Genetic underpinnings of arthropod community distributions in Populus trichocarpa.

Community genetics seeks to understand the mechanisms by which natural genetic variation in heritable host phenotypes can encompass assemblages of organisms such as bacteria, fungi, and many animals including arthropods. Prior studies that focused on plant genotypes have been unable to identify genes controlling community composition, a necessary step to predict ecosystem structure and function as underlying genes shift within plant populations. We surveyed arthropods within an association population of Populus trichocarpa in three common gardens to discover plant genes that contributed to arthropod community composition. We analyzed our surveys with traditional single-trait genome-wide association analysis (GWAS), multitrait GWAS, and functional networks built from a diverse set of plant phenotypes. Plant genotype was influential in structuring arthropod community composition among several garden sites. Candidate genes important for higher level organization of arthropod communities had broadly applicable functions, such as terpenoid biosynthesis and production of dsRNA binding proteins and protein kinases, which may be capable of targeting multiple arthropod species. We have demonstrated the ability to detect, in an uncontrolled environment, individual genes that are associated with the community assemblage of arthropods on a host plant, further enhancing our understanding of genetic mechanisms that impact ecosystem structure.

F-Chin/Feminizing the Chin: A Genioplasty Technique with Virtual Planning for Male-to-Female Transgender Patients.

The chin is an essential structure in facial harmony and an important gender marker. Advancing a receding chin is fundamental to improve the facial appearance, particularly in male-to-female transgender patients. However, in patients with microgenia and/or retrognathia, desiring a more feminine appearance, a chin advancement can result in a wider, square shape; an undesirable effect. Genioplasty is a versatile procedure used in facial feminization surgery that allows modifying the natural anatomy of the chin in all three spatial dimensions. The technique herein described proposes a simple genioplasty procedure for feminizing the chin (F-chin genioplasty) in transgender patients where anteroposterior advance is required. Virtual planning was used to establish the landmarks for an anteroposterior advancement with transverse reduction in the chin. A perpendicular line to the Frankfurt plane passing through the incisal edge of the upper central incisor was used to plan the anteroposterior movement, and two vertical lines on the outer wall of the nasal cavity  for the chin transverse measurement. The authors present three case reports with the F-chin genioplasty transgender technique with satisfactory results, ensuring a more feminine facial appearance.Level of Evidence V This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Temporomandibular Joint Minimally Invasive Procedures in the Pediatric Population: A Prospective Study.

Over recent years, temporomandibular joint (TMJ) minimally invasive procedures, such as arthrocentesis and arthroscopy, have been appointed as an initial TMJ intra-articular treatment. Both procedures present safe and effective clinical results in managing temporomandibular disorders (TMD) by reducing pain and improving mouth opening. The use of these techniques in adults is validated in the literature. However, data on the safety and effectiveness of minimally invasive TMJ interventions in pediatric patients are scarce. This study aims to investigate the effectiveness of TMJ arthrocentesis and arthroscopy in the pediatric population. A prospective study was conducted at Instituto Português da Face (IPF) in Lisbon, Portugal, including patients treated for TMD from 1 June 2019 to 30 June 2023. In the present study, 26 patients (17 female and 9 male) were included, representing a total of 48 joints operated. A statistically significant reduction was observed in the primary outcome, TMJ pain, from 3.93 ± 2.80 preoperatively (mean ± SD) to 0.50 ± 1.53 (mean ± SD) postoperatively (p < 0.05). An improvement in the secondary outcome, maximum mouth opening, from 36.92 ± 8.79 preoperatively to 42.96 ± 5.07 postoperatively, was observed (p < 0.05). The overall success rate was 84.62%. This prospective study showed that TMJ arthrocentesis and arthroscopy appear to benefit pediatric patients with TMD, significantly lowering pain and improving MMO without relevant postoperative complications.

Skin Bioimpedance Analysis to Determine Cellular Integrity by Phase Angle in Women with Fibromyalgia: A Cross-Sectional Study.

Oxidative stress has been proposed as a significant part of the pathogenesis of fibromyalgia, and the phase angle in bioelectrical impedance analysis has been explored as a potential technique to screen oxidative abnormalities. This study recruited 35 women with fibromyalgia and 35 healthy women, who underwent bioelectrical impedance analysis and maximum isometric handgrip strength tests. Women with fibromyalgia showed lower bilateral handgrip strength (right hand: 16.39 ± 5.87 vs. 27.53 ± 4.09, p < 0.001; left hand: 16.31 ± 5.51 vs. 27.61 ± 4.14, p < 0.001), as well as higher body fat mass (27.14 ± 10.21 vs. 19.94 ± 7.25, p = 0.002), body fat percentage (37.80 ± 8.32 vs. 30.63 ± 7.77, p < 0.001), and visceral fat area (136.76 ± 55.31 vs. 91.65 ± 42.04, p < 0.01) compared with healthy women. There was no statistically significant difference in muscle mass between groups, but women with fibromyalgia showed lower phase angles in all body regions when compared with healthy control women (right arm: 4.42 ± 0.51 vs. 4.97 ± 0.48, p < 0.01; left arm: 4.23 ± 0.48 vs. 4.78 ± 0.50, p < 0.001; trunk: 5.62 ± 0.77 vs. 6.78 ± 0.84, p < 0.001; right leg: 5.28 ± 0.56 vs. 5.81 ± 0.60, p < 0.001; left leg: 5.07 ± 0.51 vs. 5.69 ± 0.58, p < 0.001; whole body: 4.81 ± 0.47 vs. 5.39 ± 0.49, p < 0.001). Moreover, whole-body phase-angle reduction was only predicted by the presence of fibromyalgia (R2 = 0.264; ß = 0.639; F(1,68) = 24.411; p < 0.001). Our study revealed significantly lower phase angle values, lower handgrip strength, and higher fat levels in women with fibromyalgia compared to healthy controls, which are data of clinical relevance when dealing with such patients.

Differences in Motor Imagery Ability between People with Parkinson's Disease and Healthy Controls, and Its Relationship with Functionality, Independence and Quality of Life.

Motor imagery (MI) has been shown to be effective for the acquisition of motor skills; however, it is still unknown whether similar benefits can be achieved in neurological patients. Previous findings of differences in MI ability between people with Parkinson's disease (PwPD) and healthy controls (HCs) are mixed. This study examined differences in the ability to both create and maintain MI as well as investigating the relationship between the ability to create and maintain MI and motor function, independence and quality of life (QoL). A case-control study was conducted (31 PwPD and 31 HCs), collecting gender, age, dominance, socio-demographic data, duration and impact of the disease. MI intensity (MIQ-RS and KVIQ-34) and temporal accuracy of MI (imagined box and block test [iBBT], imagined timed stand and walk test [iTUG]) were assessed. Functional and clinical assessments included upper limb motor function, balance, gait, independence in activities of daily living and quality of life measures. Statistically significant differences in temporal accuracy were observed and partial and weak relationships were revealed between MI measures and functioning, independence and QoL. PwPD retain the ability to create MI, indicating the suitability of MI in this population. Temporal accuracy might be altered as a reflection of bradykinesia on the mentally simulated actions.

Molecular and functional correction of a deep intronic splicing mutation in CFTR by CRISPR-Cas9 gene editing.

Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in the CFTR gene. The 10th most common mutation, c.3178-2477C>T (3849+10kb C>T), involves a cryptic, intronic splice site. This mutation was corrected in CF primary cells homozygous for this mutation by delivering pairs of guide RNAs (gRNAs) with Cas9 protein in ribonucleoprotein (RNP) complexes that introduce double-strand breaks to flanking sites to excise the 3849+10kb C>T mutation, followed by DNA repair by the non-homologous end-joining pathway, which functions in all cells of the airway epithelium. RNP complexes were delivered to CF basal epithelial cell by a non-viral, receptor-targeted nanocomplex comprising a formulation of targeting peptides and lipids. Canonical CFTR mRNA splicing was, thus, restored leading to the restoration of CFTR protein expression with concomitant restoration of electrophysiological function in airway epithelial air-liquid interface cultures. Off-target editing was not detected by Sanger sequencing of in silico-selected genomic sites with the highest sequence similarities to the gRNAs, although more sensitive unbiased whole genome sequencing methods would be required for possible translational developments. This approach could potentially be used to correct aberrant splicing signals in several other CF mutations and other genetic disorders where deep-intronic mutations are pathogenic.

Effects of a Therapeutic Exercise Protocol for Patients with Chronic Non-Specific Back Pain in Primary Health Care: A Single-Group Retrospective Cohort Study.

BACKGROUND: Back pain is highly prevalent; in Spain, it produces a very high economic cost and the scientific evidence supporting treatments shows low to moderate evidence for exercise. Therefore, the aim of this study was to assess the effectiveness of a therapeutic group exercise protocol in reducing pain intensity and disability in patients with back pain in primary health care setting. METHODS: A total sample of 149 patients who suffered from chronic non-specific back pain was selected. Patients received a therapeutic exercise protocol, including auto-mobilization exercises for the neck and lumbar regions, as well as core stabilization exercises. Pain intensity and disability were evaluated before and after the therapeutic exercise protocol. RESULTS: Statistically significant differences (p < 0.05) were shown in pain intensity and disability for patients with non-specific neck and low-back pain, with an effect size from moderate to large. CONCLUSIONS: A therapeutic exercise protocol may provide beneficial effects upon disability and pain intensity in patients with chronic non-specific back pain, including neck and low-back pain conditions In addition, It could be considered for inclusion as a back-pain-approach program in primary healthcare.

Considerations for the Use of Alloplastic Temporomandibular Joint Replacement in Irradiated Patients: Report of an Off-Label Indication.

BACKGROUND: Custom-made alloplastic temporomandibular joint replacement (ATMJR) is not validated in irradiated patients. However, in specific situations, after previous reconstructive surgical failures, the authors hypothesized the role of a customized ATMJR after radiotherapy. METHODS: A 65-year-old male patient was referred to Instituto Português da Face-Lisbon, Portugal-after failed attempts of mandibular reconstruction secondary to oral carcinoma resection and partial hemi-mandibulectomy plus radiotherapy of 60 total Grays. Primary reconstruction was performed with fibula free flap. Due to failure, secondary reconstructions were performed with osteosynthesis plate without success. The patient was unable to have adequate mastication and deglutition due to a severe crossbite. The authors treated the patient with an extended customized alloplastic temporomandibular joint replacement (F0M2). RESULTS: With 3 years of follow-up, the patient showed an improvement in masticatory function, mandibular motion, pain levels, and overall quality of life. No complications were observed related to ATMJR. CONCLUSIONS: The presented case described how ATMJR, although not a validated option after radiotherapy, can be considered to restore functionality in complex cases with bone and soft tissues problems.

Ultrasonographic reliability and repeatability of simultaneous bilateral assessment of diaphragm muscle thickness during normal breathing.

Background: The diaphragm is considered the main muscle involved in breathing and also linked to trunk stabilization functions. Up to date, rehabilitative ultrasound imaging (RUSI) has been the most used technique to evaluate unilaterally the transcostal diaphragm thickness. Nevertheless, the inspiratory activity of both hemi-diaphragms is bilaterally performed at the same time, and its simultaneous evaluation with a thoracic orthosis could improve its assessment as well as its re-education with visual biofeedback of both hemi-diaphragms at the same time. The purpose was to evaluate the reliability and repeatability of simultaneous thickness measurements of both hemi-diaphragms bilaterally during normal breathing using a thoracic orthosis that allowed bilateral fixation of both right and left ultrasound probes. Methods: The study was conducted in 46 healthy subjects, whose diaphragm thickness was measured bilaterally and simultaneously in the anterior axillary line during relaxed breathing with a designed thoracic orthosis and 2 ultrasound tools. Intra-examiner (same examiner), inter-examiner (2 examiners), intra-session (1 hour) and inter-session (1 week) reliability and repeatability between each pair of measurements of diaphragm muscle thickness were analyzed during normal breathing. Results: Reliability and repeatability for intra-session evaluations using the thoracic orthosis were excellent to evaluate simultaneous thickness of both hemi-diaphragms by bilateral probes fixation (intraclass correlation coefficient =0.919-0.997; standard error of measurement =0.002-0.007 cm; minimum detectable change =0.006-0.020 cm), without systematic errors (P>0.05) between each pair of measurements. Nevertheless, inter-session evaluations varied from good to excellent using the bilateral probes fixation (intraclass correlation coefficient =0.614-0.984; standard error of measurement =0.006-0.028 cm; minimum detectable change =0.017-0.079 cm), although some systematic errors were presented (P<0.05). Conclusions: Good to excellent reliability and repeatability was shown for simultaneous thickness measurements of both hemi-diaphragms bilaterally during normal breathing. Despite systematic errors were presented for some inter-examiner assessments, the use of the thoracic orthosis that allowed bilateral fixation of ultrasound probes could be recommended for simultaneous hemi-diaphragms breathing re-education by visual biofeedback.

Therapeutic Exercise Parameters, Considerations and Recommendations for the Treatment of Non-Specific Low Back Pain: International DELPHI Study.

BACKGROUND: Therapeutic exercise (TE) recommendations for non-specific low back pain (LBP) are meant to support therapy choices for people who suffer from this condition. The aim of this study was to reach an agreement on the definition and use of TE in the care of people with LBP. METHODS: A Delphi study was carried out with a formal consensus procedure and sufficient scientific evidence, using an established methodology. Four rounds of anonymous questionnaires were administered to create useful suggestions and instructions in terms of the therapeutic activity for patients with LBP, and a group consensus conference. RESULTS: A consensus was reached on most of the questions after 35 physiotherapists completed the questionnaires. Participants agreed that proper TE requires correct posture, body awareness, breathing, movement control, and instruction. Patients with LBP were advised to participate in supervised sessions twice a week for 30 to 60 min for a period of 3 to 6 months. Participants added that tailored evaluation and exercise prescription, monitoring, and functional integration of exercise, as well as using specific equipment, would benefit patients with LBP. CONCLUSIONS: TE recommendations for patients with LBP should be dosed and customized based on their personal psychological needs, level of fitness, and kinesiophobia.

Effectiveness of double-puncture temporomandibular joint arthrocentesis with viscosupplementation in different categories of severity - a prospective study.

This 3-year prospective study evaluated the efficacy of temporomandibular joint (TMJ) arthrocentesis with viscosupplementation in different severity stages based on the Dimitroulis classification (categories 2-4 were included). TMJ arthrocentesis was performed under local anaesthesia, and the protocol consisted of a double-puncture technique with lavage of ≥150 cc Ringer Lactate plus viscosupplementation. Incobotulinum toxin A was administered 10-15 days preoperatively in patients with concomitant masticatory myalgia. The primary outcome was TMJ pain, assessed by visual analogue scale (VAS, 0-10), and the secondary outcomes were the maximum mouth opening (MMO, mm) and myalgia degree (0-3). All outcomes were assessed on the intervention day (T0) and after the procedure (T1) (minimum 1 month and then 3 months, 6 months, 1 year and every year since). A total of 108 patients were enrolled (mean age of 43.1 ± 18.9 years); 86 (80%) were women and 22 (20%) were men. Preoperative pain was 4.02 ± 3.12 (mean ± SD), MMO was 38.10 ± 9.56 (mean ± SD) and myalgia degree was 1.80 ± 1.18 (mean ± SD). After an average of 215.4 days (31-1253 days), a statistically significant improvement of pain (P < 0.0001), MMO (P = 0.005) and myalgia degree (P < 0.0001) was observed. The overall successful outcome of TMJ arthrocentesis with viscosupplementation was 76%. The authors observed increased arthrocentesis effectiveness and success rate with viscosupplementation in Dimitroulis category 2 (88.6%) compared to 3-4 (71.4%). An association was found between arthrocentesis with viscosupplementation failure and painful myalgia (ρ = 0.477; P < 0.0001). Thirteen patients (12%) underwent a second TMJ intervention after finalising the present trial. With a low complication rate, TMJ arthrocentesis with viscosupplementation led to an overall benefit for all the included patients. This study reinforces the important role of minimally invasive TMJ arthrocentesis as a first treatment option, with better results in the early stages compared to more severe stages.

Effectiveness of Dry Needling and Ischaemic Trigger Point Compression of the Levator Scapulae in Patients with Chronic Neck Pain: A Short-Term Randomized Clinical Trial.

BACKGROUND: Chronic neck pain (CNP) may be associated with latent myofascial trigger points (MTrPs) in the levator scapulae (LS), which can be treated with ischemic compression (IC) and dry needling (DN). Variables and elastography changes are evaluated to compare the short-term efficacy of two treatments with DN. METHODS: A randomized clinical trial is conducted with 80 participants in two groups: the DN group (n = 40) and IC group (n = 40). The duration is 12 weeks, and mechanical heterogeneity index, pressure pain threshold (PPT), and pain intensity are measured at baseline, immediately after, 48 h after, and one week after treatment. RESULTS: Statistically significant changes were immediately observed between the two groups: PPT decreased in the DN group (p = 0.05), while it increased in the IC group. At 48 h and one week after treatment, these values increased in the DN group and remained higher than in the IC group. The heterogeneity index improved in both groups but more significantly in the DN group than in the IC group. CONCLUSIONS: In subjects with CNP who had latent plus hyperalgesic MTrPs in the LS muscle, DN outperformed IC in PPT, pain intensity, and mechanical heterogeneity index at 48 h and one week after initiating therapy.

Comparison between virtual and hybrid education for psychological factors and academic stress in freshman nursing students: a case-control study.

BACKGROUND: The coronavirus 2019 (COVID-19) pandemic has prompted several changes in the learning methods of students. The purpose of this study was to establish whether a relationship between levels of resilience, self-esteem, anxiety, depression, and academic stress in both hybrid and virtual learning education exist. METHODS: A descriptive and observational case-control study was carried out in universities that offer nursing designation. A total sample of 140 freshman nursing students was recruited. Concretely, 70 participants were recruited from an university receiving hybrid education and 70 participants were recruited from another university receiving virtual learning education. Nursing students self-reported the following questionnaires: the Rosenberg Self-Esteem scale, the 10 CD-Risk Connor-Davidson Risk Resilience Scale, the Beck Anxiety Inventory, the Beck Depression Inventory and the Academic Stress Coping Scale. RESULTS: Significant differences (P = 0.001) showed higher depression levels for students who received virtual education versus received hybrid education. Differences in Rosenberg test for self-esteem and Beck Anxiety Inventory for anxiety (P > 0.05) were not found. CONCLUSION: Students who received online education presented higher depression levels which could be due to they had not face-to-face relationships with teachers or classmates, whereas the hybrid education group received a different type of direct interaction with teachers and peers.

Effects of Myofascial Induction Therapy on Ankle Range of Motion and Pressure Pain Threshold in Trigger Points of the Gastrocnemius-A Clinical Trial.

BACKGROUND: The myofascial induction technique (MIT) has been shown to increase shoulder range of motion (ROM) in breast cancer survivors and decrease pain pressure threshold over the radial nerve in patients with epicondylalgia. To the authors' best knowledge, no study on trigger points and MIT has been published to date. The effect on ROM of latent trigger points is also unknown. METHODS: A total of 20 twins with one latent trigger point of the gastrocnemius muscle were evaluated pre- and post-MIT in the calf. We measured static footprint variables in a pre-post study. RESULTS: We found differences in PPT (p = 0.001) and no differences in ROM with knee flexed (p = 0.420) or stretched (p = 0.069). CONCLUSIONS: After Calf MIT, latent myofascial trigger points improve PPT but no change in ankle dorsiflexion with knee bent or knee flexed were found in non-restriction healthy subjects.

Activation Capacity of the Intrinsic Musculature of the Foot in Handball Athletes with Chronic Ankle Instability.

Chronic ankle instability (CAI) is a common pathology in handball. The role of the intrinsic musculature of the foot in these players in relation to proprioception and stability has not been stablished. The objective of this study was to compare the ultrasound morphology of the heel fat pad of the foot in professional handball players to CAI in healthy players and establish relationships between CAI and physical and psychological variables. The study has been a descriptive observational case-control study in which 20 professional handball male players over 18 years of age were divided into 8 cases (CAI) and 12 controls (healthy). An ultrasound evaluation, the thickness and/or cross-sectional area at rest and the contraction measurement of the Abductor Digiti Minimi, Abductor Hallucis, Flexor Digitorum Brevis and Quadratus Plantae muscles were analyzed. Moreover, the compressibility index of the heel fat pad and the activation of the abdominal wall musculature (ultrasound), the flexion strength of the hallux and lesser toes (dynamometry), the foot functionality (Bristol Foot Score (BFS) questionnaire) and the psychological variables (self-reported questionnaires) were measured. There were no significant differences between the activation capacity values of the foot muscles of healthy and CAI athletes. Significant differences were found between groups regarding the BFS score (p = 0.007), d = 1.404), and significant correlations were also found between hallux flexion strength and lesser toes flexion strength in the total sample. Although there were no differences between the two groups, the identification of the activation pattern of these muscles in handball athletes is essential to the improvement of performance and preventing injuries such as CAI.

A New Test for Achilles Tendinopathy Based on Kager's Fat Pad Clinical Assessment Predictive Values.

Background This study aimed to check the diagnostic accuracy of a new test to identify Achilles tendinopathy. STUDY DESIGN: Observational study. METHODS: Seventy patients recruited from a private medical centre met the diagnostic criteria for unilateral Achilles tendinopathy (age, 45.1 ± 12.7 years; weight, 75.00 ± 10 kg; height, 1.75 ± 0.1 m) and were tested based on both Achilles tendons. Seventy patients with a unilateral Achilles tendinopathy ultrasound diagnosis were tested using David's test. RESULTS: Most (86%) subjects demonstrated Kager's fat pad asymmetry in relation to the Achilles tendon in the complete passive dorsiflexion in the prone position (David's sign). No healthy tendons had David's sign. CONCLUSIONS: The presence of asymmetry in Kager's fat pad in relation to the Achilles tendon during complete passive dorsiflexion is strongly indicative of ultrasound-diagnosed tendinopathy. David's test demonstrated a sensitivity of 85.71% (95% CI, 77.51% to 93.91%) and a specificity of 100% (95% CI, 100% to 100%), while noting the lack of blinding of the assessors and the uncertainty of the diagnostic measures (95% CI). Asymmetry of the fat pad could potentially serve as a characteristic marker for patients with Achilles tendinopathy.

Bilateral arthroscopy of the temporomandibular joint: clinical outcomes and the role of a second intervention-a prospective study.

OBJECTIVE: Evaluate the efficacy of bilateral temporomandibular joint (TMJ) arthroscopy in patients with different categories of severity based on Dimitroulis classification (categories 2-4) and the role of a second TMJ intervention in primary failure. METHODS: A 3-year prospective study was designed, including patients submitted to bilateral TMJ arthroscopy. The primary outcome was TMJ pain (VAS, 0-10) and the secondary outcomes were the maximum mouth opening (MMO) and masticatory myalgia degree (0-3). In cases of symptomatic relapse, a second TMJ intervention was performed (TMJ arthrocentesis or TMJ open surgery). RESULTS: Eighty patients (93.4% women) were enrolled, with a mean age of 32.40 ± 11.41 years. With an average follow-up of 523.7 days (34-1606), a statistically significant improvement in TMJ pain, MMO, and myalgia degree was observed (P < 0.0001). The overall successful outcome of one-single bilateral arthroscopy was ~ 69%. Twenty-two patients relapsed: (1) arthralgia (n = 15, 68.18%); (2) arthralgia + myalgia (n = 4, 18.18%); (3) dislocated disc without reduction (DDwoR) (n = 2, 9.09%); (4) DDwoR + osteoarthrosis (OA) (n = 1, 4.55%). Arthralgia was re-managed with TMJ arthrocentesis with local anesthesia (n = 19, 86.36%). New DDwoR with or without OA was re-treated with TMJ open surgery (n = 3, 13.64%). After the second intervention, the success rate increased to 85%. CONCLUSIONS: Bilateral TMJ arthroscopy presented overall benefit in all parameters evaluated. CLINICAL RELEVANCE: This study highlights the importance of TMJ arthroscopy as the first line of treatment for moderate-severe temporomandibular disorders cases contributing to the reduction of TMJ open surgeries. In cases of arthroscopy unsuccess, TMJ arthrocentesis under local anesthesia was an effective and safe intervention for patients with recurrent TMJ arthralgia.

Use of adenine base editing and homology-independent targeted integration strategies to correct the cystic fibrosis causing variant, W1282X.

Small molecule drugs known as modulators can treat ~90% of people with cystic fibrosis (CF), but do not work for premature termination codon variants such as W1282X (c.3846G>A). Here we evaluated two gene editing strategies, Adenine Base Editing (ABE) to correct W1282X, and Homology-Independent Targeted Integration (HITI) of a CFTR superexon comprising exons 23-27 (SE23-27) to enable expression of a CFTR mRNA without W1282X. In Flp-In-293 cells stably expressing a CFTR expression minigene bearing W1282X, ABE corrected 24% of W1282X alleles, rescued CFTR mRNA from nonsense mediated decay and restored protein expression. However, bystander editing at the adjacent adenine (c.3847A>G), caused an amino acid change (R1283G) that affects CFTR maturation and ablates ion channel activity. In primary human nasal epithelial cells homozygous for W1282X, ABE corrected 27% of alleles, but with a notably lower level of bystander editing, and CFTR channel function was restored to 16% of wild-type levels. Using the HITI approach, correct integration of a SE23-27 in intron 22 of the CFTR locus in 16HBEge W1282X cells was detected in 5.8% of alleles, resulting in 7.8% of CFTR transcripts containing the SE23-27 sequence. Analysis of a clonal line homozygous for the HITI-SE23-27 produced full-length mature protein and restored CFTR anion channel activity to 10% of wild-type levels, which could be increased three-fold upon treatment with the triple combination of CF modulators. Overall, these data demonstrate two different editing strategies can successfully correct W1282X, the second most common class I variant, with a concomitant restoration of CFTR function.

Outcomes of IncobotulinumtoxinA Injection on Myalgia and Arthralgia in Patients Undergoing Temporomandibular Joint Arthroscopy: A Randomized Controlled Trial.

BACKGROUND: Several studies have considered Botulinum Neurotoxin Type A injections effective in treating temporomandibular joint disorder (TMD) symptoms. A double-blind, randomized, controlled clinical trial investigated the benefit of complementary incobotulinumtoxinA (inco-BoNT/A) injections in the masticatory muscles of patients submitted to bilateral temporomandibular joint (TMJ) arthroscopy. METHODS: Fifteen patients with TMD and an indication for bilateral TMJ arthroscopy were randomized into inco-BoNT/A (Xeomin, 100 U) or placebo groups (saline solution). Injections were carried out five days before TMJ arthroscopy. The primary outcome variable was a Visual Analogue Scale for TMJ arthralgia, and secondary outcomes were the myalgia degree, maximum mouth opening, and joint clicks. All outcome variables were assessed preoperatively (T0) and postoperatively (T1-week 5; T2-6-month follow-up). RESULTS: At T1, the outcomes in the inco-BoNT/A group were improved, but not significantly more than in the placebo group. At T2, significant improvements in the TMJ arthralgia and myalgia scores were observed in the inco-BoNT/A group compared to the placebo. A higher number of postoperative reinterventions with further TMJ treatments were observed in the placebo group compared to inco-BoNT/A (63% vs. 14%). CONCLUSIONS: In patients submitted to TMJ arthroscopy, statistically significant long-term differences were observed between the placebo and inco-BoNT/A groups.