortex) was greater in old‐ALS than in young‐ALS and middle‐ALS. TDP‐43 burden in the middle frontal gyrus was sparse and did not differ between the three groups. The average of ALS‐CBS was not different between the three groups. The present study shows that the amygdala and hippocampus are vulnerable to TDP‐43 pathology in older patients with ALS. We discuss the evidence for and against this pathology being related to concurrent limbic‐predominant, age‐related TDP‐43 encephalopathy neuropathologic change. [ABSTRACT FROM AUTHOR]

Introduction/aims: Amyotrophic lateral sclerosis (ALS) is a progressive, fatal, neurodegenerative disorder of motor neurons in which the cause is mostly unknown. Early identification of genetic ALS cases, of which C9ORF72 (C9ALS) is the most frequent, can have important implications for evaluation, prognosis, and therapeutics. Here, we aimed to characterize the clinical and electrophysiological hallmarks of C9ALS and investigate differences from C9ORF72 negative ALS (non-C9ALS).Methods: We retrospectively reviewed clinical and electrodiagnostic (EDX) data for all genetically confirmed C9ALS cases seen between 1/1/2012 and 10/1/2020 who met Gold Coast criteria and compared them 1:1 with non-C9ALS patients within the same time frame.Results: A total of 99 C9ALS and 99 non-C9ALS cases were identified. Compared to non-C9ALS, C9ALS demonstrated higher prevalence in women, lesser racial variability, stronger family history of ALS, and higher frequency of upper motor neuron signs. EDX testing of C9ALS showed higher median sensory nerve and lower fibular compound muscle action potential amplitudes.Discussion: Although the differences between C9ALS and non-C9ALS reached statistical significance in certain nerve conduction parameters, they were not sufficient to discriminate between groups on a case-by-case basis. Genetic testing is required to identify C9ALS patients. [ABSTRACT FROM AUTHOR]

Background: Achalasia‐addisonianism‐alacrima syndrome, frequently referred to as Allgrove syndrome or Triple A syndrome, is a multisystem disorder resulting from homozygous or compound heterozygous pathogenic variants in the gene encoding aladin (AAAS). Aladin is a member of the WD‐repeat family of proteins and is a component of the nuclear pore complex. It is thought to be involved in nuclear import and export of molecules. Here, we describe an individual with a paternally inherited truncating variant and a maternally inherited, novel missense variant in AAAS presenting with alacrima, achalasia, anejaculation, optic atrophy, muscle weakness, dysarthria, and autonomic dysfunction. Methods: Whole‐exome sequencing was performed in the proband, sister, and parents. Variants were confirmed by Sanger sequencing. The localization of aladin to the nuclear pore was assessed in cells expressing the patient variant. Results: Functional testing of the maternally inherited variant, p.(Arg270Pro), demonstrated decreased localization of aladin to the nuclear pore in cells expressing the variant, indicating a deleterious effect. Follow‐up testing in the proband's affected sister revealed that she also inherited the biallelic AAAS variants. Conclusions: Review of the patient's clinical, pathological, and genetic findings resulted in a diagnosis of Triple A syndrome. [ABSTRACT FROM AUTHOR]

Introduction/Aims: ALS is a heterogeneous disease that may be complicated or in part driven by inflammation. NP001, a regulator of macrophage activation, was associated with slowing disease progression in those with higher levels of the plasma inflammatory marker C‐reactive protein (CRP) in phase 2A studies in ALS. Here, we evaluate the effects of NP001 in a phase 2B trial, and perform a post hoc analysis with combined data from the preceding phase 2A trial. Methods: The phase 2B trial enrolled 138 participants within 3 y of symptom onset and with plasma hs‐CRP values >1.13 mg/L. They were randomized 1:1 to receive either placebo or NP001 for 6 mo. Change from baseline ALSFRS‐R scores was the primary efficacy endpoint. Secondary endpoints included vital capacity (VC) change from baseline and percentage of participants showing no decline of ALSFRS‐R score over 6 mo (non‐progressor). Results: The phase 2B study did not show significant differences between placebo and active treatment with respect to change in ALSFRS‐R scores, or VC. The drug was safe and well tolerated. A post hoc analysis identified a 40‐ to 65‐y‐old subset in which NP001‐treated patients demonstrated slower declines in ALSFRS‐R score by 36% and VC loss by 51% compared with placebo. A greater number of non‐progressors were NP001‐treated compared with placebo (p =.004). Discussion: Although the phase 2B trial failed to meet its primary endpoints, post hoc analyses identified a subgroup whose decline in ALSFRS‐R and VC scores were significantly slower than placebo. Further studies will be required to validate these findings. [ABSTRACT FROM AUTHOR]

The challenges of diversion during the stimulations of carbonate formations have been widely studied for decades. It has been shown that viscoelastic surfactants (VES) are among the effective diverting solutions which can be used during the stimulation of carbonate formations. These chemicals benefit from the reaction products between the acid and the calcite to increase the viscosity of the acid, therefore reducing, temporarily, the permeability of the first invaded rock layer, which holds the highest permeability. This temporary blockage steers the remaining acid to the layers with lower permeability that need treatment. This is usually called self‐diverting acidizing treatment. However, the same approach may not necessarily be applied for sandstone formations that are not calcite rich. In such cases, combining acid stages with batches of diverting agents is still feasible. For this approach, VES is also a suitable, non‐damaging solution that is often overlooked. In this study, the application of VES as a diverting agent was investigated during the chemical treatment operations in sandstone formations. Several dual core‐flooding experiments were performed at high pressure and high temperature (HPHT) conditions using sandstone core samples with high permeability contrast. [ABSTRACT FROM AUTHOR]

Objective: Dual leucine zipper kinase (DLK), which regulates the c‐Jun N‐terminal kinase pathway involved in axon degeneration and apoptosis following neuronal injury, is a potential therapeutic target in amyotrophic lateral sclerosis (ALS). This first‐in‐human study investigated safety, tolerability, and pharmacokinetics (PK) of oral GDC‐0134, a small‐molecule DLK inhibitor. Plasma neurofilament light chain (NFL) levels were explored in GDC‐0134‐treated ALS patients and DLK conditional knockout (cKO) mice. Methods: The study included placebo‐controlled, single and multiple ascending‐dose (SAD; MAD) stages, and an open‐label safety expansion (OLE) with adaptive dosing for up to 48 weeks. Results: Forty‐nine patients were enrolled. GDC‐0134 (up to 1200 mg daily) was well tolerated in the SAD and MAD stages, with no serious adverse events (SAEs). In the OLE, three study drug‐related SAEs occurred: thrombocytopenia, dysesthesia (both Grade 3), and optic ischemic neuropathy (Grade 4); Grade ≤2 sensory neurological AEs led to dose reductions/discontinuations. GDC‐0134 exposure was dose‐proportional (median half‐life = 84 h). Patients showed GDC‐0134 exposure‐dependent plasma NFL elevations; DLK cKO mice also exhibited plasma NFL compared to wild‐type littermates. Interpretation: This trial characterized GDC‐0134 safety and PK, but no adequately tolerated dose was identified. NFL elevations in GDC‐0134‐treated patients and DLK cKO mice raised questions about interpretation of biomarkers affected by both disease and on‐target drug effects. The safety profile of GDC‐0134 was considered unacceptable and led to discontinuation of further drug development for ALS. Further work is necessary to understand relationships between neuroprotective and potentially therapeutic effects of DLK knockout/inhibition and NFL changes in patients with ALS. [ABSTRACT FROM AUTHOR]

The dynamic growth of the skeleton during childhood and adolescence renders it vulnerable to adverse effects of cancer treatment. The lifetime risk and patterns of skeletal morbidity have not been described in a population‐based cohort of childhood cancer survivors. A cohort of 26 334 1‐year cancer survivors diagnosed before 20 years of age was identified from the national cancer registries of Denmark, Finland, Iceland and Sweden as well as a cohort of 127 531 age‐ and sex‐matched comparison subjects randomly selected from the national population registries in each country. The two cohorts were linked with data from the national hospital registries and the observed numbers of first‐time hospital admissions for adverse skeletal outcomes among childhood cancer survivors were compared to the expected numbers derived from the comparison cohort. In total, 1987 childhood cancer survivors had at least one hospital admission with a skeletal adverse event as discharge diagnosis, yielding a rate ratio (RR) of 1.35 (95% confidence interval, 1.29‐1.42). Among the survivors, we observed an increased risk for osteonecrosis with a RR of 25.9 (15.0‐44.5), osteoporosis, RR 4.53 (3.28‐6.27), fractures, RR 1.27 (1.20‐1.34), osteochondropathies, RR 1.57 (1.28‐1.92) and osteoarthrosis, RR 1.48 (1.28‐1.72). The hospitalization risk for any skeletal adverse event was higher among survivors up to the age of 60 years, but the lifetime pattern was different for each type of skeletal adverse event. Understanding the different lifetime patterns and identification of high‐risk groups is crucial for developing strategies to optimize skeletal health in childhood cancer survivors. What's new? The dynamic growth of the skeleton during childhood renders it vulnerable to adverse effects of cancer treatment. In this comprehensive, large‐scale population‐based retrospective cohort study, childhood cancer survivors were more likely to be hospitalised for skeletal adverse events than matched population comparison subjects. Although the risk of adverse events was highest in the period close to the cancer treatment, the excess risk continued for decades. Osteonecrosis, osteoporosis, fractures, osteochondropathies, and osteoarthrosis all showed different lifetime patterns. Understanding the lifetime patterns of skeletal adverse events and identifying high‐risk groups could help develop strategies to optimise skeletal health in childhood cancer survivors. [ABSTRACT FROM AUTHOR]

Summary: Relapse constitutes the greatest threat to event‐free survival after completion of treatment for childhood acute lymphoblastic leukaemia (ALL). However, evidence on optimal follow‐up schedules is limited. The aims of the present population‐based cohort study were to assess the value of current follow‐up schedules after completion of Nordic Society of Paediatric Haematology and Oncology ALL protocol treatment and to estimate the impact of relapse detection mode on overall survival (OS). Among 3262 patients diagnosed between 1992 and 2014 and who completed treatment, 338 developed a relapse. Relapse detection was equally distributed between extra visits (50·8%) and scheduled follow‐up visits (49·2%). All cases detected at an extra visit and 64·3% of cases detected at a scheduled visit presented with symptoms or objective findings. Neither the mode of detection {adjusted hazard ratio 0·95, [95% confidence interval (CI) 0·61–1·48] for scheduled visits} nor the duration of symptoms was an independent risk factor for OS after relapse. The estimated number of scheduled blood samples needed to diagnose one subclinical relapse during the first 5 years after treatment cessation was 1269 (95% CI 902–1637). In conclusion, based on OS data, scheduled visits after cessation of therapy seem to yield no extra benefit. These results should frame future follow‐up strategies. [ABSTRACT FROM AUTHOR]

Introduction/aims: Cortical hyperexcitability is a feature of amyotrophic lateral sclerosis (ALS) and cortical excitability can be measured using transcranial magnetic stimulation (TMS). Resting motor threshold (MT) is a measure of cortical excitability, largely driven by glutamate. Perampanel, a glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor blocker, is predicted to increase the cortical excitability threshold. This study aimed to evaluate TMS to functionally assess target engagement in a study of perampanel in ALS.Method: We studied the MT of ALS patients randomized to a single dose of perampanel or placebo 5:1 hourly for 4 h. Twelve patients participated at 4 mg and 7 returned for dosing and retesting at 8 mg. The study was terminated in April 2020 due to coronavirus disease 2019-related restrictions, after 7 out of 12 planned patients had received the 8 mg dose. Serum concentrations were also measured.Results: Ten patients received the 4 mg dose (2 received placebo) and 5 received the 8 mg dose (2 received placebo). Motor Threshold increased at 2 h after dosing in the combined treatment group +7% of maximal stimulator output (P < .01). Change could be detected in the larger 4 mg group (P = .02), but not in the smaller 8 mg dose group (P = .1). No side effects were reported after single dose exposure.Discussion: This study shows that perampanel effects the physiology of upper motor neurons. Studies aiming at gauging the effect of perampanel on ALS disease progression are already ongoing. Motor threshold may serve as a marker of biological target engagement. [ABSTRACT FROM AUTHOR]

Introduction: We conducted an open-label study to examine the effects of the flavonoid (-)-epicatechin in seven ambulatory adult patients with Becker muscular dystrophy (BMD).Methods: Seven participants received (-)-epicatechin 50 mg twice per day for 8 weeks. Pre- and postprocedures included biceps brachii biopsy to assess muscle structure and growth-relevant endpoints by western blotting, mitochondria volume measurement, and cristae abundance by electron microscopy, graded exercise testing, and muscle strength and function tests.Results: Western blotting showed significantly increased levels of enzymes modulating cellular bioenergetics (liver kinase B1 and 5'-adenosine monophosphate-activated protein kinase). Peroxisome proliferator-activated receptor gamma coactivator-1alpha, a transcriptional coactivator of genes involved in mitochondrial biogenesis and cristae-associated mitofilin levels, increased as did cristae abundance. Muscle and plasma follistatin increased significantly while myostatin decreased. Markers of skeletal muscle regeneration myogenin, myogenic regulatory factor-5, myoblast determination protein 1, myocyte enhancer factor-2, and structure-associated proteins, including dysferlin, utrophin, and intracellular creatine kinase, also increased. Exercise testing demonstrated decreased heart rate, maximal oxygen consumption per kilogram, and plasma lactate levels at defined workloads. Tissue saturation index improved in resting and postexercise states.Discussion: (-)-Epicatechin, an exercise mimetic, appears to have short-term positive effects on tissue biomarkers indicative of mitochondrial biogenesis and muscle regeneration, and produced improvements in graded exercise testing parameters in patients with BMD. [ABSTRACT FROM AUTHOR]

Introduction: Radiologically inserted gastrostomy (RIG) placement in patients with amyotrophic lateral sclerosis (ALS) carries risks related to periprocedural sedation and analgesia. To minimize these risks, we used a paravertebral block (PVB) technique for RIG placement.Methods: We retrospectively reviewed patients with ALS undergoing RIG placement under PVB between 2013 and 2017.Results: Ninety-nine patients with ALS underwent RIG placement under PVB. Median (range) age was 66 (28 to 86) years, ALS Functional Rating Scale-Revised score was 27 (6 to 45), and forced vital capacity was 47% (8%-79%) at time of RIG placement. Eighty-five (85.9%) patients underwent RIG placement as outpatients, with a mean postanesthesia care unit stay of 2.3 hours. The readmission rate was 4% at both 1 and 30 days postprocedure.Discussion: PVB for RIG placement has a low rate of adverse events and provides effective periprocedural analgesia in patients with ALS, the majority of whom can be treated as outpatients. [ABSTRACT FROM AUTHOR]

Introduction: Although perinatal distress is acknowledged as a burdening condition for pregnant women, its effects on pregnancy are not well known. This study was conducted to increase knowledge regarding the effects of distress on pregnancy‐related problems. The study also assessed women's need for sick leave and increased prenatal care due to distress, and the effects of weak social support and dissatisfaction with their partner relationships. Methods: In total, 2523 women were screened for perinatal distress three times during pregnancy in this quantitative cohort study. Structured psychiatric interviews were conducted following the screening, with 562 of the participants. Data from participants' pregnancy records were also analysed. The study was conducted in primary healthcare centres in Iceland after receiving approval from the Icelandic National Bioethical Committee. The main outcome measures were pregnancy problems, sick leave issued and prenatal service needs. Results: Data from 503 women were analysed. The perinatal distress group (PDG) was significantly more likely than was the nondistressed group (NDG) to experience fatigue, vomiting and pelvic pain after controlling for background variables. Distressed women who reported weak family support experienced symptoms of nausea and heartburn. The PDG needed more frequent prenatal care than did the NDG and was issued sick leave for up to 42 days longer. Dissatisfaction in the partner relationship and with the division of household tasks and childcare was strongly associated with distress, the development of complications and the need for sick leave. Discussion: Identification of perinatal distress by midwives and other healthcare professionals is important, since distress may be linked to women's complaints of fatigue, vomiting, pelvic pain and need for prolonged sick leave, and additional prenatal care services will be needed. Perceived dissatisfaction in the partner relationship and with the division of household tasks should also form part of clinical practice and assistance provided. [ABSTRACT FROM AUTHOR]

Introduction: Our research aim was to develop a novel clinimetric scale sensitive enough to detect disease progression in primary lateral sclerosis (PLS).Methods: A prototype of the PLS Functional Rating Scale (PLSFRS) was generated. Seventy-seven participants with PLS were enrolled and evaluated at 21 sites that comprised the PLSFRS study group. Participants were assessed using the PLSFRS, Neuro-Quality of Life (QoL), Schwab-England Activities of Daily Living (ADL), and the Clinical Global Impression of Change scales. Participants completed telephone assessments at 12, 24, and 48 weeks after enrollment.Results: The PLSFRS demonstrated internal consistency as well as intrarater, interrater, telephone test-retest reliability, and construct validity. Significant changes in disease progression were detected at 6 and 12 months; changes measured by the PLSFRS vs the ALSFRS-R were significantly higher.Discussion: The PLSFRS is a valid tool to assess the natural history of PLS in a shorter study period. [ABSTRACT FROM AUTHOR]

This study's aim was to explore high school students' suggestions for supporting younger pupils prevent and deal with cyberbullying. Seventy‐eight high school students participated in 11 focus groups, and had many concrete suggestions for ways they could support younger pupils against cyberbullying. The suggestions covered a range of activities, for instance advising younger pupils on how to avoid becoming victims of cyberbullying by teaching them netiquette. Furthermore, the students were positive toward involving adults in counteracting cyberbullying among younger pupils, for example educating younger pupils' parents about cyberbullying. Moreover, the students suggested that they could show support for victims of cyberbullying by taking on the role of a friend when a younger pupil is cyberbullied and spend time with her/him during breaks. They also had ideas about supporting younger pupils in getting cyberbullies to stop, for instance by teaching the younger pupils technical skills for dealing with the cyberbullying on the Internet. To conclude, the findings in this study indicate that high school students want to be involved in supporting younger pupils against cyberbullying, and have many concrete suggestions for how this can be done. These findings have implications for counteracting cyberbullying in schools. [ABSTRACT FROM AUTHOR]

An optimized one‐pot recipe has been developed to synthesize a surfactant molecule, referred to as OMID, consisting of an imidazoline head group and aliphatic tail, which is an exemplar corrosion inhibitor for carbon steel in acidic solutions. As evidenced by gas chromatography, 1H and 13C nuclear magnetic resonance, and Fourier‐transform infrared data, a high‐purity product was achieved without the use of either a solvent or catalyst. Critical micelle concentration values and corrosion inhibition efficiencies (η%) were determined in aqueous solutions of hydrochloric acid and sulfuric acid using surface tensiometry and linear polarization resistance measurements, respectively. Hydrolysis of the imidazoline head group as a function of pH (0–11) was explored with ultraviolet–visible absorption spectroscopy. In addition, N 1s and C 1s X‐ray photoelectron spectroscopy data were acquired from both surface‐adsorbed OMID and a multilayer of the imidazoline head group of OMID. These latter data are highly relevant to those attempting to understand OMID inhibition chemistry. [ABSTRACT FROM AUTHOR]

This article explores a great contradiction in rural land debates in India: on the one hand, explosive political contestation that is often able to halt proposed land acquisition; on the other, an unprecedented urban‐industrial expansion that is appropriating rural land. The authors argue that land grabbing for mining proceeds in an incremental manner, yet its cumulative effect leads to territorial transformation. To investigate this incremental appropriation, a temporal study of the North Karanpura coal mining tract in eastern India was conducted, combining remote sensing, interviews and official land‐use data. The results reveal a cumulative land grab of thousands of hectares from the late 1980s to the present day as open‐cut coal mines swallow up vast swathes of agricultural fields and forests. The political economy mechanism behind this immense land grab, which to date has gone undetected, consists of three phases: the reservation of the land as a coalfield with multiple coal blocks; the division of the blocks into separate mines; and the flexible expansion of individual mines wherever reduced resistance to land acquisition is encountered. This research indicates that an aggregate analysis of land dynamics can more robustly place the dramatic rearrangements of the Indian countryside within the international land grabbing debate. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: To compare the peri‐implant tissue response to subcrestal or crestal placement of implants with or without “platform‐switched” implant/abutment connections. Material and methods: On each side of the mandible in six Labrador dogs, two “platform‐switched” (PS) implants and two implants with matching implant/abutment diameters (PM) were placed in a crestal or a 1.5 mm subcrestal position. Sulcus formers/abutments were connected, baseline radiographs obtained and the distance between the abutment‐fixture junction (A/F) and the marginal bone level (B) was determined. Five months later, radiographic and clinical examinations were repeated and biopsies were obtained and processed for histological analysis. Results: The radiographic analysis showed that marginal bone level changes occurred during the first observation period (13 weeks). PS‐implants showed minor marginal bone level alterations during the full observation period (20 weeks), regardless of placement depth. For PM‐implants, placement had a significant impact on bone level changes; crestal placement resulted in a mean bone loss of 0.4 mm and subcrestal placement in a 1.5 mm bone loss. The histometric measurements resulted in a distance A/F‐B of 0.6 and 0.0 mm for PS implants, placed in a crestal or subcrestal position, respectively. The corresponding distance at PM‐implants was 1.5 mm irrespective of placement protocol. The peri‐implant mucosa was thicker at subcrestally placed implants as compared to a crestal placement. Conclusions: Bone remodeling occurred within the early healing phase. During the full 20 weeks of observation, PS‐implants demonstrated significantly less crestal bone loss compared to PM‐implants. [ABSTRACT FROM AUTHOR]

Introduction: More than 90% of amyotrophic lateral sclerosis (ALS) patients have muscle cramps, but evidence-based treatments have not been available.Methods: A multicenter, double-blind, placebo-controlled crossover trial of mexiletine 150 mg twice daily was conducted in ALS patients requesting treatment of symptomatic muscle cramps.Results: Muscle cramp frequency was reduced in 18 of 20 patients; 13 reductions were attributed to treatment (P < 0.05). The average reduction, based on t tests, was 1.8 cramps per day (a reduction from 5.3 with placebo to 3.5 with mexiletine). The estimated reduction of cramp severity was 15 units on a 100-unit scale (P = 0.01) from a baseline average of 46. No effect on fasciculations was noted. One patient discontinued the study because of dizziness, and another patient discontinued the study to start open-label mexiletine therapy. No serious adverse event occurred.Discussion: Mexiletine is a well tolerated and effective medication for controlling the symptom of muscle cramps in ALS. Muscle Nerve, 2018. [ABSTRACT FROM AUTHOR]

Peroxisome proliferator-activated receptor alpha (PPARα) is a molecular target for perfluoroalkyl substances (PFASs). Little is known about the cellular uptake of PFASs and how it affects the PPARα activity. We investigated the relationship between PPARα activity and cellular concentration in HepG2 cells of 14 PFASs, including perfluoroalkyl carboxylates (PFCAs), perfluoroalkyl sulfonates and perfluorooctane sulfonamide (FOSA). Cellular concentrations were determined by high-performance liquid chromatography-tandem mass spectrometry and PPARα activity was determined in transiently transfected cells by reporter gene assay. Cellular uptake of the PFASs was low (0.04-4.1%) with absolute cellular concentrations in the range 4-2500 ng mg−1 protein. Cellular concentration of PFCAs increased with perfluorocarbon chain length up to perfluorododecanoate. PPARα activity of PFCAs increased with chain length up to perfluorooctanoate. The maximum induction of PPARα activity was similar for short-chain (perfluorobutanoate and perfluoropentanoate) and long-chain PFCAs (perfluorododecanoate and perfluorotetradecanoate) (approximately twofold). However, PPARα activities were induced at lower cellular concentrations for the short-chain homologs compared to the long-chain homologs. Perfluorohexanoate, perfluoroheptanoate, perfluorooctanoate, perfluorononanoate (PFNA) and perfluorodecanoate induced PPARα activities >2.5-fold compared to controls. The concentration-response relationships were positive for all the tested compounds, except perfluorooctane sulfonate PFOS and FOSA, and were compound-specific, as demonstrated by differences in the estimated slopes. The relationships were steeper for PFCAs with chain lengths up to and including PFNA than for the other studied PFASs. To our knowledge, this is the first report establishing relationships between PPARα activity and cellular concentration of a broad range of PFASs. [ABSTRACT FROM AUTHOR]

We use polygenic risk scores (PRSs) for schizophrenia (SCZ) and bipolar disorder (BPD) to predict smoking, and addiction to nicotine, alcohol or drugs in individuals not diagnosed with psychotic disorders. Using PRSs for 144 609 subjects, including 10 036 individuals admitted for in-patient addiction treatment and 35 754 smokers, we find that diagnoses of various substance use disorders and smoking associate strongly with PRSs for SCZ (P = 5.3 × 10-50 -1.4 × 10-6 ) and BPD (P = 1.7 × 10-9 -1.9 × 10-3 ), showing shared genetic etiology between psychosis and addiction. Using standardized scores for SCZ and BPD scaled to a unit increase doubling the risk of the corresponding disorder, the odds ratios for alcohol and substance use disorders range from 1.19 to 1.31 for the SCZ-PRS, and from 1.07 to 1.29 for the BPD-PRS. Furthermore, we show that as regular smoking becomes more stigmatized and less prevalent, these biological risk factors gain importance as determinants of the behavior. [ABSTRACT FROM AUTHOR]

One of the clearest results in previous studies on social trust is the robust positive relationship with educational attainment. The most common interpretation is that education has a causal effect on social trust. The theoretical argument and empirical results in this article suggest a different interpretation. We argue that common preadult factors such as cognitive abilities and personality traits rooted in genes and early-life family environment may confound the relationship between educational attainment and social trust. We provide new evidence on this question by utilizing the quasi-experiment of twinning. By looking at the relationship between education and social trust within monozygotic (MZ) twin pairs, we are able to avoid potential confounders rooted in genetic factors and common environmental influences because the monozygotic twins share both. The results suggest that when controlling for such familial factors the estimated effects of education on social trust are close to zero and far from reaching statistical significance. Further analyses show that the relationship between education and social trust largely is driven by common genetic factors. [ABSTRACT FROM AUTHOR]

Purpose Drug-induced pancreatitis is receiving increased medical and epidemiological attention. However, as no study has examined the role of polypharmacy per se in the development of acute pancreatitis, we examined the association between polypharmacy and risk of acute pancreatitis. Methods A nationwide case-control study was conducted between 2006 and 2008 of Swedish people aged 40-84 years. The Swedish Patient Register was used to identify 6161 cases of first-episode acute pancreatitis. The Swedish Register of the Total Population was used to randomly select 61 637 controls from the general population using frequency-based density sampling, matched for age, sex, and calendar year. The Swedish Prescribed Drug Register was used to assess polypharmacy, defined as the number of unique drugs prescribed during the last 6 months before the index date (i.e. the date of acute pancreatitis for cases and a random date for controls). Odds ratios (ORs), with 95% confidence intervals (CIs), of acute pancreatitis were estimated by unconditional logistic regression, adjusted for matching variables and potential confounding factors. Results The number of prescribed drugs was associated with a dose-dependent increase in the risk of acute pancreatitis. In the multivariable-adjusted model, compared to those without any prescriptions, the OR was 1.69 (95%CI: 1.55-1.86) for persons with 1-2 drugs, 2.40 (2.20-2.62) for 3-5 drugs, 3.17 (2.88-3.48) for 6-9 drugs, and 4.57 (4.12-5.06) for 10 or more drugs. Conclusion This population-based case-control study shows a dose-dependent association between increasing polypharmacy and risk of acute pancreatitis. These findings provide further insights into drug-induced pancreatitis. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Introduction: Reachable workspace is a measure that provides clinically meaningful information regarding arm function. In this study, a Kinect sensor was used to determine the spectrum of 3-dimensional reachable workspace encountered in a cross-sectional cohort of individuals with amyotrophic lateral sclerosis (ALS).Methods: Bilateral 3D reachable workspace was recorded from 10 subjects with ALS and 17 healthy controls. The data were normalized by each individual's arm length to obtain a reachable workspace relative surface area (RSA). Concurrent validity was assessed by correlation with scoring on the ALS Functional Rating Score-revised (ALSFRSr).Results: The Kinect-measured reachable workspace RSA differed significantly between the ALS and control subjects (0.579 ± 0.226 vs. 0.786 ± 0.069; P < 0.001). The RSA demonstrated correlation with ALSFRSr upper extremity items (Spearman correlation ρ = 0.569; P = 0.009). With worsening upper extremity function, as categorized by the ALSFRSr, the reachable workspace also decreased progressively.Conclusions: This study demonstrates the feasibility and potential of using a novel Kinect-based reachable workspace outcome measure in ALS. [ABSTRACT FROM AUTHOR]

Recent research has demonstrated that genetic differences explain a sizeable fraction of the variance in political orientations, but little is known about the pathways through which genes might affect political preferences. In this article, we use a uniquely assembled dataset of almost 1,000 Swedish male twin pairs containing detailed information on cognitive ability and political attitudes in order to further examine the genetic and environmental causes of political orientations. Our study makes three distinct contributions to our understanding of the etiology of political orientations: (1) we report heritability estimates across different dimensions of political ideology; (2) we show that cognitive ability and political orientations are related; and (3) we provide evidence consistent with the hypothesis that cognitive ability mediates part of the genetic influence on political orientations. These findings provide important clues about the nature of the complex pathways from molecular genetic variation to political orientations. [ABSTRACT FROM AUTHOR]

Background: Individuals with chronic pain are among the most frequent users of health care. Still, a significant percentage does not utilize health care for pain. A range of factors predict chronic pain‐related health care utilization. Design: A cross‐sectional study aimed at identifying predictors of chronic pain‐related health care utilization and comparing predictors between men and women. Methods: A postal questionnaire measuring sociodemographic variables, pain characteristics, health‐related quality of life (HRQoL) and pain‐related health care utilization, was sent to a sample of 4500 individuals randomly drawn from the national population of Iceland. The relationships between sociodemographic and pain‐related factors and pain‐related health care utilization among participants reporting chronic pain (≥3 months) were tested by using bivariate and multivariate statistical analysis. Results: Among participants reporting chronic pain, 53.2% had consulted a health care provider for pain during the previous 6 months. Predictors for chronic pain‐related health care utilization differed between men and women. Interference with life and pain pattern was the strongest predictors among women, as compared with interference with life and the physical components of HRQoL for men. Pain‐related health care utilization was not linked to sociodemographic factors. Conclusions: Pain‐related variables are better predictors of chronic pain‐related health care utilization than sociodemographic factors. Even though gender does not predict chronic pain‐related health care utilization, there are gender differences in the relationships between pain‐related variables and health care utilization. Men tend to postpone health care consultations for chronic pain longer than women. [ABSTRACT FROM AUTHOR]

MASSIF-1 (ID30A-1) is an ESRF undulator beamline operating at a fixed wavelength of 0.969 Å (12.8 keV) that is dedicated to the completely automatic characterization of and data collection from crystals of biological macromolecules. The first of the ESRF Upgrade MASSIF beamlines to be commissioned, it has been open since September 2014, providing a unique automated data collection service to academic and industrial users. Here, the beamline characteristics and details of the new service are outlined. [ABSTRACT FROM AUTHOR]

Aim: Pulse oximetry screening of newborn infants increases early detection of critical congenital heart disease and minimises the risk of circulatory collapse before surgery. This study provides an update on the implementation of pulse oximetry screening in the Nordic countries and proposes standardised guidelines.Methods: A questionnaire exploring pulse oximetry screening, clinical examination routines and availability of echocardiography was distributed to all 157 delivery units in the Nordic countries in June 2013.Results: We received responses from 156 of the 157 delivery units, and 116 (74%) were using pulse oximetry screening by September 2013. Preductal and postductal screening were both used in 59 of 116 units (51%), with just postductal screening in 51 of 116 (44%) and just preductal screening alone in 6 of 116 (5%). Screening was performed before 24 h in 105 of 116 units (91%). The implementation of screening was highest in Finland (29/30, 97%), Sweden (42/46, 91%) and Norway (43/48, 90%) and lowest in Denmark (2/24, 8%) and Iceland (0/8 units).Conclusion: In Sweden, Norway and Finland, the implementation of pulse oximetry screening is currently the highest in the world and coverage will be close to 100% in 2014. We propose uniform Nordic guidelines using preductal and postductal screening before 24 h of age. [ABSTRACT FROM AUTHOR]

Aim The aim of this study was to examine possible signs of impairment of the microcirculation in the lower extremities of female patients suffering from primary restless legs syndrome ( RLS)/ Willis- Ekbom disease. Methods This study was performed in eight female patients, mean age 48 years (range 21-65), diagnosed with primary RLS but otherwise healthy. Eight healthy female control subjects, mean age 47 years (range 27-64), were also included in the study. Laser Doppler flowmetry was used to determine intramuscular blood flow by placing an optical single fiber in the tibialis anterior muscle belly. The studies were performed between 08.00 and 10.00 hours and 20.00 and 22.00 hours. Blood flow was expressed in perfusion units. Results The median intramuscular blood flow in the RLS patients' tibialis anterior muscles, recorded from both legs, was significantly higher in the morning, at 17.9 perfusion units, than in the evening, at 12.1 perfusion units ( P = 0.004). Corresponding values for the healthy controls were 13.1 perfusion units and 12.0 perfusion units, a non-significant difference. The relative fold changes of microcirculation in the RLS group compared to healthy age-matched controls were 0.7 ± 0.3 and 1.1 ± 0.6, respectively ( P = 0.04). Conclusion Our results suggest that in female patients with primary RLS, the microcirculation in the tibialis anterior muscle is higher in the morning compared with in the evening. [ABSTRACT FROM AUTHOR]

The discriminatory power of the noncoding control region ( CR) of domestic dog mitochondrial DNA alone is relatively low. The extent to which the discriminatory power could be increased by analyzing additional highly variable coding regions of the mitochondrial genome (mtGenome) was therefore investigated. Genetic variability across the mtGenome was evaluated by phylogenetic analysis, and the three most variable ~1 kb coding regions identified. We then sampled 100 Swedish dogs to represent breeds in accordance with their frequency in the Swedish population. A previously published dataset of 59 dog mtGenomes collected in the United States was also analyzed. Inclusion of the three coding regions increased the exclusion capacity considerably for the Swedish sample, from 0.920 for the CR alone to 0.964 for all four regions. The number of mt DNA types among all 159 dogs increased from 41 to 72, the four most frequent CR haplotypes being resolved into 22 different haplotypes. [ABSTRACT FROM AUTHOR]

Objective Type 1 diabetes ( T1 D) is associated with low IGF-I and altered levels of IGF-binding proteins ( IGFBPs) in plasma. This may be of importance for insulin sensitivity and the risk of developing diabetic complications. We hypothesized that IGF-I bioactivity is affected by the route of insulin administration and that continuous intraperitoneal insulin infusion ( CIPII) has a more pronounced effect than continuous subcutaneous insulin infusion ( CSII). Design and methods We compared 10 patients with T1 D on CIPII with 20 age- and sex-matched patients on CSII. Blood sampling was carried out 7-9 am after an overnight fast. All patients were C-peptide negative. IGF-I bioactivity was measured in vitro using a specific IGF-I kinase receptor activation ( KIRA) assay. IGF-I was also measured by immunoassay together with IGF- II, IGFBP-1 and IGFBP-2. Results When compared with subcutaneous insulin, intraperitoneal insulin resulted in ( CIPII vs CSII) higher IGF-I bioactivity (1·83 ± 0·76 vs 1·16 ± 0·24 μg/l; P = 0·02), IGF-I (120 ± 35 vs 81 ± 19 μg/l; P = 0·01) and IGF- II (1050 ± 136 vs 879 ± 110 μg/l; P = 0·02). By contrast, log-transformed IGFBP-1 was reduced ( P = 0·013), whereas log-transformed IGFBP-2 was not different ( P = 0·12). There was a positive correlation between IGF bioactivity and IGF-I ( r = 0·69; P < 0·001) and an inverse correlation between IGF-I bioactivity and log10 IGFBP-1 ( r = −0·68, P < 0·001). Conclusion The in vitro IGF-I bioactivity was higher in patients treated with CIPII compared with CSII supporting the theory that the route of insulin administration is of importance for the activity of the IGF system. Intraperitoneal insulin administration may therefore be beneficial by correcting the alterations of the IGF system in T1 D. [ABSTRACT FROM AUTHOR]

Authors' reply We thank Yeoh I et al i . for their comments1 on our article.2 We fully agree that relapse detection is only one of many purposes of follow-up programmes in survivors of childhood acute lymphoblastic leukaemia (ALL). In our study, we present the best available evidence on the association between relapse detection mode and post-relapse survival in a large, population-based cohort of childhood ALL patients. Hence, our present findings cannot be generalised to all ALL survivors i .'2 We find it a strength of our study that post-haematopoietic stem cell transplantation (HSCT) relapses and second relapses were excluded because of a very poor outcome in these patients; including these relapses would potentially have biased the results. [Extracted from the article]

Aim Exercise-induced adaptations of skeletal muscle are related to training mode and can be muscle fibre type specific. This study aimed to investigate heat shock protein expression in type I and type II muscle fibres in resting skeletal muscle of subjects with different training backgrounds. Methods Three groups of subjects were included: healthy active not engaged in any training programme ( ACT, n = 12), resistance trained ( RES, n = 6) and endurance trained ( END, n = 8). Biopsies were obtained from vastus lateralis, and immunohistochemistry was performed using monoclonal antibodies against myosin heavy chain I and IIA, α B-crystallin, HSP27, HSP60 and HSP70. Results In ACT and RES, but not in END, a fibre type-specific expression with higher staining intensity in type I than type II fibres was seen for α B-crystallin. The opposite ( II > I) was found for HSP27 in subjects from ACT (6 of 12 subjects) and RES (3 of 6), whereas all subjects from END displayed uniform staining. HSP60 showed no fibre-specific expression. HSP70 displayed a fibre-specific expression pattern (I > II) in ACT (4 of 12), but not in END or RES. Conclusion This study shows that the level of expression of the different HSPs in human skeletal muscle is influenced by muscle fibre phenotype. The fibre type-specific expression of HSP70 is influenced by resistance and endurance training, whereas those of α B-crystallin and HSP27 is influenced only by endurance training, suggesting the existence of a training-modality-specific action on the adaptive processes including heat shock proteins in human skeletal muscle. [ABSTRACT FROM AUTHOR]

The article offers the author's insights on her study regarding why economic sanctions imposed on authoritarian regimes failed to bring about political change. The author says that she explores how economic sanctions in Iraq affect its political economy between 1990 and 2003 and the case of Libya under sanctions in 1990s. She mentions that Iraq and Libya has been under sanctions due to their support for the developments of mass destruction weapons and terrorism.

Here we report two paediatric cases of Kimura′s disease, which is a rare, chronic inflammatory disorder with undetermined aetiology. The first patient was a 17-year-old boy presenting with a swelling behind his right ear and a nephrotic syndrome. The second patient was a 9-year-old boy presenting with a left-sided preauricular swelling. Both displayed peripheral blood eosinophilia, raised levels of serum IgE and typical histological findings. Initial response to prednisolone was excellent but both relapsed as medication was tapered or discontinued. Adding cyclosporine to the regimen resulted in prolonged remission in both patients. Conclusion: We support the use of cyclosporine for maintaining remission in paediatric patients with Kimura′s disease. [ABSTRACT FROM AUTHOR]