Readily Accessible Strained Difunctionalized trans-Cyclooctenes with Fast Click and Release Capabilities.

The click reaction between a functionalized trans-cyclooctene (TCO) and a tetrazine (Tz) is a compelling method for bioorthogonal conjugation in combination with payload releasing capabilities. However, the synthesis of difunctionalized TCOs remains challenging. As a result, these compounds are poorly accessible, which impedes the development of novel applications. In this work, the scalable and accessible synthesis of a new bioorthogonal difunctionalized TCO is reported in only four single selective high yielding steps starting from commercially available compounds. The TCO-Tz click reaction was assessed and revealed excellent kinetic rates and subsequently payload release was shown with various functionalized derivatives. Tetrazine triggered release of carbonate and carbamate payloads was demonstrated up to 100 % release efficiency and local drug release was shown in a cellular toxicity study which revealed a >20-fold increase in cytotoxicity.

Intramuscular Electrical Stimulation for the Treatment of Trigger Points in Patients with Chronic Migraine: A Protocol for a Pilot Study Using a Single-Case Experimental Design.

Background and Objectives: Trigger points (TrPs) are prevalent in patients with migraine headaches. Needling interventions targeting TrPs in migraine patients may reduce the intensity and frequency of headaches, yet systematic reviews reveal a lack of robust evidence. Intramuscular electrical stimulation (IMES) is a modality that delivers electrical current into muscles and TrPs, with recent studies suggesting it may amplify the therapeutic effects of dry needling peripherally and centrally. This could be advantageous for patients with migraine and symptomatic TrPs. Materials and Methods: This study will implement a multiple baseline single-case experimental design (SCED). In a clinical setting, a SCED study lends itself to conducting research with only a few patients that each serve as their own controls. In this SCED study, four participants with chronic migraine will be enrolled in a non-concurrent manner and randomized to one of four baseline measurement periods (4, 5, 6 or 7 weeks), leading to four potentially different start dates for each participant in the intervention phase. During the intervention phase, patients will receive five sessions of dry needling with IMES, one session per week for five weeks. The primary outcome measure will be headache frequency, i.e., the reduction in the number of headache days over a one-month period using electronic headache diary data from the Migraine Buddy smartphone application. Secondary outcome measures will be changes in mean migraine pain intensity using a numeric pain rating scale (NPRS), migraine disability using the Migraine Disability Assessment Test (MIDAS), the Headache Impact Test (HIT-6), and changes in selected cervical musculoskeletal impairments including pressure pain thresholds (PPTs) over TrPs, the craniocervical flexion test (CCFT), and cervical active range of motion (AROM). Primary and secondary outcome measures will be analyzed separately using both visual and statistical analyses. Results: Actively recruiting participants. This project was approved by the Mass General Brigham Institutional Review Board (protocol #2023P000931) and is registered with ClinicalTrials.gov (NCT05893914). Conclusions: This study will seek to determine the effects of a five-week intervention period of IMES to TrPs in the posterior cervical muscles of subjects with chronic migraine.

Spinopelvic alignment and low back pain after total hip arthroplasty: a scoping review.

OBJECTIVE: Spinopelvic alignment is increasingly considered as an essential factor for maintaining an energy-efficient posture in individuals with normal or pathological status. Although several previous studies have shown that changes in the sagittal spinopelvic alignment may occur in patients undergoing total hip arthroplasty (THA), no review of this area has been completed so far. Thus, the objective of this scoping review was to summarize the evidence investigating changes in spinopelvic alignment and low back pain (LBP) following THA. DATA SOURCES: We adhered to the established methodology for scoping reviews. Four electronic databases were systematically searched from inception-December 31, 2021. STUDY SELECTION: We selected prospective or retrospective observational or intervention studies that included patients with THA. DATA EXTRACTION: Data extraction and levels of evidence were independently performed using standardized checklists. DATA SYNTHESIS: A total of 45 papers were included in this scoping review, involving 5185 participants with THA. Pelvic tilt was the most common parameter measured in the eligible studies (n = 26). The results were not consistent across all studies; however, it was demonstrated that the distribution of pelvic tilt following THA had a range of 25° posterior to 20° anterior. Moreover, decreased sacral slope and lower pelvic incidence were associated with increased risk of dislocation in patients with THA. Lumbar spine scoliosis did not change significantly after THA in patients with bilateral hip osteoarthritis (5.50°(1.16°) vs. 3.73°(1.16°); P-value = 0.29). Finally, one study indicated that LBP improvement was not correlated with postoperative changes in spinopelvic alignment parameters. Several methodological issues were addressed in this study, including no sample size calculation and no type-I error adjustment for outcome multiplicity. CONCLUSIONS: Changes in spinopelvic alignment may occur after THA and may improve with time. Patients with a THA dislocation usually show abnormal spinopelvic alignment compared to patients without a THA dislocation. LBP usually improves markedly over time following THA.

Efficacy of Dry Needling in Treating Scars following Total Hip Arthroplasty: A Case Report.

Background: In this case report of a 31-year-old female, we describe the effects of dry needling on scar tissue following total hip arthroplasty. Case report: A 31-year-old woman underwent an elective bilateral total hip replacement due to a motor vehicle accident. Based on physical examination, the patient had burning pain at the incision site at the time of menstruation and limited hip range of motion worse on the right side. The treatment program consisted of six sessions of dry needling over a three-week period alongside infrared radiation for 20 minutes during each session. The needles were spaced along the entire length of the scar tissue and rotation was performed back and forth across the scar region to release the adhesion between the scar line and the underlying tissue, focusing more on the painful-to-touch spots and adhesive points. Following the completion of the dry needling treatments hip range of motion and the patient's functional outcome improved. Dry needling may be an effective and rapid treatment for scar tissue adhesion after surgical procedures. High-quality randomized-controlled studies are needed to verify the efficacy of this method.

Changes in the macroscopic morphology of hip muscles in low back pain.

Low back pain is a major health issue affecting the lumbopelvic muscles. Morphological changes in hip muscles, such as alterations in the muscle cross-sectional area and muscle volume, may occur in patients with low back pain. This systematic review was conducted to investigate whether patients with low back pain have macroscopic changes in their hip muscle morphology compared with asymptomatic, healthy individuals, based on current evidence. The electronic databases of PubMed/Medline, Ovid, Scopus, Embase® , and Google Scholar were searched from the inception to August 31, 2018. We only included full texts of original studies regarding macroscopic morphological alterations, including atrophy and fat infiltration, in hip muscles of patients with low back pain compared with asymptomatic controls. The quality of the included studies was determined using an assessment tool based on the Newcastle-Ottawa Scale. The scale was modified for the purposes of this study. Sixteen comparative observational studies were found eligible to be included in this review. Eleven were classified as high quality and four as moderate quality. The morphological changes in the psoas major, gluteus maximus, gluteus medius, gluteus minimus, and piriformis muscles were assessed in the primary studies. All selected studies were considered B level of evidence studies. The strength of conclusions for the psoas major, gluteal, and piriformis muscles was moderate. The results revealed that there is substantial controversy about the morphological changes in hip muscles in patients with low back pain; however, the majority of high-quality studies concluded that atrophy of hip muscles is evident in patients with low back pain. The psoas major muscle was the most commonly investigated hip muscle for morphological changes. Major methodological limitations of the included studies were identified and discussed. The present systematic review does not include a formal meta-analysis because of very significant differences in the primary studies in terms of study populations and methodologies. Finally, in clinical practice, it is recommended that physical therapists develop exercise programs to improve hip muscle function in patients with low back pain.

The Effect of Dry Needling on Lower Limb Dysfunction in Poststroke Survivors.

BACKGROUND: Spasticity is one of the main complications in poststroke survivors leading to difficulties in walking and standing resulting in high levels of disability. OBJECTIVE: The aim of the study was to investigate the effects of deep dry needling on lower limb dysfunction in poststroke spastic patients. METHODS: A randomized clinical trial conducted in poststroke survivors who were assigned to one of 2 groups: Deep dry needling (intervention group) and sham dry needling (control group). The primary outcome measures were Modified Modified Ashworth Scale (MMAS) and functional tests (timed up and go test, 10-meter walk test). Secondary outcome measures were active ankle dorsiflexion range of motion (AROM), passive ankle dorsiflexion range of motion (PROM), single leg stance test, and Barthel index. All measurements were assessed at baseline (T0), immediately after the third session 1 week later (T1), and 1 month after the end of the intervention (T2). RESULTS: We recruited 24 patients (71% male; mean age 57 ± 10 years; 26.4 ± 1.8 kg•m-2; time since event: 25.2 ± 12.5 months). There were significant improvements in MMAS, timed up and go test, 10-meter walk test, Barthel scale, and PROM (P < .05) in the intervention group compared to controls across the time-points. There were no significant improvements in AROM assessments (P > .05). CONCLUSIONS: Deep dry needling decreases muscle spasticity and improves lower limb function and gait speed in poststroke survivors.

Dry Needling for Hamstring Flexibility: A Single-Blind Randomized Controlled Trial.

CONTEXT: Hamstring muscle tightness is one of the most common problems in athletic and healthy people. Dry needling (DN) was found to be an effective approach for improving muscle flexibility, but there is no study to compare this approach with static stretching (SS) as a common technique for the increase of muscle length. OBJECTIVE: To compare the immediate effects of DN and SS on hamstring flexibility in healthy subjects with hamstring tightness. STUDY DESIGN: A single-blind randomized controlled trial. SETTING: A musculoskeletal physiotherapy clinic at Tehran University of Medical Sciences. SUBJECTS: Forty healthy subjects (female: 32, age range: 18-40 y) with hamstring tightness were randomly assigned into 2 groups of DN and SS. INTERVENTION: The DN group received a single session of DN on 3 points of the hamstring muscles, each for 1 minute. The SS group received a single session of SS of the hamstrings, consisting of 3 sets of 30-second SS with a 10-second rest between sets in the active knee extension test (AKET) position. MAIN OUTCOME MEASURES: The AKET, muscle compliance, passive peak torque, and stretch tolerance were measured at the baseline, immediately, and 15 minutes after the interventions. RESULTS: Improvements in all outcomes was better for the DN group than for the SS group. DN increased muscle compliance significantly 15 minutes after the intervention, but it did not improve in the SS group. CONCLUSION: DN is effective in improving hamstring flexibility compared with SS. One session of DN can be an effective treatment for hamstring tightness and increase hamstring flexibility. The improvements suggest that DN is a novel treatment for hamstring flexibility.

Immediate Effects of Dry Needling as a Novel Strategy for Hamstring Flexibility: A Single-Blinded Clinical Pilot Study.

CONTEXT: There are numerous studies on the benefits of dry needling (DN) for pain relief. No studies exist examining the effects of DN on hamstring flexibility. OBJECTIVE: To determine the immediate effects of DN on hamstring flexibility in healthy subjects with shortened hamstrings. DESIGN: A single-blinded, pretest-posttest clinical pilot study. SETTING: A university physiotherapy clinic. SUBJECTS: A total of 15 healthy subjects (female = 11; age = 23.26 [4.3] y) with shortened hamstrings participated in this study. INTERVENTION: Subjects received a single session of DN. Three locations on the hamstring muscle group were needled, each for 1 minute. MAIN OUTCOME MEASURES: The active knee extension test, muscle compliance, passive peak torque, and stretch tolerance were measured at baseline, immediately, and 15 minutes after DN. RESULTS: There were statistically significant improvements in all outcome measures immediately after DN and at the 15-minute follow-up. The effect sizes for all outcome measures were large (Cohen's d ≥ 0.8). No serious adverse events were observed with DN. CONCLUSIONS: This is the first study that demonstrates the beneficial effects of DN on hamstring flexibility, muscle compliance, and stretch tolerance without added stretching. The beneficial effects of DN should encourage clinicians to use DN as a novel strategy for increasing muscle flexibility.

International Consensus on Diagnostic Criteria and Clinical Considerations of Myofascial Trigger Points: A Delphi Study.

Objective: There is no consensus on the essential diagnostic criteria for diagnosing a trigger point (TrP). In fact, a variety of diagnostic criteria are currently being used. Our aim was to conduct a Delphi panel to achieve an international consensus on the cluster of criteria needed for the TrP diagnosis to reach a consensus on the definition of active and latent TrPs and to clarify different clinical considerations about TrPs. Methods: Following international guidelines, an international three-round Delphi survey was conducted. Questions were created based on a systematic literature search of the diagnostic criteria for TrPs. Results: Sixty experts from 12 countries completed all rounds of the survey. A cluster of three diagnostic criteria was proposed as essential for the TrP diagnosis: a taut band, a hypersensitive spot, and referred pain. Eighty percent of the experts agreed that the referred pain elicited by a TrP can include different sensory sensations and not just pain, that is, pain spreading to a distant area, deep pain, dull ache, tingling, or burning pain. Eighty-four percent of the international experts consistently answered that the main clinical differences between active and latent TrPs are the reproduction of any of the symptoms experienced by a patient and the recognition of pain. No specific location of the pain referral area and TrP location should be expected. Conclusions: This Delphi panel has produced an expert-based standardized definition of a TrP with a discussion of the clinical components, including the definition of referred pain and the difference between active and latent TrPs, thereby providing a foundation for future research in MPS.

Prevalence of Myofascial Pain Syndrome in Chronic Non-Specific Neck Pain: A Population-Based Cross-Sectional Descriptive Study.

BACKGROUND: Chronic non-specific neck pain is a frequent complaint. It is a recognized medical and socioeconomic problem and a frequent cause of job absenteeism. In recent years, case reports about myofascial pain syndrome (MPS) are emerging among patients suffering from pain. MPS is a regional pain syndrome characterized by myofascial trigger points (MTrP) in palpable taut bands of skeletal muscle that refer pain to a distance, and that can cause distant motor and autonomic effects. OBJECTIVE: To assess the prevalence of active and latent MTrPs in subjects suffering from chronic non-specific neck pain. DESIGN: A population-based cross-sectional descriptive study was carried out from January 2012 to December 2014. SETTING: Three primary healthcare centers in Alcalá de Henares, Madrid (Spain). SUBJECTS: Two hundred and twenty-four participants diagnosed by their family doctor with chronic non-specific neck pain. METHODS: Participants were examined by a physical therapist to determine the presence of MPS. Pain descriptions from the subjects and pain body diagrams guided the physical examination. The subjects were not given any information concerning MPS or other muscle pain syndromes. RESULTS: All participants presented with MPS. MTrPs of the trapezius muscles were the most prevalent, in 93.75% of the participants. The most prevalent active MTrPs were located right (82.1%) and left (79%) in the nearly-horizontal fibers of the upper trapezius muscle. Furthermore, active MTrPs in the levator scapulae, multifidi, and splenius cervicis muscles reached a prevalence of 82.14%, 77.68%, and 62.5%, respectively. CONCLUSIONS: MPS is a common source of pain in subjects presenting chronic non-specific neck pain.

The effect of dry needling on the radiating pain in subjects with discogenic low-back pain: A randomized control trial.

BACKGROUND: Disk herniation is the most common cause of radiating low back pain (LBP) in subjects under 60 years of age. The present study aims to compare the effect of dry needling (DN) and a standard conservative approach on the pain and function in subjects with discogenic radiating LBP. MATERIALS AND METHODS: Fifty-eight subjects with discogenic radicular LBP were screened and randomized into control (Standard physical therapy, n = 29) and experimental group (Standard physical therapy and DN, n = 29). Radiating pain intensity and disability were measured using visual analog scale (VAS) and Oswestry Disability indices at baseline, at the end of treatment and 2 months after the last intervention session. The changes in pain intensity and disability were studied using a 3 × 2 repeated measures analysis of variance considering time as the within-subject factor and group as the between-subject. RESULTS: Pain intensity and disability scores decreased significantly in both experimental and control groups (experimental group: VAS = 37.24, Oswestry Disability Index [ODI] =28.48, control group: VAS = 45.5, ODI = 32.96), following the intervention. The change continued during the follow-up period (P < 0.001 for all comparisons). Pain and disability improvement, however, were more significant in experimental group, both in post intervention (experimental group: VAS = 25.17, ODI = 22.17, control group: VAS = 42.4, ODI = 30.27) (P = 0.05 and P = 0.03, respectively) and follow-up measures (P = 0.006 and P = 0.002, respectively). CONCLUSION: Both intervention strategies seem to significantly improve pain and disability immediately following intervention, where the improvement continued during 2 months after the last active intervention. Therefore, supplementary DN application may enhance the effect of the standard intervention considerably.

Strain-promoted oxidation-controlled cyclooctyne-1,2-quinone cycloaddition (SPOCQ) for fast and activatable protein conjugation.

A main challenge in the area of bioconjugation is to devise reactions that are both activatable and fast. Here, we introduce a temporally controlled reaction between cyclooctynes and 1,2-quinones, induced by facile oxidation of 1,2-catechols. This so-called strain-promoted oxidation-controlled cyclooctyne-1,2-quinone cycloaddition (SPOCQ) shows a remarkably high reaction rate when performed with bicyclononyne (BCN), outcompeting the well-known cycloaddition of azides and BCN by 3 orders of magnitude, thereby allowing a new level of orthogonality in protein conjugation.

Dry needling for the management of thoracic spine pain.

Thoracic spine pain is as disabling as neck and low back pain without receiving the same level of attention in the scientific literature. Among the different structures that can refer pain to the thoracic spine, muscles often play a relevant role. Trigger points (TrPs) from neck, shoulder and spinal muscles can induce pain in the region of the thoracic spine. There is a lack of evidence reporting the presence of TrPs in the region of the thoracic spine, but clinical evidence suggests that TrPs can be a potential source of thoracic spine pain. The current paper discusses the role of TrPs in the thoracic spine and dry needling (DN) for the management of TrPs in the thoracic multifidi and longissimus thoracis. This paper also includes a brief discussion of the application of DN in other tissues such as tendons, ligaments and scars.

Myofascial trigger points: peripheral or central phenomenon?

Trigger points (TrP) are hyperirritable spots in a taut band of a skeletal muscle, which usually have referred pain. There is controversy over whether TrP are a peripheral or central nervous system phenomenon. Referred pain, the most characteristic sign of TrP, is a central phenomenon initiated and activated by peripheral sensitization, whereby the peripheral nociceptive input from the muscle can sensitize dorsal horn neurons that were previously silent. TrP are a peripheral source of nociception, and act as ongoing nociceptive stimuli contributing to pain propagation and widespread pain. Several studies support the hypothesis that TrP can induce central sensitization, and appropriate TrP treatment reduces central sensitization. In contrast, preliminary evidence suggests that central sensitization can also promote TrP activity, although further studies are needed. Proper TrP management may prevent and reverse the development of pain propagation in chronic pain conditions, because inactivation of TrP attenuates central sensitization.

Adverse events following trigger point dry needling: a prospective survey of chartered physiotherapists.

OBJECTIVES: Trigger point dry needling (TrP-DN) is commonly used to treat persons with myofascial pain, but no studies currently exist investigating its safety. The aim of this study was to determine the incidence of Adverse Events (AEs) associated with the use of TrP-DN by a sample of physiotherapists in Ireland. METHODS: A prospective survey was undertaken consisting of two forms recording mild and significant AEs. Physiotherapists who had completed TrP-DN training with the David G Simons Academy (DGSA) were eligible to take part in the study. Data were collected over a ten-month period. RESULTS: In the study, 39 physiotherapists participated and 1463 (19.18%) mild AEs were reported in 7629 treatments with TrP-DN. No significant AEs were reported giving an estimated upper risk rate for significant AEs of less than or equal to (≤) 0.04%. Common AEs included bruising (7.55%), bleeding (4.65%), pain during treatment (3.01%), and pain after treatment (2.19%). Uncommon AEs were aggravation of symptoms (0.88%), drowsiness (0.26%), headache (0.14%), and nausea (0.13%). Rare AEs were fatigue (0.04%), altered emotions (0.04%), shaking, itching, claustrophobia, and numbness, all 0.01%. DISCUSSION: While mild AEs were very commonly reported in this study of TrP-DN, no significant AEs occurred. For the physiotherapists surveyed, TrP-DN appeared to be a safe treatment.

The Effect of Ankle Muscles Dry Needling on Brain Activity Map Based on fMRI: a Study Protocol for Randomized Controlled Trial.

Importance: Neuromodulation may be one of the underlying mechanisms of dry needling (DN); however, the mechanism has not yet been fully clarified. Objective: This randomized controlled trial is designed to evaluate DN stimulation of the tibialis anterior and peroneus longus muscles in chronic ankle instability (CAI) and healthy subjects, employing functional magnetic resonance imaging (fMRI). Design: Clinical study protocol, SPIRIT compliant. Setting: Brain Mapping Laboratory. Population: A total of thirty participants aged between 18 and 40 years old will be included in this study. Twenty healthy participants will be randomized into 2 groups (real DN and sham DN). Ten patients with CAI will also be recruited to the third group and receive only real DN for comparison. Exposures: Real and sham DN. Main Outcomes and Measures: The voxel count, coordinates of peak activation, and peak intensity will be obtained as primary outcomes to report brain map activation. Measurements will be taken before, during, and after DN treatment. The strength of the ankle dorsiflexors, active dorsiflexion range of motion, and McGill pain questionnaire short-form will be used as secondary outcome measures. Results: The results from this study will be published in peer-reviewed journals and disseminated as presentations at national and international congresses. Conclusion: This trial will explore brain responses to real and sham DN in healthy participants and to real DN in CAI patients. Overall, our results will provide preliminary evidence of the neural mechanism of DN.

Effects of dry needling session frequency on wrist flexor spasticity and motor recovery after stroke: a single-blind randomized clinical trial.

BACKGROUND: Determining the optimal number of dry needling (DN) sessions to satisfactorily treat a stroke patient with spasticity is important from both clinical and economic perspective. OBJECTIVE: To explore the effects of one versus three sessions of DN on spasticity of the wrist flexors and motor recovery after stroke. METHODS: In this single-blind randomized clinical trial, 24 patients were randomly and equally divided into two groups: one group received one session of DN, while the other group received three sessions of DN in one week. Both groups received one minute of DN of the flexor carpi radialis and flexor carpi ulnaris. The outcome measures were the Modified Modified Ashworth Scale (MMAS), passive resistance torque (PRT), wrist active and passive extension range of motion (ROM), and the Brunnstrom Stages of Stroke Recovery (BSSR) measured before, immediately after, and one week after the last DN session. RESULTS: Both groups demonstrated a significant improvement in all outcomes (p < .05). The MMAS scores in both groups meaningfully improved (p < .001). No significant differences were found between the two groups; however, a significant time-by-group interaction was observed for the PRT (p = .02; Cohen's d = 0.23-0.73), wrist active extension ROM (p = .001; Cohen's d = 0.37-0.67), and wrist passive extension ROM (p = .02; Cohen's d = 0.32-1.30). The BSSR significantly improved from 3 to 4 in both groups (p < .001). CONCLUSION: Administering three sessions of DN can effectively improve spasticity and motor function after stroke.

Diaphragm and core stabilization exercises in low back pain: A narrative review.

INTRODUCTION: Core stabilization is a vital concept in clinical rehabilitation (including low back pain rehabilitation) and competitive athletic training. The core comprises of a complex network of hip, trunk and neck muscles including the diaphragm. AIMS: The paper aims to discuss the role of the diaphragm in core stability, summarize current evidence and put forth ideal core training strategies involving the diaphragm. METHOD: Narrative review RESULTS: The diaphragm has a dual role of respiration and postural control. Evidence suggests that current core stability exercises for low back pain are superior than minimal or no treatment, however, no more beneficial than general exercises and/or manual therapy. There appears to be a higher focus on the transversus abdominis and multifidi muscles and minimal attention to the diaphragm. We propose that any form of core stabilization exercises for low back pain rehabilitation should consider the diaphragm. Core stabilization program could commence with facilitation of normal breathing patterns and progressive systematic restoration of the postural control role of the diaphragm muscle. CONCLUSION: The role of the diaphragm is often overlooked in both research and practice. Attention to the diaphragm may improve the effectiveness of core stability exercise in low back pain rehabilitation.

Genetic encoding of a bicyclo[6.1.0]nonyne-charged amino acid enables fast cellular protein imaging by metal-free ligation.

Visualizing biomolecules by fluorescent tagging is a powerful method for studying their behaviour and function inside cells. We prepared and genetically encoded an unnatural amino acid (UAA) that features a bicyclononyne moiety. This UAA offered exceptional reactivity in strain-promoted azide-alkyne cycloadditions. Kinetic measurements revealed that the UAA reacted also remarkably fast in the inverse-electron-demand Diels-Alder cycloaddition with tetrazine-conjugated dyes. Genetic encoding of the new UAA inside mammalian cells and its subsequent selective labeling at low dye concentrations demonstrate the usefulness of the new amino acid for future imaging studies.