Prognostic clinical and biological markers for amyotrophic lateral sclerosis disease progression: validation and implications for clinical trial design and analysis.

BACKGROUND: With increasing recognition of the value of incorporating prognostic markers into amyotrophic lateral sclerosis (ALS) trial design and analysis plans, there is a pressing need to understand which among the prevailing clinical and biochemical markers have real value, and how they can be optimally used. METHODS: A subset of patients with ALS recruited through the multi-center Phenotype-Genotype-Biomarker study (clinicaltrials.gov: NCT02327845) was identified as "trial-like" based on meeting common trial eligibility criteria. Clinical phenotyping was performed by evaluators trained in relevant assessments. Serum neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH), urinary p75ECD, plasma microRNA-181, and an array of biochemical and clinical measures were evaluated for their prognostic value. Associations with functional progression were estimated by random-slopes mixed models of ALS functional rating scale-revised (ALSFRS-R) score. Associations with survival were estimated by log-rank test and Cox proportional hazards regression. Potential sample size savings from adjusting for given biomarkers in a hypothetical trial were estimated. FINDINGS: Baseline serum NfL is a powerful prognostic biomarker, predicting survival and ALSFRS-R rate of decline. Serum NfL <40 pg/mL and >100 pg/mL correspond to future ALSFRS-R slopes of ∼0.5 and ∼1.5 points/month, respectively. Serum NfL also adds value to the best available clinical predictors, encapsulated by the European Network to Cure ALS (ENCALS) predictor score. In models of functional decline, the addition of NfL yields ∼25% sample size saving above those achieved by inclusion of either clinical predictors or ENCALS score alone. The prognostic value of serum pNfH, urinary p75ECD, and plasma miR-181ab is more limited. INTERPRETATION: Among the multitude of biomarkers considered, only blood NfL adds value to the ENCALS prediction model and should be incorporated into analysis plans for all ongoing and future ALS trials. Defined thresholds of NfL might also be used in trial design, for enrichment or stratified randomisation, to improve trial efficiency. FUNDING: NIH (U01-NS107027, U54-NS092091). ALSA (16-TACL-242).

Prognostic Clinical and Biological Markers for Amyotrophic Lateral Sclerosis Disease Progression: Validation and Implications for Clinical Trial Design and Analysis.

Background: With increasing recognition of the value of incorporating prognostic markers into amyotrophic lateral sclerosis (ALS) trial design and analysis plans, there is a pressing need to understand which among the prevailing clinical and biochemical markers have real value, and how they can be optimally used. Methods: A subset of patients with ALS recruited through the multi-center Phenotype-Genotype-Biomarker study (clinicaltrials.gov: NCT02327845) was identified as "trial-like" based on meeting common trial eligibility criteria. Clinical phenotyping was performed by evaluators trained in relevant assessments. Serum neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH), urinary p75ECD, plasma microRNA-181, and an array of biochemical and clinical measures were evaluated for their prognostic value. Associations with functional progression were estimated by random-slopes mixed models of ALS functional rating scale-revised (ALSFRS-R) score. Associations with survival were estimated by log-rank test and Cox proportional hazards regression. Potential sample size savings from adjusting for given biomarkers in a hypothetical trial were estimated. Findings: Baseline serum NfL is a powerful prognostic biomarker, predicting survival and ALSFRS-R rate of decline. Serum NfL <40pg/ml and >100pg/ml correspond to future ALSFRS-R slopes of ~0.5 and 1.5 points/month, respectively. Serum NfL also adds value to the best available clinical predictors, encapsulated by the European Network to Cure ALS (ENCALS) predictor score. In models of functional decline, the addition of NfL yields ~25% sample size saving above those achieved by inclusion of either clinical predictors or ENCALS score alone. The prognostic value of serum pNfH, urinary p75ECD, and plasma miR-181ab is more limited. Interpretation: Among the multitude of biomarkers considered, only blood NfL adds value to the ENCALS prediction model and should be incorporated into analysis plans for all ongoing and future ALS trials. Defined thresholds of NfL might also be used in trial design, for enrichment or stratified randomisation, to improve trial efficiency. Funding: NIH (U01-NS107027, U54-NS092091). ALSA (16-TACL-242).

Sustainability-Driven Accelerated Shear-Mediated Immunoassay for Amyotrophic Lateral Sclerosis Detection.

Healthcare facilities produce millions of tons of waste annually, with a significant portion consisting of diagnostic plasticware. Here, we introduce a new detection platform that completely replaces traditional assay plates with a piece of membrane, offering a much greener and more sustainable alternative. The membrane, integrated within the portable vortex fluidic device (P-VFD), enables rapid detection of a clinically relevant protein biomarker, urinary p75ECD. This biomarker is utilized to evaluate the prognosis, disease severity, and progression of amyotrophic lateral sclerosis (ALS). This assay has a limit-of-detection (LOD) of 4.03 pg, which is comparable to the plate-based assay (2.24 pg) and has been optimised through a full factorial design of experiments (DOE) and response surface methodology (RSM). P-VFD has great potential in quantifying p75ECD in human biofluids and can significantly reduce the assay time to 5 min compared to the current plate-based p75ECD ELISA assay (3 days), with at least a 4.4-fold reduction in the usage of the detection antibody.

Urinary biomarkers for amyotrophic lateral sclerosis: candidates, opportunities and considerations.

Amyotrophic lateral sclerosis is a relentless neurodegenerative disease that is mostly fatal within 3-5 years and is diagnosed on evidence of progressive upper and lower motor neuron degeneration. Around 15% of those with amyotrophic lateral sclerosis also have frontotemporal degeneration, and gene mutations account for ∼10%. Amyotrophic lateral sclerosis is a variable heterogeneous disease, and it is becoming increasingly clear that numerous different disease processes culminate in the final degeneration of motor neurons. There is a profound need to clearly articulate and measure pathological process that occurs. Such information is needed to tailor treatments to individuals with amyotrophic lateral sclerosis according to an individual's pathological fingerprint. For new candidate therapies, there is also a need for methods to select patients according to expected treatment outcomes and measure the success, or not, of treatments. Biomarkers are essential tools to fulfil these needs, and urine is a rich source for candidate biofluid biomarkers. This review will describe promising candidate urinary biomarkers of amyotrophic lateral sclerosis and other possible urinary candidates in future areas of investigation as well as the limitations of urinary biomarkers.

The Molecular Link Between TDP-43, Endogenous Retroviruses and Inflammatory Neurodegeneration in Amyotrophic Lateral Sclerosis: a Potential Target for Triumeq, an Antiretroviral Therapy.

Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), is a progressive neurological disorder, characterised by the death of upper and lower motor neurons. The aetiology of ALS remains unknown, and treatment options are limited. Endogenous retroviruses (ERVs), specifically human endogenous retrovirus type K (HERV-K), have been proposed to be involved in the propagation of neurodegeneration in ALS. ERVs are genomic remnants of ancient viral infection events, with most being inactive and not retaining the capacity to encode a fully infectious virus. However, some ERVs retain the ability to be activated and transcribed, and ERV transcripts have been found to be elevated within the brain tissue of MND patients. A hallmark of ALS pathology is altered localisation of the transactive response (TAR) DNA binding protein 43 kDa (TDP-43), which is normally found within the nucleus of neuronal and glial cells and is involved in RNA regulation. In ALS, TDP-43 aggregates within the cytoplasm and facilitates neurodegeneration. The involvement of ERVs in ALS pathology is thought to occur through TDP-43 and neuroinflammatory mediators. In this review, the proposed involvement of TDP-43, HERV-K and immune regulators on the onset and progression of ALS will be discussed. Furthermore, the evidence supporting a therapy based on targeting ERVs in ALS will be reviewed.

Biomarkers for predicting disease course in Sanfilippo syndrome: An urgent unmet need in childhood-onset dementia.

Sanfilippo syndrome (MPS III) is an autosomal recessive inherited disorder causing dementia in children, following an essentially normal early developmental period. First symptoms typically include delayed language development, hyperactivity and/or insomnia from 2 years of age, followed by unremitting and overt loss of previously acquired skills. There are no approved treatments, and the median age of death is 18 years. Treatments under clinical trial demonstrate therapeutic benefit when applied pre-symptomatically in children diagnosed early through known familial inheritance risk. Newborn screening for Sanfilippo syndrome would enable pre-symptomatic diagnosis and optimal therapeutic benefit, however, many fold more patients with Sanfilippo syndrome are expected to be identified in the population than present with childhood dementia. Therefore, the capacity to stratify which Sanfilippo infants will need treatment in toddlerhood is necessary. While diagnostic methods have been developed, and continue to be refined, currently there are no tools or laboratory-based biomarkers available to provide pre-symptomatic prognosis. There is also a lack of progression and neurocognitive response-to-treatment biomarkers; disease stage and rate of progression are currently determined by age at symptom onset, loss of cerebral grey matter volume by magnetic resonance imaging and developmental quotient score for age. Robust blood-based biomarkers are an urgent unmet need. In this review, we discuss the development of biomarker assays for Sanfilippo based on the neuropathological pathways known to change leading into symptom onset and progression, and their performance as biomarkers in other neurodegenerative diseases. We propose that neural-derived exosomes extracted from blood may provide an ideal liquid biopsy to detect reductions in synaptic protein availability, and mitochondrial function. Furthermore, given the prominent role of neuroinflammation in symptom expression, glial fibrillary acidic protein detection in plasma/serum, alongside measurement of active brain atrophy by neurofilament light chain, warrant increased investigation for prognostic, progression and neurocognitive response-to-treatment biomarker potential in Sanfilippo syndrome and potentially other childhood dementias.

Family Functioning Profiles in Emerging Adults: Associations with Personal and Parental Psychological Problems.

Although recent research has examined family profiles in younger children, emerging adults have not been examined as extensively despite evidence that families continue to be important to emerging adults. The current study examined family functioning profiles and associated psychological problems of both offspring and parents from the perspective of 585 college-attending emerging adults. Results supported six profiles where lower functioning groups generally had more psychological problems relative to higher functioning groups and with specific maternal and paternal differences. The current study advances family functioning research by demonstrating that family profiles can be identified and associated with psychological problems for both parents and emerging adults.

Emerging Adult Report of Childhood Maltreatment and Related Facets of Impulsivity.

Childhood maltreatment is related to a host of outcomes, many of which may be partially explained by the transdiagnostic factor of impulsivity. The research linking maltreatment to impulsivity is well supported. However, research differentiating between emotional and physical maltreatment and impulsivity is lacking, particularly with regard to facets of trait impulsivity. Thus, the current study examined the links between childhood emotional and physical maltreatment and current impulsivity traits of positive and negative urgency, lack of perseverance, lack of premeditation, and sensation seeking in emerging adults. Furthermore, effects of maltreatment are known to differ by the gender of the parent and the gender of the child. Thus, differences between parent-emerging adult child gender dyads were also examined. Results suggested both physical and emotional maltreatment were associated with negative urgency across the parent-child gender dyads. Emotional maltreatment and physical maltreatment differed in relation to impulsivity facet across parent and child gender. Results contribute to a knowledge base to use in future exploration of emotional and physical maltreatment outcomes and targets of intervention.

Urinary neopterin: A novel biomarker of disease progression in amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: The aim was to evaluate urinary neopterin, a marker of pro-inflammatory state, as a potential biomarker of disease prognosis and progression in amyotrophic lateral sclerosis (ALS); and to compare its utility to urinary neurotrophin receptor p75 extracellular domain (p75ECD ). METHODS: This was an observational study including 21 healthy controls and 46 people with ALS, 29 of whom were sampled longitudinally. Neopterin and p75ECD were measured using enzyme-linked immunoassays. Baseline and longitudinal changes in clinical measures, neopterin and urinary p75ECD were examined, and prognostic utility was explored by survival analysis. RESULTS: At baseline, urinary neopterin was higher in ALS compared to controls (181.7 ± 78.9 µmol/mol creatinine vs. 120.4 ± 60.8 µmol/mol creatinine, p = 0.002, Welch's t test) and correlated with the Revised ALS Functional Rating Scale (r = -0.36, p = 0.01). Combining previously published urinary p75ECD results from 22 ALS patients with a further 24 ALS patients, baseline urinary p75ECD was also higher compared to healthy controls (6.0 ± 2.7 vs. 3.2 ± 1.0 ng/mg creatinine, p < 0.0001) and correlated with the Revised ALS Functional Rating Scale (r = -0.36, p = 0.01). Urinary neopterin and p75ECD correlated with each other at baseline (r = 0.38, p = 0.009). In longitudinal analysis, urinary neopterin increased on average (±SE) by 6.8 ± 1.1 µmol/mol creatinine per month (p < 0.0001) and p75ECD by 0.19 ± 0.02 ng/mg creatinine per month (p < 0.0001) from diagnosis in 29 ALS patients. CONCLUSION: Urinary neopterin holds promise as marker of disease progression in ALS and is worthy of future evaluation for its potential to predict response to anti-inflammatory therapies.

Drosophila suzukii (Diptera: Drosophilidae): A Decade of Research Towards a Sustainable Integrated Pest Management Program.

Drosophila suzukii (Matsumura) (Diptera: Drosophilidae) also known as spotted-wing drosophila (SWD), is a pest native to Southeast Asia. In the last few decades, the pest has expanded its range to affect all major European and American fruit production regions. SWD is a highly adaptive insect that is able to disperse, survive, and flourish under a range of environmental conditions. Infestation by SWD generates both direct and indirect economic impacts through yield losses, shorter shelf life of infested fruit, and increased production costs. Fresh markets, frozen berries, and fruit export programs have been impacted by the pest due to zero tolerance for fruit infestation. As SWD control programs rely heavily on insecticides, exceedance of maximum residue levels (MRLs) has also resulted in crop rejections. The economic impact of SWD has been particularly severe for organic operations, mainly due to the limited availability of effective insecticides. Integrated pest management (IPM) of SWD could significantly reduce chemical inputs but would require substantial changes to horticultural management practices. This review evaluates the most promising methods studied as part of an IPM strategy against SWD across the world. For each of the considered techniques, the effectiveness, impact, sustainability, and stage of development are discussed.

Listening to the Whispers in Neuroimmune Crosstalk: A Comprehensive Workflow to Investigate Neurotrophin Receptor p75NTR Under Endogenous, Low Abundance Conditions.

Inflammatory conditions are critically influenced by neuroimmune crosstalk. Cytokines and neurotrophic factors shape the responses of both nervous and immune systems. Although much progress has been made, most findings to date are based on expression of recombinant (tagged) proteins. The examination of receptor interactions by immunoprecipitation (IP) at endogenous levels provides further insight into the more subtle regulations of immune responses. Here, we present a comprehensive workflow and an optimized IP protocol that provide step-by-step instructions to investigate neurotrophin receptor p75NTR at endogenous, low abundance levels: from lysate preparation and confirmation of receptor expression to antibody validation and successful detection of protein-protein interactions. We employ human melanoma cell line A375 to validate specific antibodies and IP conditions, and apply these methods to explore p75NTR interactions in human leukemic plasmacytoid dendritic cell line PMDC05 detecting 14-3-3ϵ:p75NTR interaction in this cell type. With p75NTR as an exemplary protein, our approach provides a strategy to detect specific interaction partners even under endogenous, low abundance expression conditions.

Cultural Control of Drosophila suzukii in Small Fruit-Current and Pending Tactics in the U.S.

Spotted-wing drosophila, Drosophila suzukii (Matsumura) (Diptera: Drosophilidae), a vinegar fly of Asian origin, has emerged as a devastating pest of small and stone fruits throughout the United States. Tolerance for larvae is extremely low in fresh market fruit, and management is primarily achieved through repeated applications of broad-spectrum insecticides. These applications are neither economically nor environmentally sustainable, and can limit markets due to insecticide residue restrictions, cause outbreaks of secondary pests, and select for insecticide resistance. Sustainable integrated pest management programs include cultural control tactics and various nonchemical approaches for reducing pest populations that may be useful for managing D. suzukii. This review describes the current state of knowledge and implementation for different cultural controls including preventative tactics such as crop selection and exclusion as well as strategies to reduce habitat favorability (pruning; mulching; irrigation), alter resource availability (harvest frequency; sanitation), and lower suitability of fruit postharvest (cooling; irradiation). Because climate, horticultural practices, crop, and market underlie the efficacy, feasibility, and affordability of cultural control tactics, the potential of these tactics for D. suzukii management is discussed across different production systems.

The adaptation and feasibility of dialectical behaviour therapy for adults with intellectual developmental disabilities and transdiagnoses: A pilot community-based randomized controlled trial.

INTRODUCTION: Preliminary evidence suggests dialectical behaviour therapy (DBT) may be beneficial for persons with intellectual disabilities. This pilot randomized controlled trial aimed to determine the feasibility of adapted DBT for adults with intellectual disabilities and co-morbid psychiatric disorders in the community. METHODS: An adapted DBT programme (aDBT-ID) was delivered to adults with mild-to-moderate intellectual disability (n = 20) and their caregivers (n = 20). A single-blind, mixed-methods design was employed with treatment (n = 10) and control (n = 10). In addition to feasibility, pre-post-measures of emotional regulation, anger and mental health were taken from clients and caregivers. RESULTS: Results suggest it was feasible and beneficial to deliver adapted DBT in the community. Qualitative findings found both participants and caregivers were satisfied with the treatment delivery. No differences between conditions were found. CONCLUSION: This pilot study highlights the feasibility of adapted DBT for individuals with intellectual disabilities and the practicalities of delivering community-based inclusive research.

Soldiers' Perception of a Behavioral Intervention for Positive Airway Pressure Therapy Adherence in a Military Treatment Facility.

INTRODUCTION: The incidence of obstructive sleep apnea in military personnel has increased over 500% since the early 2000s. Adherence to continuous positive airway pressure (PAP), an efficacious treatment, has been suboptimal. This article presents a behavioral intervention model for enhancing PAP therapy adherence and describes how the model was received by military personnel. MATERIALS AND METHODS: The study population comprised 254 out of 280 military personnel (93% men, mean age 39 years) who attended a 90-minute behavioral intervention class within the first 8 weeks of PAP use. They were coached on the Knowledge, Skills, Attitudes (KSA) model of PAP therapy success: Knowledge about obstructive sleep apnea and PAP treatment; Skills to develop a habitual loop for nightly PAP use; and Attitudes that address readiness, barriers, and solutions for sustaining PAP use. Participants completed a voluntary, anonymous postclass survey that inquired of their perception of various elements of the class. Data were analyzed using descriptive statistics and a paired sample t-test. RESULTS: In participants' self-rating of how much they know about PAP treatment before and after the class, their ratings indicated that they experienced a significant increase in knowledge (P < 0.0001). On the postclass survey, 77% of the participants (N = 195/254) "agree a lot" or "strongly agree" that the class gave them tools to have a successful treatment and 78% (N = 198/254) noted that it was a valuable educational experience. The Knowledge portion was rated by 79% (N = 201/254) of the participants as "quite a lot" or "extremely" beneficial. The Skills segment was rated as "quite a lot" or "extremely" beneficial by 72% (N = 183/254) of the participants. The Attitudes discussion was perceived as "quite a lot" or "extremely" beneficial by 70% (N = 178/254) of the participants. Participants' free-text responses to "what was most helpful" were generally positive. CONCLUSIONS: A KSA model of behavioral intervention for enhancing PAP therapy adherence was well received by participants. Future research will assess the impact of this intervention on adherence as measured by objective indicators.

Deterrent Effects of Essential Oils on Spotted-Wing Drosophila (Drosophila suzukii): Implications for Organic Management in Berry Crops.

Due to concerns about frequent applications of spinosad and other broad spectrum insecticides for managing spotted-wing drosophila (Drosophila suzukii Matsumura, SWD), we investigated the use of essential oils as an alternative to current insecticides. Essential oils from a number of plant species have been studied for their attraction and deterrence of SWD. However, these botanical products have not been thoroughly tested in the field. We conducted laboratory and field studies to determine the efficacy of botanical products, including lavender (Lavandula angustifolia Mill.) oil, catnip (Nepeta cataria L.) oil, KeyPlex Ecotrol® PLUS, and KeyPlex Sporan® EC2 on preventing SWD infestation in raspberry (Rubus idaeus L.) and blueberry (Vacciniumcorymbosum L.) crops. In a two-choice laboratory bioassay, lavender oil, Ecotrol, and Sporan treatments deterred SWD from a yeast-cornmeal-sugar based fly diet. In the field trials, raspberry fruit treated with Ecotrol had lower SWD infestation (6%), compared to the control (17%), and was comparable to spinosad (6%). No differences were seen in blueberry infestation. The combination of essential oils in Ecotrol may work to decrease SWD fruit infestation under certain conditions in the field, however more research is needed on the longevity of these products.

Sex Differences in Autoimmune Multimorbidity in Type 1 Diabetes Mellitus and the Risk of Cardiovascular and Renal Disease: A Longitudinal Study in the United States, 2001-2017.

Background: Autoimmune diseases are usually more prevalent in women. The risks of cardiovascular and renal disease in those with multiple autoimmune diseases have not been fully described. Materials and Methods: Using a national database from a large health insurer in the United States (years 2001-2017) containing ∼75 million members, we calculated age- and sex-specific co-prevalence of 12 autoimmune disorders for individuals with type 1 diabetes. We then evaluated whether concomitant autoimmune diseases were associated with renal failure, ischemic stroke, and myocardial infarction. Results: Of the 179,248 people diagnosed with type 1 diabetes, 1 in 4 had a concomitant autoimmune disease (27.03%; 95% confidence interval [CI] = 26.83%-27.24%), with hypothyroidism, rheumatoid arthritis, and celiac disease being the most common. The prevalence of autoimmune disease was 1.9 times greater in female than male patients (p < 0.001). In female patients with type 1 diabetes, one in three had another autoimmune disease (35.62%; 95% CI = 35.30%-35.94%) compared with one in five male patients (19.17%; 95% CI = 18.92%-19.42%). The risk of renal failure, ischemic stroke, and myocardial infarction increased with a greater number of concomitant autoimmune diseases (p < 0.001, test for trend for both female and male patients). Patients with type 1 diabetes who had multiple sclerosis or myasthenia gravis experienced an approximate threefold increase in risk of ischemic stroke (odds ratio [OR] = 3.57, OR = 3.22, respectively). Patients with type 1 diabetes and Addison's disease had a threefold increased risk of renal failure. Conclusions: Patients with type 1 diabetes, particularly women, frequently have coexisting autoimmune diseases that are associated with higher rates of renal failure, ischemic stroke, and myocardial infarction. Additional study is warranted, as are preventive efforts in this high-risk population.

From maternal tending to adolescent befriending: The adolescent transition of social support.

Attachment theory holds that parental relationships have lifelong effects on offspring social lives. The tend-and-befriend hypothesis posits that female friendships among humans evolved as part of a primate-wide coping mechanism to mediate stress by relying on social support. Here we bridge developmental and evolutionary frameworks to examine adolescent girls' perception of their reliance on female friendship for social support, how perceptions of parental relationships affect peer relationships, and the extent to which parent and peer relationships buffer depressive symptoms. We predict perceived maternal relationship quality will be positively associated with close female friendships, and maternal relationships, paternal relationships, and female friendship will buffer depressive symptoms. Participants were adolescent girls from a summer science camp (N = 95). Participants filled out demographic information, social network surveys, the Parent-Adolescent Communication Scale, and the Center for Epidemiology Depression Scale. Data was analyzed with Pearson's correlations, t tests, and path analysis. Adolescent girls with few female friends, compared with girls who had more than two very close female friends, experienced more depressive symptoms (t = 3.382, p = .001, D = 0.784). Adolescent girls with few female friends experienced more depressive symptoms compared to girls with two or more very close female friends (t = 3.382, p = .001, D = 0.784). Stronger maternal and paternal relationships were associated with having more female friends (maternal: t = -3.213, p = .003, D = 0.837; paternal: t = -2.432; p = .017). In the path analysis model, only maternal relationship quality significantly predicted female friendship category (ß = .33, CR = 2.770, p < .006). Furthermore, participants with two or more very close female friends and higher paternal relationship quality had significantly fewer depressive symptoms (friends; ß = -.19, CR = -2.112, p = .035; paternal: ß = -.33, CR = -3.220, p < .001), and older participants had more depressive symptoms (ß = .17, CR = -1.931, p = .036). These results provide additional support for the tend-and-befriend hypothesis, suggesting that maternal tending sets the stage for close female friendships.