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Adaptive laboratory evolution (ALE) is a widely used microbial strain development and optimization method. ALE experiments, to select for faster‐growing strains, are commonly performed as serial batch cultivations in shake flasks, serum bottles, or microtiter plates or as continuous cultivations in bioreactors on a laboratory scale. To combine the advantages of higher throughput in parallel shaken cultures with continuous fermentations for conducting ALE experiments, a new Continuous parallel shaken pH‐auxostat (CPA) was developed. The CPA consists of six autonomous parallel shaken cylindrical reactors, equipped with real‐time pH control of the culture medium. The noninvasive pH measurement and control are realized by biocompatible pH sensor spots and a programmable pump module, to adjust the dilution rate of fresh medium for each reactor separately. Two different strains of the methylotrophic yeast Ogataea polymorpha were used as microbial model systems for parallel chemostat and pH‐auxostat cultivations. During cultivation, the medium is acidified by the microbial activity of the yeast. For pH‐auxostat cultivations, the growth‐dependent acidification triggers the addition of fresh feed medium into the reactors, leading to a pH increase and thereby to the control of the pH to a predetermined set value. By controlling the pH to a predetermined set value, the dilution rate of the continuous cultivation is adjusted to values close to the washout point, in the range of the maximum specific growth rate of the yeast. The pH control was optimized by conducting a step‐response experiment and obtaining tuned PI controller parameters by the Chien‐Hrones‐Reswick (CHR) PID tuning method. Two pH‐auxostat cultivations were performed with two different O. polymorpha strains at high dilution rates for up to 18 days. As a result, up to 4.8‐fold faster‐growing strains were selected. The increased specific maximum growth rates of the selected strains were confirmed in subsequent batch cultivations. [ABSTRACT FROM AUTHOR]

Berth allocation decisions affect all subsequent decisions in port terminals. Thus assigning berthing positions and berthing times to vessels—known as the berth allocation problem (BAP)—is one of the most important problems in port terminals. Because this is an NP‐hard problem, most of the solution methods proposed for solving it are heuristics. Although very different, some heuristics applied to the continuous BAP share a common step usually performed several times: the insertion of vessels from an insertion sequence in the time‐space diagram that represents a BAP solution. This process is frequently done by using minimum cost sequential insertion heuristics such as bottom‐left‐based heuristics. Although fast and simple, these heuristics may not lead to high‐quality solutions. In this paper, we propose improved sequential insertion heuristics that generally outperform the traditional ones and keep their simplicity and speed. The proposed heuristics are tested on a large set of instances of BAPs with different optimization objectives, and the obtained results show that they can lead to solutions up to 70% better than those obtained by traditional sequential insertion heuristics. [ABSTRACT FROM AUTHOR]

Quay cranes are among the most important resources in port terminals, and their efficient use is crucial for port terminals to remain competitive in the market. The problem of determining the sequence of tasks performed by the quay cranes that minimizes the turnaround time of a vessel is an NP‐hard problem known as the quay crane scheduling problem (QCSP). In this paper, we consider the unidirectional QCSP under uncertain processing times, where the cranes are only allowed to move in a specific direction. We start by presenting the first distributionally robust optimization (DRO) model for this problem and an exact decomposition algorithm to solve it. The proposed DRO model makes it possible to derive a stochastic programming model and a robust optimization model for the unidirectional QCSP by an appropriate choice of the risk‐averse parameter of the model. Through extensive numerical results, we compare these three approaches—stochastic programming, robust optimization, and DRO—to investigate whether significant differences among the solutions obtained exist. Finally, we propose a new method for helping practitioners to determine a representative set of different DRO solutions. [ABSTRACT FROM AUTHOR]

Grounded in hedonic assumptions, evidence suggests that people tend to engage in activities they consider pleasurable and enjoyable, while trying to avoid pain and displeasure. This suggests that the dynamic between positive and negative affect can influence current behavior and the intentions to continue performing. Regarding resistance training (RT), research focusing on how to promote a better affective response is still scarce and much needed. Given existing limitations and theoretical suggestions, a RT program was developed and applied to recreational exercisers in a quasi‐experimental design aiming to (1) explore the affective response dynamic through an assessment after the last set of each exercise; and (2) analyze possible differences of preference and tolerance profiles in affective variables (core affect and enjoyment). For that purpose, 43 participants (21 male and 22 female; Mage = 34.69 ± 6.71 years; Mexperience = 8.32 ± 4.54 years; MBMI = 24.26 ± 2.64 kg/m2) accepted to participate in this study. Descriptive statistics, correlational, and group comparisons analyses were performed to provide evidence for proposed objectives. The present study showed that measures of affective valence/arousal applied immediately after a set represents a feasible and ecologically valid approach to tap core affect. Results presented evidence that recreationally trained exercisers in a common RT program would need a minimum of one measurement to assess the affective response. However, additional assessments could refine the understanding of exercise pleasurable experience. Results also suggest that exercisers with distinct profiles of preference/tolerance depicted differentiated patterns for the affective response, possibly justifying a distinct approach when promoting affective regulation. [ABSTRACT FROM AUTHOR]

The rising interest in the use of high strength steel (HSS) materials is justified by several advantages that they provide. In the field of construction, their benefits range from streamlined and elegant structures to lower CO2 emissions and energy consumption. High‐rise buildings and large span bridges can be designed with smaller foundations and less structural weight, since the application of HSS makes the design with slender steel sections possible. However, special attention should be given to the stability of the compressive members since the buckling resistance generally governs their design. The existing codes to evaluate the capacity of HSS columns and beam‐columns are based on rules from experimental tests related to normal strength steel (NSS) materials, which is responsible for inconsistencies. Therefore, this current work aims to present a numerical model created and validated to evaluate the major‐ and minor‐axis flexural buckling of HSS welded I‐section columns and the combined flexural and lateral‐torsional buckling of HSS welded I‐section beam‐columns. In the following, a parametric study is also conducted, in which different cross‐sections, normalized slenderness, steel grades (from S460 up), bending moment distributions and application of restraints are considered. Finally, a comparison between the European design rules and the resistances from the Finite Element model is led, evidencing the underrating expressed by the code with a level of safety even higher when superior steel grades are evaluated. [ABSTRACT FROM AUTHOR]

EN 1993‐1‐1 gives stability design rules for columns, beams and beam‐columns up to S460, whereas EN 1993‐1‐12 gives additional guidance for S500 up to S700 (based mainly on numerical work available at the time). Recent studies on flexural buckling of welded H, I and box columns in steel grades S460 to S960, even though limited, show that improved curves can be used for members in high strength steel (HSS). The research project RUOSTE also reported improved buckling curves for HSS box and tubular sections compared to those in Table 6.2 of EN 1993‐1‐1. This improved behaviour is usually attributed due to the improved material properties but mainly due to the more favourable residual stress distribution. Recently, within the European Project STROBE evaluation of the European stability design rules was carried out covering columns, beams, and beam‐columns. The research was based on experimental programme covering 20 full‐scale tests, residual stress measurements, advanced numerical models, analytical derivations, and statistical evaluation. Finally, it was possible to provide new, more relaxed recommendations for the buckling curve selection for HSS members. This paper provides a summary of the project conclusions regarding the stability design of steel members in high strength steel, where firstly a brief overview of the experimental results is presented, followed by the numerical parametric study, results evaluation, and discussion. [ABSTRACT FROM AUTHOR]

Background: Huntington's disease (HD) is a rare neurodegenerative disease that presents with progressive psychological, cognitive and motor impairment. These diverse symptoms place a high burden on the patient, families and the healthcare systems they rely on. This study aimed to describe the epidemiology and clinical burden in individuals with HD compared with controls from the general population. Methods: This cohort study utilised data from general practitioner medical records to estimate the prevalence and incidence of HD between January 2000 and December 2018. A cohort of incident HD cases were matched 1:3 to controls from the general population, in whom common clinical diagnoses, medications and healthcare interventions were compared at the time of first recorded diagnosis and at a time close to death. Incidence rates of common diagnoses and mortality were compared with matched controls in the time following HD diagnosis. Results: Prevalence of HD increased between 2000 and 2018, whilst incidence remained stable. Prevalence of psychiatric diagnoses and symptomatic treatments were higher in HD cases than controls. A higher relative risk of psychotic disorders, depression, insomnia, dementia, weight loss, pneumonia and falls was observed in HD cases. Risk of death was >4 times higher in HD, with a median survival of ~12 years from first recorded diagnosis. Conclusions: This study demonstrates the significant and progressive clinical burden in individuals with HD up to 18 years after first recorded diagnosis. [ABSTRACT FROM AUTHOR]

Background: Juvenile‐onset Huntington's disease (JOHD) is a rare and particularly devastating form of Huntington's disease (HD) for which clinical diagnosis is challenging and robust outcome measures are lacking. Neurofilament light protein (NfL) in plasma has emerged as a prognostic biomarker for adult‐onset HD. Methods: We performed a retrospective analysis of samples and data collected between 2009 and 2020 from the Kids‐HD and Kids‐JHD studies. Plasma samples from children and young adults with JOHD, premanifest HD (preHD) mutation carriers, and age‐matched controls were used to quantify plasma NfL concentrations using ultrasensitive immunoassay. Results: We report elevated plasma NfL concentrations in JOHD and premanifest HD mutation‐carrying children. In pediatric HD mutation carriers who were within 20 years of their predicted onset and patients with JOHD, plasma NfL level was associated with caudate and putamen volumes. Conclusions: Quantifying plasma NfL concentration may assist clinical diagnosis and therapeutic trial design in the pediatric population. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: Huntington's disease (HD) is a rare neurodegenerative disorder with protean clinical manifestations. Its management is challenging, consisting mainly of off‐label treatments. Objectives: The International Parkinson and Movement Disorder Society commissioned a task force to review and evaluate the evidence of available therapies for HD gene expansion carriers. Methods: We followed the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Eligible randomized controlled trials were identified via an electronic search of the CENTRAL, MEDLINE, and EMBASE databases. All eligible trials that evaluated one or more of 33 predetermined clinical questions were included. Risk of bias was evaluated using the Cochrane Risk of Bias tool. A framework was adapted to allow for efficacy and safety conclusions to be drawn from the balance between the GRADE level of evidence and the importance of the benefit/harm of the intervention. Results: Twenty‐two eligible studies involving 17 interventions were included, providing data to address 8 clinical questions. These data supported a likely effect of deutetrabenazine on motor impairment, chorea, and dystonia and of tetrabenazine on chorea. The data did not support a disease‐modifying effect for premanifest and manifest HD. There was no eligible evidence to support the use of specific treatments for depression, psychosis, irritability, apathy, or suicidality. Similarly, no evidence was eligible to support the use of physiotherapy, occupational therapy, exercise, dietary, or surgical treatments. Conclusions: Data for therapeutic interventions in HD are limited and support only the use of VMAT2 inhibitors for specific motor symptoms. © 2021 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Objectives: To study the natural history of renal oncocytomas and address indications for intervention by determining how growth is associated with renal function over time, the reasons for surgery and ablation, and disease‐specific survival. Patients and Methods: The study was conducted in a retrospective cohort of consecutive patients with renal oncocytoma on active surveillance reviewed at the Specialist Centre for Kidney Cancer at the Royal Free London NHS Foundation Trust (2012 to 2019). Comparison between groups was performed using Mann–Whitney U‐tests and chi‐squared tests. A mixed‐effects model with a random intercept for patient was used to study the longitudinal association between tumour size and estimated glomerular filtration rate (eGFR). Results: Longitudinal data from 98 patients with 101 lesions were analysed. Most patients were men (68.3%) and the median (interquartile range [IQR]) age was 69 (13) years. The median (IQR) follow‐up was 29 (26) months. Most lesions were small renal masses, and 24% measured over 4 cm. Over half (64.4%) grew at a median (IQR) rate of 2 (4) mm per year. No association was observed between tumour size and eGFR over time (P = 0.871). Nine lesions (8.9%) were subsequently treated. Two deaths were reported, neither were related to the diagnosis of renal oncocytoma. Conclusion: Natural history data from the largest active surveillance cohort of renal oncocytomas to date show that renal function does not seem to be negatively impacted by growing oncocytomas, and confirms clinical outcomes are excellent after a median follow‐up of over 2 years. Active surveillance should be considered the 'gold standard' management of renal oncocytomas up to 7cm. [ABSTRACT FROM AUTHOR]

EN 1993‐1‐1 gives stability design rules for columns, beams and beam‐columns up to S460, whereas EN 1993‐1‐12 gives additional guidance for S500 up to S700. Recent studies on flexural buckling of welded H, I and box columns in steel grades S460 to S960, even though limited, show that improved curves can be used for members in high strength steel (HSS). This enhanced behavior is usually attributed to the improved material properties but mainly due to the more favorable residual stress distribution. Furthermore, the behavior of unrestrained beams in HSS has not been studied. At present in EN 1993‐1‐1, the design rules for lateral torsional buckling of beams are not dependent on the steel grade, meaning that the code does not distinguish between beams in conventional strength steel or HSS. In pursuit of answer to the mentioned shortcomings, within the European Project STROBE evaluation of the European stability design rules is carried out. The research is based on experimental programme covering 14 full‐scale tests, residual stress measurements, advanced numerical models and analytical derivations. This paper provides a summary of the experimental programme, the results for lateral‐torsional buckling of beams are discussed and further compared with the current code recommendations. [ABSTRACT FROM AUTHOR]

Converging lines of evidence from several models, and post-mortem human brain tissue studies, support the involvement of the kynurenine pathway (KP) in Huntington's disease (HD) pathogenesis. Quantifying KP metabolites in HD biofluids is desirable, both to study pathobiology and as a potential source of biomarkers to quantify pathway dysfunction and evaluate the biochemical impact of therapeutic interventions targeting its components. In a prospective single-site controlled cohort study with standardised collection of cerebrospinal fluid (CSF), blood, phenotypic and imaging data, we used high-performance liquid-chromatography to measure the levels of KP metabolites--tryptophan, kynurenine, kynurenic acid, 3-hydroxykynurenine, anthranilic acid and quinolinic acid--in CSF and plasma of 80 participants (20 healthy controls, 20 premanifest HD and 40 manifest HD). We investigated short-term stability, intergroup differences, associations with clinical and imaging measures and derived sample-size calculation for future studies. Overall, KP metabolites in CSF and plasma were stable over 6 weeks, displayed no significant group differences and were not associated with clinical or imaging measures. We conclude that the studied metabolites are readily and reliably quantifiable in both biofluids in controls and HD gene expansion carriers. However, we found little evidence to support a substantial derangement of the KP in HD, at least to the extent that it is reflected by the levels of the metabolites in patient-derived biofluids. [ABSTRACT FROM AUTHOR]

Perceptions of fitness trainers' need‐supportive and need‐thwarting behaviors have been shown to impact exercisers' psychological need satisfaction and frustration. Currently, it is unknown whether an agreement or disagreement between exercisers' and fitness trainers' reported perceptions of these behaviors leads to the satisfaction and/or frustration of psychological needs. Based on self‐determination theory, the present study examined the effect of congruency between fitness trainers' and exercisers' perceptions of need‐supportive and need‐thwarting interpersonal behaviors on basic psychological need satisfaction and frustration. A sample of 130 fitness trainers (43 females; Mage = 31.58 ± 7.65) and a total of 640 gym exercisers (350 females; Mage = 34.23 ± 11.59) participated in this study. Findings suggested that the majority of fitness trainers tended to over‐report their use of need‐supportive behavior and under‐report their need‐thwarting behaviors. Results showed that when there was congruency between fitness trainers' reported use and exercisers' perception of interpersonal behaviors, basic need satisfaction tended to increase. This effect was greater for exercisers that rated their respective fitness trainer high on relatedness support. Fitness trainers should be self‐aware of their interpersonal behaviors when engaging with exercisers and interventions based on self‐determination theory could serve as a promising avenue to improve the quality of exercisers' experience. [ABSTRACT FROM AUTHOR]

Objective: The present study aimed to examine the bright and dark sides of motivation, based on self‐determination theory, as predictors of enjoyment, intention to continue exercising, and exercise persistence. In addition, we analyzed the mediation role of each variable and tested the model invariance between male and female exercisers. Methods: A total of 575 gym exercisers (female = 230) aged between 18 and 65 years (M = 34.07; SD = 11.47) participated in this study. All participants had at least 6 months of regular exercise practice; exercise frequency of the participants ranged from 2 to 7 sessions per week (M = 3.52; SD = 1.28) and training sessions lasted approximately 30 and 120 minutes (M = 61.54; SD = 17.64). Participants completed a multisection questionnaire assessing interpersonal behaviors, basic psychological needs satisfaction and frustration, behavioral regulations, enjoyment, and intentions to continue exercising. Exercise persistence was assessed 6 months after initial assessment using gym computer system attendance records. Several analyses, namely, confirmatory factor analysis, structural equation modeling, serial mediation analysis, and structural invariance testing, were performed to increase theoretical and empirical knowledge. Results: Positive associations were observed among the bright side of motivation, enjoyment, intention to continue exercising, and persistence. On the other hand, the dark side of motivation was negatively associated with the bright side constructs, enjoyment, intention, and exercise persistence. Both measurement [χ2(370) = 1496.708, χ2/df = 4.05; B‐S P <.001, CFI = 0.907, TLI = 0.901, SRMR = 0.056, RMSEA = 0.073 (CI 90% = 0.063, 0.083)] and structural models [χ2(393) = 2484.994, χ2/df = 6.323; B‐S P <.001, CFI = 0.908, TLI = 0.900, SRMR = 0.075, RMSEA = 0.071 (CI 90% = 0.067, 0.075)] displayed acceptable fit to the data. The results also showed that basic psychological needs satisfaction, autonomous motivation, enjoyment, and intention to continue exercising were significant mediators. However, enjoyment had the highest effect on exercise persistence. In addition, structural model invariance was confirmed between male and female exercisers. Conclusion: Motivational determinants have implications for predicting emotional, cognitive, and behavior‐related outcomes. Individuals should perceive exercise instructors as supportive and exercising as a fun activity to endorse long‐term exercise persistence. [ABSTRACT FROM AUTHOR]

Background: Investigating early white matter (WM) change in Huntington's disease (HD) can improve our understanding of the way in which disease spreads from the striatum. Objectives: We provide a detailed characterization of pathology‐related WM change in HD. We first examined WM microstructure using diffusion‐weighted imaging and then investigated both underlying biological properties of WM and products of WM damage including iron, myelin plus neurofilament light, a biofluid marker of axonal degeneration—in parallel with the mutant huntingtin protein. Methods: We examined WM change in HD gene carriers from the HD–CSFcohort, baseline visit. We used standard‐diffusion magnetic resonance imaging to measure metrics including fractional anisotropy, a marker of WM integrity, and diffusivity; a novel diffusion model (neurite orientation dispersion and density imaging) to measure axonal density and organization; T1‐weighted and T2‐weighted structural magnetic resonance imaging images to derive proxy iron content and myelin‐contrast measures; and biofluid concentrations of neurofilament light (in cerebrospinal fluid (CSF) and plasma) and mutant huntingtin protein (in CSF). Results: HD gene carriers displayed reduced fractional anisotropy and increased diffusivity when compared with controls, both of which were also associated with disease progression, CSF, and mutant huntingtin protein levels. HD gene carriers also displayed proxy measures of reduced myelin contrast and iron in the striatum. Conclusion: Collectively, these findings present a more complete characterization of HD‐related microstructural brain changes. The correlation between reduced fractional anisotropy, increased axonal orientation, and biofluid markers suggest that axonal breakdown is associated with increased WM degeneration, whereas higher quantitative T2 signal and lower myelin‐contrast may indicate a process of demyelination limited to the striatum. [ABSTRACT FROM AUTHOR]

Motivation plays an important role when it comes to regular physical exercise. Hence, low levels of intentions to continue exercising in the future may ultimately lead to higher rates of exercise dropout. The first objective of the present research was to test a theoretical model considering the dark side of motivational determinants on intentions towards exercising in the future. The second objective consisted in comparing groups with different characteristics, as a way to identify individuals with weaker intention, which is believed to be an indicator of a higher dropout risk. In total, 544 (294 female; 250 male) gym exercisers aged between 18 and 58 years (M = 35.00; SD = 11.57) partook in the present research. Participants were engaged in fitness group classes (n = 273) or in cardio/resistance workouts (n = 271), and their exercise experience ranged from 3 to 120 months (M = 47.41; SD = 7.54). Results showed that the measurement and the structural model had an excellent fit. In addition, the structural model was invariant between gender, fitness activities, and exercise experience. Each group displayed different explained variance in intention to continue exercising. Overall, male, young adults and more experienced exercisers had stronger intentions towards exercising. Fitness instructors should be aware of their own thwarting behaviors, especially when interacting with female, young and less experienced exercisers, since they have weaker intentions to exercise in the future, possibly representing an increased risk of withdrawal. [ABSTRACT FROM AUTHOR]

Multiple targeted therapeutics for Huntington's disease are now in clinical trials, including intrathecally delivered compounds. Previous research suggests that CSF dynamics may be altered in Huntington's disease, which could be of paramount relevance to intrathecal drug delivery to the brain. To test this hypothesis, we conducted a prospective cross‐sectional study comparing people with early stage Huntington's disease with age‐ and gender‐matched healthy controls. CSF peak velocity, mean velocity and mean flow at the level of the cerebral aqueduct, and sub‐arachnoid space in the upper and lower spine, were quantified using phase contrast MRI. We calculated Spearman's rank correlations, and tested inter‐group differences with Wilcoxon rank‐sum test. Ten people with early Huntington's disease, and 10 controls were included. None of the quantified measures was associated with potential modifiers of CSF dynamics (demographics, osmolality, and brain volumes), or by known modifiers of Huntington's disease (age and HTTCAG repeat length); and no significant differences were found between the two studied groups. While external validation is required, the attained results are sufficient to conclude tentatively that a clinically relevant alteration of CSF dynamics – that is, one that would justify dose‐adjustments of intrathecal drugs – is unlikely to exist in Huntington's disease. [ABSTRACT FROM AUTHOR]

Background: Huntington's disease like 2 (HDL2) is the most common Huntington's disease (HD) phenocopy in many countries and described as the phenocopy with the greatest resemblance to HD. The current clinical description of HDL2 is based on retrospective data. It is unknown whether HDL2 has clinical features that distinguish it from HD. Objective: To describe the HDL2 phenotype and compare it to HD systematically. Methods: A blinded cross‐sectional design was used to compare the HDL2 (n = 15) and HD (n = 13) phenotypes. African ancestry participants underwent assessments, including the Unified Huntington's Disease Rating Scale (UHDRS). The UHDRS motor component was video recorded and evaluated by blinded experts and the inter‐rater reliability calculated. Results: Both groups were homogeneous in terms of demographics and disease characteristics. However, HDL2 patients presented three years earlier with more prominent dysarthria and dystonia. Raters could not distinguish between the two diseases with a high level of agreement. No significant differences in the TMS between HDL2 and HD were found. In both disorders, disease duration correlated with motor scores, with the exception of chorea. Psychiatric and cognitive scores were not significantly different between the groups. Conclusions: The HDL2 phenotype is similar to HD and is initially characterized by dementia, chorea, and oculomotor abnormalities, progressing to a rigid and bradykinetic state, suggesting the UHDRS is useful to monitor disease progression in HDL2. Although HDL2 patients scored higher on some UHDRS domains, this did not differentiate between the two diseases; it may however be emerging evidence of HDL2 having a more severe clinical phenotype. [ABSTRACT FROM AUTHOR]

Anti‐tumour necrosis factor (TNF) drugs have been extensively used in non‐infectious uveitis (NIU), when corticosteroids or conventional immunosuppressive drugs cannot adequately control inflammation or intolerable side‐effects occur. However, systemic anti‐TNF therapies are also associated with a myriad of side‐effects. Therefore, intravitreal administration of anti‐TNF biologics has been employed to minimize patient morbidity and systemic adverse effects, while maintaining therapeutic effectivity. We undertook a systematic review to determine evidence of efficacy and safety of intravitreal administration of anti‐TNF drugs in adults with NIU. We conducted this systematic review according to the PRISMA guidelines. The protocol was registered with PROSPERO (CRD42016041946). We searched CENTRAL, MEDLINE and EMBASE, from inception to April 2017, as well as clinical trial registries and grey literature. The qualitative analysis included all studies of adult patients with a diagnosis of NIU and who received intravitreal anti‐TNF drugs with a 4‐week minimum follow‐up. A total of 4840 references were considered for title and abstract screening. Seven full texts were screened, and five studies were considered for analysis. All studies were open‐label, single‐centre, prospective, non‐randomized, interventional case series with a follow‐up between 4 and 26 weeks, employing either adalimumab in two studies and infliximab in three. Three studies showed a treatment effect of anti‐TNF intravitreal injections, while one study revealed short‐term improvement and one study revealed no efficacy of anti‐TNF intravitreal therapy. None of the studies reported ocular adverse effects but only two studies included electrophysiological assessment in the safety analysis and no study assessed systemic human anti‐drug antibodies. The available evidence is not sufficiently robust to conclude about the clinical effectivity of intravitreal anti‐TNF in NIU and so no recommendation can be made. In conclusion, intravitreal injection of anti‐TNF antibodies remains a possible treatment option to be explored through robust clinical investigation. [ABSTRACT FROM AUTHOR]

Abstract: Limitation of functional ability is a major feature of Huntington's disease (HD). The International Parkinson and Movement Disorder Society (MDS) commissioned the appraisal of the use and clinimetric properties of clinical measures of functional ability that have been applied in HD studies and trials to date, to make recommendations regarding their use based on standardized criteria. After a systematic literature search, we included a total of 29 clinical measures grouped into two categories: (1) performance‐based measures (e.g., balance, walking, and reaching/grasping), and (2) rating scales. Three performance‐based measures are rated as “recommended”: the Tinetti Mobility Test for screening of fall risk and for severity assessment of mobility in patients with manifest HD (up to stage III); the Berg Balance Scale for severity of balance impairment; and the Six‐Minute Walk Test for assessment of walking endurance (severity) in HD subjects with preserved ambulation. No rating scale targeting functional ability reached a “recommended” status either for screening or severity measurement. The main challenges identified in this review include applying widely accepted conceptual frameworks to the identified measures, the lack of validation of clinical measures to detect change over time, and absence of validated measures for upper limb function. Furthermore, measures of capacity or ability to perform activities of daily living had ceiling effects in people with early and pre‐manifest HD. We recommend that the MDS prioritize the development of new scales that capture small, but meaningful changes in function over time for outcome assessment in clinical trials, particularly in earlier stages of HD. [ABSTRACT FROM AUTHOR]

We consider a stochastic single item production‐inventory‐routing problem with a single producer, multiple clients, and multiple vehicles. At the clients, demand is allowed to be backlogged incurring a penalty cost. Demands are considered uncertain. A recourse model is presented, and valid inequalities are introduced to enhance the model. A new general approach that explores the sample average approximation (SAA) method is introduced. In the sample average approximation method, several sample sets are generated and solved independently in order to obtain a set of candidate solutions. Then, the candidate solutions are tested on a larger sample, and the best solution is selected among the candidates. In contrast to this approach, called static, we propose an adjustable approach that explores the candidate solutions in order to identify common structures. Using that information, part of the first‐stage decision variables is fixed, and the resulting restricted problem is solved for a larger size sample. Several heuristic algorithms based on the mathematical model are considered within each approach. Computational tests based on randomly generated instances are conducted to test several variants of the two approaches. The results show that the new adjustable SAA heuristic performs better than the static one for most of the instances. [ABSTRACT FROM AUTHOR]

The compromise of quality of life in Huntington's disease is a major issue, both for individuals with the disease as well as for their caregivers. The International Parkinson and Movement Disorder Society commissioned a review of the use and clinimetric validation status of measures used in Huntington's disease to assess aspects related with quality of life and to make recommendations on their use following standardized criteria. We included both patient-centered measures (patient health-related quality-of-life measures) and caregiver-centered measures (caregiver quality-of-life measures). After conducting a systematic literature search, we included 12 measures of patient health-related quality of life and 2 measures of caregiver quality of life. Regarding patient-centered measures, the Medical Outcomes Study 36-Item Short-Form Health Survey is "recommended" as a generic assessment of health-related quality of life in patients with Huntington's disease. The 12-Item Short Form Health Survey, the Sickness Impact Profile, the 12-item World Health Organization Disability Assessment Schedule, and the Huntington's Disease Health-Related Quality of Life questionnaire are "suggested." No caregiver-centered quality-of-life measure obtained a "recommended" status. The Alzheimer's Carer's Quality of Life Inventory and the Huntington's Disease Quality of Life Battery for Carers are "suggested." Recognizing that the assessment of patient health-related quality of life can be challenging in Huntington's disease, as patients may lack insight and there is insufficient clinimetric testing of these scales, the committee concluded that further validation of currently available health-related quality-of-life measures should be undertaken, namely, those Huntington's disease-specific health-related quality-of-life measures that have recently been reported and used. © 2018 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background Huntington's disease ( HD) is a rare and fatal inherited genetic disorder characterized by progressive motor, cognitive, and behavioral impairment. It leads to premature death, but data regarding advanced-stage disease are scarce. We sought to determine HD-associated survival, mortality, and causes and places of death. Methods Data from the European HD Network prospective study ( REGISTRY) collected from 2001 through 2013 were used, including the Unified Huntington's Disease Rating Scale and death report forms. Group comparisons were performed using the t test or the χ2 test. Survival analyses were computed through Kaplan-Meier estimates of median survival. All tests were 2-sided with a significance level of P = 0.05. Results In total, 5164 participants were analyzed. The mean age at diagnosis was 49 years, and the mean age at death was 58 years. At the end of the study period, there were 533 deaths (10.3% of patients). Median survival was 24 years from diagnosis and 35 years from symptom onset. The most frequent causes of death were pneumonia (19.5%), other infections (6.9%), and suicide (6.6%). The most frequent places of death were the hospital (29.8%), the home (23.9%), and nursing houses (19.8%). Conclusions Patients with HD tend to die from the same conditions as patients with other neurodegenerative diseases. However, compared with nonhereditary Parkinson's disease and Alzheimer's disease, the median time from onset to death is longer, and the places of death are distinctive. [ABSTRACT FROM AUTHOR]

Background Tetrabenazine is the only US Food and Drug Administration-approved drug for Huntington's disease, and deutetrabenazine was recently tested against placebo. A switching-trial from tetrabenazine to deutetrabenazine is underway, but no head-to-head, blinded, randomized controlled trial is planned. Using meta-analytical methodology, the authors compared these molecules. Methods RCTs comparing tetrabenazine or deutetrabenazine with placebo in Huntington's disease were searched. The authors assessed the Cochrane risk-of-bias tool, calculated indirect treatment comparisons, and applied the Grading of Recommendations Assessment, Development, and Evaluation ( GRADE) framework. Results The evidence network for this report comprised 1 tetrabenazine trial and 1 deutetrabenazine trial, both against placebo. Risk of bias was moderate in both. Participants in the tetrabenazine and deutetrabenazine trials did not differ significantly on motor scores or adverse events. Depression and somnolence scales significantly favored deutetrabenazine. Conclusion There is low-quality evidence that tetrabenazine and deutetrabenazine do not differ in efficacy or safety. It is important to note that these results are likely to remain the only head-to-head comparison between these 2 compounds in Huntington's disease. [ABSTRACT FROM AUTHOR]

Huntington's disease (HD) is a hereditary neurodegenerative condition with no therapeutic intervention known to alter disease progression, but several trials are ongoing and biomarkers of disease progression are needed. Tau is an axonal protein, often altered in neurodegeneration, and recent studies pointed out its role on HD neuropathology. Our goal was to study whether cerebrospinal fluid (CSF) tau is a biomarker of disease progression in HD. After informed consent, healthy controls, pre-symptomatic and symptomatic gene expansion carriers were recruited from two HD clinics. All participants underwent assessment with the Unified HD Rating Scale '99 (UHDRS). CSF was obtained according to a standardized lumbar puncture protocol. CSF tau was quantified using enzyme-linked immunosorbent assay. Comparisons between two groups were tested using ancova. Pearson's correlation coefficients were calculated for disease progression. Significance level was defined as p < 0.05. Seventy-six participants were included in this cross-sectional multicenter international pilot study. Age-adjusted CSF tau was significantly elevated in gene expansion carriers compared with healthy controls ( p = 0.002). UHDRS total functional capacity was significantly correlated with CSF tau ( r = −0.29, p = 0.004) after adjustment for age, and UHDRS total motor score was significantly correlated with CSF tau after adjustment for age ( r = 0.32, p = 0.002). Several UHDRS cognitive tasks were also significantly correlated with CST total tau after age-adjustment. This study confirms that CSF tau concentrations in HD gene mutation carriers are increased compared with healthy controls and reports for the first time that CSF tau concentration is associated with phenotypic variability in HD. These conclusions strengthen the case for CSF tau as a biomarker in HD. [ABSTRACT FROM AUTHOR]

Bull rays ( Pteromylaeus bovinus) and Dolphinfish ( Coryphaena hippurus and Coryphaena equiselis) were collected in Olhão (south of Portugal). These animals hosted multiple parasites, namely Caligus spp., and underwent a variety of treatments to remove them. Of all treatments tested, hydrogen peroxide showed the best results, although only concentrations above 100 ppm were effective in parasite removal. These high concentrations, however, proved to be highly toxic for the fish and led to the loss of some animals, especially those which had been handled before treatment. A total of 14 Bull rays were transported to Bolougne-Sur-Mer (France) by road and some animals were lost, which was attributed to excessive time in transit (>45 hr). In another transport, three Bull rays and 10 Dolphinfishes were moved to Stralsund (Germany) by road and air. The mechanical wounds suffered by one of the Bull rays during transport led to its death and, consequently, a deterioration of water quality in the tank containing two other conspecifics. This deterioration of water quality resulted in problems for the other two Bull rays, and one perished approximately 48 hr after arrival. The authors concluded that Dolphinfish can be transported with a low bioload for at least 27 hr, and Bull rays should not undergo transports longer than 35 hr. Special attention must be taken to injured animals, since this can lead to a decrease in water quality and consequently affect other animals in the same transport tank. Zoo Biol. 32:222-229, 2013. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

A letter to the editor in response to the article "Cost effectiveness of treatments for relapsed/refractory multiple myeloma," published in a previous issue is presented.