Patients with sporadic FTLD exhibit similar increases in lysosomal proteins and storage material as patients with FTD due to GRN mutations.

Loss of function progranulin (GRN) mutations are a major autosomal dominant cause of frontotemporal dementia (FTD). Patients with FTD due to GRN mutations (FTD-GRN) develop frontotemporal lobar degeneration with TDP-43 pathology type A (FTLD-TDP type A) and exhibit elevated levels of lysosomal proteins and storage material in frontal cortex, perhaps indicating lysosomal dysfunction as a mechanism of disease. To investigate whether patients with sporadic FTLD exhibit similar signs of lysosomal dysfunction, we compared lysosomal protein levels, transcript levels, and storage material in patients with FTD-GRN or sporadic FTLD-TDP type A. We analyzed samples from frontal cortex, a degenerated brain region, and occipital cortex, a relatively spared brain region. In frontal cortex, patients with sporadic FTLD-TDP type A exhibited similar increases in lysosomal protein levels, transcript levels, and storage material as patients with FTD-GRN. In occipital cortex of both patient groups, most lysosomal measures did not differ from controls. Frontal cortex from a transgenic mouse model of TDP-opathy had similar increases in cathepsin D and lysosomal storage material, showing that TDP-opathy and neurodegeneration can drive these changes independently of progranulin. To investigate these changes in additional FTLD subtypes, we analyzed frontal cortical samples from patients with sporadic FTLD-TDP type C or Pick's disease, an FTLD-tau subtype. All sporadic FTLD groups had similar increases in cathepsin D activity, lysosomal membrane proteins, and storage material as FTD-GRN patients. However, patients with FTLD-TDP type C or Pick's disease did not have similar increases in lysosomal transcripts as patients with FTD-GRN or sporadic FTLD-TDP type A. Based on these data, accumulation of lysosomal proteins and storage material may be a common aspect of end-stage FTLD. However, the unique changes in gene expression in patients with FTD-GRN or sporadic FTLD-TDP type A may indicate distinct underlying lysosomal changes among FTLD subtypes.

Best Practices for Chiropractic Management of Adult Patients With Mechanical Low Back Pain: A Clinical Practice Guideline for Chiropractors in the United States.

OBJECTIVE: The purpose of this paper was to update the previously published 2016 best-practice recommendations for chiropractic management of adults with mechanical low back pain (LBP) in the United States. METHODS: Two experienced health librarians conducted the literature searches for clinical practice guidelines and other relevant literature, and the investigators performed quality assessment of included studies. PubMed was searched from March 2015 to September 2021. A steering committee of 10 experts in chiropractic research, education, and practice used the most current relevant guidelines and publications to update care recommendations. A panel of 69 experts used a modified Delphi process to rate the recommendations. RESULTS: The literature search yielded 14 clinical practice guidelines, 10 systematic reviews, and 5 randomized controlled trials (all high quality). Sixty-nine members of the panel rated 38 recommendations. All but 1 statement achieved consensus in the first round, and the final statement reached consensus in the second round. Recommendations covered the clinical encounter from history, physical examination, and diagnostic considerations through informed consent, co-management, and treatment considerations for patients with mechanical LBP. CONCLUSION: This paper updates a previously published best-practice document for chiropractic management of adults with mechanical LBP.

METTL3 regulates viral m6A RNA modification and host cell innate immune responses during SARS-CoV-2 infection.

It is urgent and important to understand the relationship of the widespread severe acute respiratory syndrome coronavirus clade 2 (SARS-CoV-2) with host immune response and study the underlining molecular mechanism. N6-methylation of adenosine (m6A) in RNA regulates many physiological and disease processes. Here, we investigate m6A modification of the SARS-CoV-2 gene in regulating the host cell innate immune response. Our data show that the SARS-CoV-2 virus has m6A modifications that are enriched in the 3' end of the viral genome. We find that depletion of the host cell m6A methyltransferase METTL3 decreases m6A levels in SARS-CoV-2 and host genes, and m6A reduction in viral RNA increases RIG-I binding and subsequently enhances the downstream innate immune signaling pathway and inflammatory gene expression. METTL3 expression is reduced and inflammatory genes are induced in patients with severe coronavirus disease 2019 (COVID-19). These findings will aid in the understanding of COVID-19 pathogenesis and the design of future studies regulating innate immunity for COVID-19 treatment.

Patient-centered outcomes used in pediatric focused manual therapies research studies: a secondary data analysis of a systematic review.

BACKGROUND: Patient-reported outcome measurements (PROM) are instruments that seek a patient's health or functional status. Inclusion of standardized PROMs in research studies and clinical practice provides a more comprehensive understanding of an intervention from the patient's viewpoint. This secondary analysis identified PROM usage and appropriateness of references for property measurements from clinical trials included in a recent systematic review of pediatric manual therapy. METHODS: All included manuscripts within a recent systematic review had two authors extract PROM and associated property measurement data, including the property measurements supporting citations. Inclusion criteria for the articles were published clinical trials (observational or experimental) of pediatric children receiving manual therapy (any profession) for any condition between 2001-March 2018. For each PROM's associated property measurement, two authors used the COSMIN study design checklist to appraise the quality of the cited study to evaluate the property measurement. RESULTS: Of the 50 manuscripts included in the systematic review, 20 manuscripts reported the use of 52 PROMs. Of the 52 PROMs assessed, 31 did not make a statement about the instrument's property measurement, 7 PROMs had property measurements stated but not referenced, 4 PROMs stated that the property measurement information was unknown, and 10 had property measurement data with reference(s). These 10 PROMs with referenced property measurements were from 7 unique PROMs: constipation assessment scale, satisfaction visual analog scale (VAS), crying time diary, sleep diary, fear avoidance belief questionnaire (FABQ), pain VAS, and autism treatment evaluation checklist. The assessment of the referenced property measurements found that several property measurement's dimensions had not been assessed and those that had were evaluated were done so with poor or fair standards. CONCLUSIONS: This secondary analysis finds that clinical studies of pediatric manual therapy lack consistent use of PROMs with high quality property measurements. Further research to establish and implement PROMs to be used in future research studies and in clinical settings should become a priority for professions using manual therapy in children.

Response to 'Methodological flaws on "manual therapy for the pediatric population: a systematic review" by Prevost et al. (2019)'.

Correspondence from Yu et al. identify methodological issues with the systematic review of manual therapy for pediatric manuscript. Like any research study, limitations are important for readers to keep in consideration when reviewing study findings. The primary authors maintain full confidence in the use of the review to provide practicing clinicians with a comprehensive overview of the limited and low-quality available evidence regarding manual therapies for the pediatric patient.

Best Practices for Chiropractic Management of Patients with Chronic Musculoskeletal Pain: A Clinical Practice Guideline.

Objective: To develop an evidence-based clinical practice guideline (CPG) through a broad-based consensus process on best practices for chiropractic management of patients with chronic musculoskeletal (MSK) pain. Design: CPG based on evidence-based recommendations of a panel of experts in chronic MSK pain management. Methods: Using systematic reviews identified in an initial literature search, a steering committee of experts in research and management of patients with chronic MSK pain drafted a set of recommendations. Additional supportive literature was identified to supplement gaps in the evidence base. A multidisciplinary panel of experienced practitioners and educators rated the recommendations through a formal Delphi consensus process using the RAND Corporation/University of California, Los Angeles, methodology. Results: The Delphi process was conducted January-February 2020. The 62-member Delphi panel reached consensus on chiropractic management of five common chronic MSK pain conditions: low-back pain (LBP), neck pain, tension headache, osteoarthritis (knee and hip), and fibromyalgia. Recommendations were made for nonpharmacological treatments, including acupuncture, spinal manipulation/mobilization, and other manual therapy; modalities such as low-level laser and interferential current; exercise, including yoga; mind-body interventions, including mindfulness meditation and cognitive behavior therapy; and lifestyle modifications such as diet and tobacco cessation. Recommendations covered many aspects of the clinical encounter, from informed consent through diagnosis, assessment, treatment planning and implementation, and concurrent management and referral. Appropriate referral and comanagement were emphasized. Conclusions: These evidence-based recommendations for a variety of conservative treatment approaches to the management of common chronic MSK pain conditions may advance consistency of care, foster collaboration between provider groups, and thereby improve patient outcomes.

Manual therapy for the pediatric population: a systematic review.

BACKGROUND: This systematic review evaluates the use of manual therapy for clinical conditions in the pediatric population, assesses the methodological quality of the studies found, and synthesizes findings based on health condition. We also assessed the reporting of adverse events within the included studies and compared our conclusions to those of the UK Update report. METHODS: Six databases were searched using the following inclusion criteria: children under the age of 18 years old; treatment using manual therapy; any type of healthcare profession; published between 2001 and March 31, 2018; and English. Case reports were excluded from our study. Reference tracking was performed on six published relevant systematic reviews to find any missed article. Each study that met the inclusion criteria was screened by two authors to: (i) determine its suitability for inclusion, (ii) extract data, and (iii) assess quality of study. RESULTS: Of the 3563 articles identified, 165 full articles were screened, and 50 studies met the inclusion criteria. Twenty-six articles were included in prior reviews with 24 new studies identified. Eighteen studies were judged to be of high quality. Conditions evaluated were: attention deficit hyperactivity disorder (ADHD), autism, asthma, cerebral palsy, clubfoot, constipation, cranial asymmetry, cuboid syndrome, headache, infantile colic, low back pain, obstructive apnea, otitis media, pediatric dysfunctional voiding, pediatric nocturnal enuresis, postural asymmetry, preterm infants, pulled elbow, suboptimal infant breastfeeding, scoliosis, suboptimal infant breastfeeding, temporomandibular dysfunction, torticollis, and upper cervical dysfunction. Musculoskeletal conditions, including low back pain and headache, were evaluated in seven studies. Twenty studies reported adverse events, which were transient and mild to moderate in severity. CONCLUSIONS: Fifty studies investigated the clinical effects of manual therapies for a wide variety of pediatric conditions. Moderate-positive overall assessment was found for 3 conditions: low back pain, pulled elbow, and premature infants. Inconclusive unfavorable outcomes were found for 2 conditions: scoliosis (OMT) and torticollis (MT). All other condition's overall assessments were either inconclusive favorable or unclear. Adverse events were uncommonly reported. More robust clinical trials in this area of healthcare are needed. TRIAL REGISTRATION: PROSPERA registration number: CRD42018091835.