Occult Amyloid Deposition in Older Patients Presenting With Bilateral Carpal Tunnel Syndrome or Multiple Trigger Digits.

PURPOSE: The diagnosis of amyloidosis is important for early intervention, disease monitoring, and prevention of complications and progression. Carpal tunnel syndrome (CTS) and trigger digit (TD) are two common conditions associated with early disease. The purpose of this study was to define disease prevalence among patients with bilateral CTS and multiple TDs and assess for an increased rate of diagnosis in the presence of both. METHODS: Men older than 50 years and women older than 60 years of age diagnosed with bilateral CTS, multiple TDs, or a combination of the 2 were prospectively enrolled in our study. Tenosynovial biopsy samples taken at the time of surgery were tested for the presence of amyloid using Congo red staining. Demographic and medical covariates were also collected and analyzed for differences between amyloid-positive and -negative patients. RESULTS: Fifty-six patients were enrolled in the study, and nine patients tested positive for amyloid deposition. The demographics and medical comorbidities were similar between amyloid-positive and -negative patients. Thirty patients with bilateral CTS were enrolled, and four tested positive for amyloid. For patients with multiple TDs, a total of 17 patients were enrolled, and 4 tested positive for amyloid. Among patients with multiple TDs, only men tested positive for amyloid and were, on average, younger than those who tested negative (61 and 73 years, respectively). Patients presenting with a combination of CTS and TD did not exhibit increased amyloid discovery. CONCLUSIONS: Hand surgeons should consider tenosynovial biopsy in men older than 50 years and women older than 60 years presenting with either bilateral CTS or multiple TDs. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic IV.

SARS-COV-2 viral load in tears of patients with COVID-19 in the early symptomatic stages: comparison of two different tear sampling methods.

PURPOSE: To evaluate the presence of SARS-CoV-2 virus in tears of patients with COVID-19 in the early symptomatic stages and to compare two different sampling methods. MATERIALS AND METHOD: In this cross-sectional study, tears sampling was performed in COVID-19 patients admitted within the first 7 days of symptom onset. The samples were collected with both conjunctival swabs and Schirmer strips. Each specimen was analyzed via RT-PCR. The viral load was evaluated in terms of the cycle threshold value. Ocular and systemic symptoms and comorbidities of the patients were also recorded. RESULTS: Forty patients were included. The average time from the initiation of symptoms was 3.15 days. Unilateral conjunctivitis has been observed in 5% of patients and foreign body sensation in 7.5% of patients. No viral RNA was detected in the tear samples of the patients with ocular findings. The positivity rate for SARS-CoV-2 in tears was 2.5% (n = 1). None of the samples collected by Schirmer test strips yielded positive polymerase chain reaction result for SARS-COV-2. The Ct value of the positive conjunctival swab was 36.03 and the nasopharyngeal Ct value of the same patient was 25.68. CONCLUSION: The SARS-CoV-2 viral shedding rate has been determined as 2.5% in the tears of early symptomatic stage COVID-19 patients. The viral load of the tears was lower than the naso-oropharynx. The conjunctival swab method is recommended in tear collection to evaluate the presence of SARS-CoV-2 by RT-PCR analysis in low viral load tears.

Radiological Evaluation of the Recesses on the Posterior Wall of the Nasopharynx with Cone-beam Computed Tomography.

BACKGROUND: The posterior wall of the nasopharynx is composed of loose connective tissue that includes many important anatomical structures. Various structures, such as the opening of the Eustachian tube (ET), the Rosenmüller fossa (RF), and the pharyngeal bursa (PB) are found here. AIM: To evaluate the nasopharynx posterior wall anatomic structures, including the Eustachian tube, Rosenmüller fossa, and pharyngeal bursa with cone-beam computed tomography. MATERIALS AND METHODS: The depth, width, and length of the Eustachian tube, Rosenmüller fossa, and pharyngeal bursa were measured in 150 patients using axial-sagittal cone-beam computed tomography. The Eustachian tube and Rosenmüller fossa distance to the midsagittal plane, the coronal region passing through the posterior end of the nasal septum, the superior-inferior extremity of the recesses, and the nasal floor plane distance were measured. The relationship between Rosenmüller fossa types and other parameters were evaluated. RESULTS: The incidence of right Rosenmüller fossa types 1, 2, and 3 were 16%, 18%, and 66%, respectively, and that of the left Rosenmüller fossa types 1, 2, and 3 were 16%, 19.3%, and 64.7%, respectively. The mean pharyngeal bursa width, length, and depth were 10.8, 5.7, and 4.0 mm, respectively; those of the Eustachian tube were 5.6, 7.1, and 7.3 m, respectively; those of the right Rosenmüller fossa were 4.0, 12.4, and 10.5 mm, respectively; and those of the left Rosenmüller fossa were 3.8, 12.5, and 10.9 mm, respectively. CONCLUSIONS: The posterior wall of the nasopharynx contains several important anatomical structures. Evaluation of these using cone-beam computed tomography has many clinical and radiological advantages. To understand and interpret the coincidental findings in CBCT, dental radiologists should have access to more detailed information concerning the anatomy of the nasopharynx.

Efficacy of a single, image-guided corticosteroid injection for glenohumeral arthritis.

BACKGROUND: Limited data are available on the efficacy of cortisone injections for glenohumeral osteoarthritis (GHOA). The amount and longevity of pain relief provided by a single cortisone injection are unclear. Additionally, it remains uncertain how the severity of radiographic GHOA and patient-reported function and pain levels impact the efficacy of an injection. Therefore, we sought to describe the relief provided by a single, image-guided glenohumeral injection in patients with GHOA. We hypothesized that patients with more severe radiographic GHOA and poorer baseline shoulder function would require earlier secondary intervention. METHODS: Patients with symptomatic GHOA who elected to receive a corticosteroid injection for pain relief were prospectively enrolled. A phone interview was conducted to record the baseline Oxford Shoulder Score (OSS) and visual analog scale (VAS) score prior to the injection, as well as the OSS and VAS score at months 1, 2, 3, 4, 6, 9, and 12 after the injection. The endpoint of the study occurred when patients required a second injection, progressed to surgery, or reached month 12. Patients were grouped by their respective baseline OSS (mild vs. moderate or severe) and Samilson-Prieto radiographic classification (mild, moderate, or severe) for analysis. RESULTS: We analyzed 30 shoulders (29 patients). Of the patients, 52% were men. The average age was 66.1 years. No significant difference in overall survival (defined as no additional intervention) was seen between groups based on either the OSS or Samilson-Prieto grade. Additionally, the OSS and VAS score at each follow-up were compared with baseline values. For the entire cohort, a clinically significant difference was seen between baseline and months 1-4 for the OSS and between baseline and months 1-4, 6, 9, and 12 for the VAS score. DISCUSSION: This study aimed to determine the efficacy of corticosteroid injections for GHOA. There were no differences in the need for secondary intervention in this population based on the severity of either the OSS or the Samilson-Prieto radiographic classification. However, patients with more severe shoulder dysfunction based on the OSS did experience statistically significantly greater symptomatic relief than patients with milder dysfunction. Additionally, following a single injection, patients in this cohort experienced statistically and clinically relevant improvements in shoulder function and pain up to 4 months after injection.

Enigmatic and Unusual Cases of Upper Extremity Pain: Mislabeling As Malingerers.

With the intricate anatomy of the hand and upper extremity, there are many possible etiologies of pain. In addition, one must be alert to conditions typically affecting other areas of the body presenting in the hand and upper extremity. To add to the complexity of diagnosis, one must also be aware of potential secondary gains. With this in mind, a thorough history, physical examination, and broad differential can help avoid mislabeling patients with uncommon ailments. In this article, we present 4 cases of unusual causes of hand and upper extremity pain.

Early Practice Patterns of Hand Surgeons: An American Board of Orthopaedic Surgery Database Study.

PURPOSE: To investigate the variety of cases that are performed by newly graduated fellowship-trained orthopedic hand surgeons. METHODS: All cases submitted by board-eligible orthopedic surgeons taking part II of their board examination between 2004 and 2013 were obtained from the database of the American Board of Orthopaedic Surgery (ABOS). Each case was then categorized based on the fellowship training of the treating surgeon and whether it was a hand surgery case. Each hand surgery case was then further categorized into 1 of the 8 surgical categories used by the ABOS to determine eligibility for the Subspecialty Certificate in Orthopaedic Surgery of the Hand (SCOSH). RESULTS: During our study period, 6,854 orthopedic surgeons submitted 858,146 cases to the ABOS. Fellowship-trained hand surgeons made up 13% of all surgeons, and 24% of all submitted cases were hand surgery cases. Based on the cases submitted, 44% of hand surgeons were not on track to become eligible for the SCOSH. The most common reason for not reaching eligibility was failure to meet the minimum requirements in 1 of either the congenital, the skin and wound problems, the contracture and joint stiffness, the microvascular, or the tumor categories. CONCLUSIONS: A large proportion of fellowship-trained orthopedic hand surgeons are not on track to meet the minimum eligibility requirements for the ABOS SCOSH during their part II case collections. Their case profile is not sufficiently diverse to be considered an active hand surgery practice for the purpose of SCOSH eligibility. CLINICAL RELEVANCE: This study highlights 1 possible reason why over one-third of young hand surgeons do not obtain their subspecialty certification.

Embedded Librarian as Research Team Member.

Adding a librarian to an upper extremity surgical and therapy practice has many advantages (educational, research, remaining on the cutting edge of technology). As an embedded team member, the librarian at the Indiana Hand to Shoulder Center prepares literature reviews, creates Google Scholar Alerts for individual clinicians, and introduces developing technologies such as 3-dimensional printers, Smartphone Apps, and online access to nontraditional resources. With the librarian relieving clinicians of these responsibilities, surgeons can devote more time to clinical and research activities. Private practices unable to support their own librarian could share access to a librarian via Skype, Face Time, and video conferencing. Another small practice alternative is contracting services from a local medical school library that designates a librarian as its liaison.

Treatment of Recurrent Dupuytren Contracture in Joints Previously Effectively Treated With Collagenase Clostridium histolyticum.

PURPOSE: Collagenase Clostridium histolyticum (CCH) is approved for the treatment of adults with Dupuytren contracture with a palpable cord. This open-label, phase 4 study evaluated the safety and efficacy of CCH for the retreatment of recurrent contractures in joints that were previously effectively treated with CCH. METHODS: Patients participating in a long-term follow-up study who had contracture recurrence (increased ≥ 20° with a palpable cord) after successful treatment in the previous study were eligible. Recurrent joint contractures were treated with up to 3 CCH injections (∼ 1 month apart). Patients were followed for 1 year to evaluate safety. Assessments included change in joint contracture, range of motion, and the percentage of joints that achieved contracture of 5° or less at day 30 after the last injection. RESULTS: The efficacy analysis included 51 patients with 1 treated joint per patient (31 metacarpophalangeal, 20 proximal interphalangeal). A total of 35 joints (69%) received 1 injection, 12 (24%) received 2 injections, and 4 (8%) received 3 injections. Fifty-seven percent of joints achieved contracture of 5° or less (29 of 51). Overall, 86% (43 of 50) patients had a 20° or greater increase in range of motion. The adverse event profile was consistent with previous studies. One ligament injury was reported. CONCLUSIONS: At a short-term follow-up of 1 year, recurrent contracture in joints previously successfully treated with CCH may be effectively retreated with up to 3 injections of CCH. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

Ancient administrative handwritten documents: X-ray analysis and imaging.

Handwritten characters in administrative antique documents from three centuries have been detected using different synchrotron X-ray imaging techniques. Heavy elements in ancient inks, present even for everyday administrative manuscripts as shown by X-ray fluorescence spectra, produce attenuation contrast. In most cases the image quality is good enough for tomography reconstruction in view of future applications to virtual page-by-page `reading'. When attenuation is too low, differential phase contrast imaging can reveal the characters from refractive index effects. The results are potentially important for new information harvesting strategies, for example from the huge Archivio di Stato collection, objective of the Venice Time Machine project.

Dupuytren Contracture Recurrence Following Treatment With Collagenase Clostridium histolyticum (CORDLESS [Collagenase Option for Reduction of Dupuytren Long-Term Evaluation of Safety Study]): 5-Year Data.

PURPOSE: Collagenase Option for Reduction of Dupuytren Long-Term Evaluation of Safety Study was a 5-year noninterventional follow-up study to determine long-term efficacy and safety of collagenase clostridium histolyticum (CCH) treatment for Dupuytren contracture. METHODS: Patients from previous CCH clinical studies were eligible. Enrolled patients were evaluated annually for contracture and safety at 2, 3, 4, and 5 years after their first injection (0.58 mg) of CCH. In successfully treated joints (≤ 5° contracture following CCH treatment), recurrence was defined as 20° or greater worsening (relative to day 30 after the last injection) with a palpable cord or any medical/surgical intervention to correct new/worsening contracture. A post hoc analysis was also conducted using a less stringent threshold (≥ 30° worsening) for comparison with criteria historically used to assess surgical treatment. RESULTS: Of 950 eligible patients, 644 enrolled (1,081 treated joints). At year 5, 47% (291 of 623) of successfully treated joints had recurrence (≥ 20° worsening)-39% (178 of 451) of metacarpophalangeal and 66% (113 of 172) of proximal interphalangeal joints. At year 5, 32% (198 of 623) of successfully treated joints had 30° or greater worsening (metacarpophalangeal 26% [119 of 451] and proximal interphalangeal 46% [79 of 172] joints). Of 105 secondary interventions performed in the successfully treated joints, 47% (49 of 105) received fasciectomy, 30% (32 of 105) received additional CCH, and 23% (24 of 105) received other interventions. One mild adverse event was attributed to CCH treatment (skin atrophy [decreased ring finger circumference from thinning of Dupuytren tissue]). Antibodies to clostridial type I and/or II collagenase were found in 93% of patients, but over the 5 years of follow-up, this did not correspond to any reported clinical adverse events. CONCLUSIONS: Five years after successful CCH treatment, the overall recurrence rate of 47% was comparable with published recurrence rates after surgical treatments, with one reported long-term treatment-related adverse event. Collagenase clostridium histolyticum injection proved to be an effective and safe treatment for Dupuytren contracture. For those receiving treatment during follow-up, both CCH and fasciectomy were elected options. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic II.

Efficacy and safety of concurrent collagenase clostridium histolyticum injections for multiple Dupuytren contractures.

PURPOSE: To assess the safety and efficacy of 2 concurrent injections of collagenase clostridium histolyticum (CCH) in the same hand to treat multiple Dupuytren flexion contractures. METHODS: In a multicenter, open-label phase IIIb study, 60 patients received two 0.58-mg CCH doses injected into cords affecting 2 joints in the same hand during 1 visit, followed by finger extension approximately 24 hours later. Efficacy at postinjection day 30 (change in flexion contracture and active range of motion, patient satisfaction, physician-rated improvement, and rates of clinical success [flexion contracture 5° or less]) and adverse events were summarized. RESULTS: The concurrent injections were most commonly administered in cords affecting metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints on the same finger (47%) or 2 MCP joints on different fingers of the same hand (37%). Mean total (sum of the 2 treated joints) flexion contracture decreased 76%, from 87° to 24° (MCP joints: 86%; PIP joints: 66%). Mean total range of motion increased from 100° to 161°. Clinical success was 76% for MCP joints and 33% for PIP joints. Most patients were very satisfied (60%) or quite satisfied (28%) with treatment. Most investigators rated treated joints as very much improved (55%) or much improved (37%). The most common treatment-related adverse events (> 75% of patients) were contusion, pain in extremity, and edema peripheral (local edema). Most adverse events were mild to moderate in severity. Serious complications included 1 pulley rupture related to study medication and 1 flexor tendon rupture (following conclusion of the study). There were no systemic complications. CONCLUSIONS: Results suggest that 2 affected joints can be effectively and safely treated with concurrent CCH injections. There was an increased incidence of some adverse events with concurrent treatment (pruritus, lymphadenopathy, blood blister, and skin laceration) compared with treatment of a single joint. High degrees of patient satisfaction and physician-rated improvement were reported. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

Final 1-Year Results of the TUTOR Randomized Trial Comparing Carpal Tunnel Release with Ultrasound Guidance to Mini-open Technique.

Background: Studies comparing carpal tunnel release with ultrasound guidance (CTR-US) to mini-open CTR (mOCTR) are limited. This randomized trial compared the efficacy and safety of these techniques. Methods: In this multicenter randomized trial, patients were randomized (2:1) to unilateral CTR-US or mOCTR. Outcomes included Boston Carpal Tunnel Questionnaire Symptom Severity Scale (BCTQ-SSS) and Functional Status Scale (BCTQ-FSS), numeric pain scale (0-10), EuroQoL-5 Dimension 5-Level (EQ-5D-5L), scar outcomes, and complications over 1 year. Results: Patients received CTR-US (n = 94) via wrist incision (mean 6 mm) or mOCTR (n = 28) via palmar incision (mean 22 mm). Comparing CTR-US with mOCTR, the mean changes in BCTQ-SSS (-1.8 versus -1.8; P = 0.96), BCTQ-FSS (-1.0 versus -1.0; P = 0.75), numeric pain scale (-3.9 versus -3.8; P = 0.74), and EQ-5D-5L (0.13 versus 0.12; P = 0.79) over 1 year were comparable between groups. Freedom from scar sensitivity or pain favored CTR-US (95% versus 74%; P = 0.005). Complications occurred in 2.1% versus 3.6% of patients (P = 0.55), all within 3 weeks postprocedure. There was one revision surgery in the CTR-US group, and no revisions for persistent or recurrent symptoms in either group. Conclusions: CTR-US and mOCTR demonstrated similar improvement in carpal tunnel syndrome symptoms and quality of life with comparable low complication rates over 1 year of follow-up. CTR-US was performed with a smaller incision and associated with less scar discomfort.

Dupuytren contracture recurrence following treatment with collagenase clostridium histolyticum (CORDLESS study): 3-year data.

PURPOSE: To evaluate long-term efficacy and safety of collagenase clostridium histolyticum (CCH) after the third year of a 5-year nontreatment follow-up study, Collagenase Option for Reduction of Dupuytren Long-Term Evaluation of Safety Study. METHODS: This study enrolled Dupuytren contracture patients from 5 previous clinical studies. Beginning 2 years after their first CCH injection, we re-evaluated patients annually for joint contracture and safety. Recurrence in a previously successfully treated joint (success = 0° to 5° contracture after CCH administration) was defined as 20° or greater worsening in contracture in the presence of a palpable cord or medical/surgical intervention to correct new or worsening contracture. We assessed partially corrected joints (joints reduced 20° or more from baseline contracture but not to 0° to 5°) for nondurable response, also defined as 20° or greater worsening of contracture or medical/surgical intervention. RESULTS: Of 1,080 CCH-treated joints (648 metacarpophalangeal [MCP]; 432 proximal interphalangeal [PIP]; n = 643 patients), 623 (451 MCP, 172 PIP) had achieved 0° to 5° contracture in the original study. Of these joints, 35% (217 of 623) recurred (MCP 27%; PIP 56%). Of these recurrences, an intervention was performed in 7%. Of the 1,080 CCH-treated joints, 301 were partially corrected in the original study. Of these, 50% (150 of 301; MCP: 38% [57 of 152]; PIP: 62% [93 of 149]) had nondurable response. We identified no new long-term or serious adverse events attributed to CCH during follow-up. Anti-clostridial type I collagenase and/or anti-clostridial type II collagenase antibodies were reported for 96% or more of patients who received 2 or more CCH injections and 82% who received 1 injection. CONCLUSIONS: The recurrence rate, which is comparable to other standard treatments, and the absence of long-term adverse events 3 years after initial treatment indicate that CCH is an effective and safe treatment for Dupuytren contracture. Most successfully treated joints had a contracture well below the threshold for surgical intervention 3 years after treatment. Recurrence rates among successfully treated joints were lower than nondurable response rates among partially corrected joints. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

Multicenter randomized trial of carpal tunnel release with ultrasound guidance versus mini-open technique.

BACKGROUND: Comparative studies of carpal tunnel release with ultrasound guidance (CTR-US) vs. mini-open CTR (mOCTR) are limited, prompting development of this randomized trial to compare efficacy and safety of these techniques. RESEARCH DESIGN AND METHODS: Patients were randomized (2:1) to CTR-US or mOCTR, treated by experienced hand surgeons (median previous cases: 12 CTR-US; 1000 mOCTR), and followed for 3 months. RESULTS: Among 149 randomized patients, 122 received CTR-US (n = 94) or mOCTR (n = 28). Mean incision length was 6 ± 2 mm in the wrist (CTR-US) vs. 22 ± 7 mm in the palm (mOCTR) (p < 0.001). Median time to return to daily activities (2 vs. 2 days; p = 0.81) and work (3 vs. 4 days; p = 0.61) were similar. Both groups reported statistically significant and clinically important improvements in Boston Carpal Tunnel Questionnaire Symptom Severity and Functional Status Scales, Numeric Pain Scale, and EuroQoL-5 Dimension 5-Level, with no statistical differences between groups. Freedom from wound sensitivity and pain favored CTR-US (61.1% vs. 17.9%; p < 0.001). Adverse event rates were low in each group (2.1% vs. 3.6%; p = 0.55). CONCLUSIONS: The efficacy and safety of CTR-US were comparable to mOCTR despite less previous surgical experience with CTR-US. The choice of CTR technique should be determined by shared decision-making between patient and physician. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov identifier is NCT05405218.

Restoration of normal BMP signaling levels and osteogenic differentiation in FOP mesenchymal progenitor cells by mutant allele-specific targeting.

Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder of progressive heterotopic ossification for which there is presently no cure. FOP is caused by a recurrent heterozygous activating mutation (c.617G>A; R206H) of Activin receptor type IA/Activin-like kinase-2 (ACVR1/ALK2), a bone morphogenetic protein (BMP) type I receptor that occurs in all classically affected individuals. The FOP mutation dysregulates BMP signaling and initiates the formation of a disabling second skeleton of heterotopic bone. We generated allele-specific siRNA (ASP-RNAi) duplexes capable of specifically suppressing the expression of the mutant c.617A allele in mesenchymal progenitor cells from FOP patients and showed that this ASP-RNAi approach decreased the elevated BMP signaling that is characteristic of patient cells to levels similar to control cells and restored enhanced osteogenic differentiation to control levels. Our results provide proof-of-principle that ASP-RNAi has potential therapeutic efficacy for the treatment of FOP.

Injectable collagenase clostridium histolyticum for Dupuytren's contracture.

BACKGROUND: Dupuytren's disease limits hand function, diminishes the quality of life, and may ultimately disable the hand. Surgery followed by hand therapy is standard treatment, but it is associated with serious potential complications. Injection of collagenase clostridium histolyticum, an office-based, nonsurgical option, may reduce joint contractures caused by Dupuytren's disease. METHODS: We enrolled 308 patients with joint contractures of 20 degrees or more in this prospective, randomized, double-blind, placebo-controlled, multicenter trial. The primary metacarpophalangeal or proximal interphalangeal joints of these patients were randomly assigned to receive up to three injections of collagenase clostridium histolyticum (at a dose of 0.58 mg per injection) or placebo in the contracted collagen cord at 30-day intervals. One day after injection, the joints were manipulated. The primary end point was a reduction in contracture to 0 to 5 degrees of full extension 30 days after the last injection. Twenty-six secondary end points were evaluated, and data on adverse events were collected. RESULTS: Collagenase treatment significantly improved outcomes. More cords that were injected with collagenase than cords injected with placebo met the primary end point (64.0% vs. 6.8%, P < 0.001), as well as all secondary end points (P < or = 0.002). Overall, the range of motion in the joints was significantly improved after injection with collagenase as compared with placebo (from 43.9 to 80.7 degrees vs. from 45.3 to 49.5 degrees, P < 0.001). The most commonly reported adverse events were localized swelling, pain, bruising, pruritus, and transient regional lymph-node enlargement and tenderness. Three treatment-related serious adverse events were reported: two tendon ruptures and one case of complex regional pain syndrome. No significant changes in flexion or grip strength, no systemic allergic reactions, and no nerve injuries were observed. CONCLUSIONS: Collagenase clostridium histolyticum significantly reduced contractures and improved the range of motion in joints affected by advanced Dupuytren's disease. (ClinicalTrials.gov number, NCT00528606.)

Different roles of GNAS and cAMP signaling during early and late stages of osteogenic differentiation.

Progressive osseous heteroplasia (POH) and fibrous dysplasia (FD) are genetic diseases of bone formation at opposite ends of the osteogenic spectrum: imperfect osteogenesis of the skeleton occurs in FD, while heterotopic ossification in skin, subcutaneous fat, and skeletal muscle forms in POH. POH is caused by heterozygous inactivating germline mutations in GNAS, which encodes G-protein subunits regulating the cAMP pathway, while FD is caused by GNAS somatic activating mutations. We used pluripotent mouse ES cells to examine the effects of Gnas dysregulation on osteoblast differentiation. At the earliest stages of osteogenesis, Gnas transcripts Gsα, XLαs and 1A are expressed at low levels and cAMP levels are also low. Inhibition of cAMP signaling (as in POH) by 2',5'-dideoxyadenosine enhanced osteoblast differentiation while conversely, increased cAMP signaling (as in FD), induced by forskolin, inhibited osteoblast differentiation. Notably, increased cAMP was inhibitory for osteogenesis only at early stages after osteogenic induction. Expression of osteogenic and adipogenic markers showed that increased cAMP enhanced adipogenesis and impaired osteoblast differentiation even in the presence of osteogenic factors, supporting cAMP as a critical regulator of osteoblast and adipocyte lineage commitment. Furthermore, increased cAMP signaling decreased BMP pathway signaling, indicating that G protein-cAMP pathway activation (as in FD) inhibits osteoblast differentiation, at least in part by blocking the BMP-Smad pathway, and suggesting that GNAS inactivation as occurs in POH enhances osteoblast differentiation, at least in part by stimulating BMP signaling. These data support that differences in cAMP levels during early stages of cell differentiation regulate cell fate decisions. Supporting information available online at http:/www.thieme-connect.de/ejournals/toc/hmr.

Optimal Lateral Ulnar Collateral Ligament Repair Site After Placement of the Internal Joint Stabilizer.

BACKGROUND: The optimal location to repair the lateral ulnar collateral ligament (LUCL) following placement of the internal joint stabilizer (IJS) has not been defined. The placement of the IJS occupies the ideal native repair site, the isometric point on the lateral epicondyle, necessitating non-anatomic repair of the LUCL. This may lead to a loss of flexion, extension, or both. We present a cadaveric study aimed to determine the ideal non-anatomic repair location that maximizes postoperative range of motion. METHODS: Range of motion of 10 cadaveric elbows were tested with the lateral ulnar collateral ligament complex intact. The ligament was then elevated from the capitellum and the IJS device was implanted. Five lateral collateral repair positions were tested using quadrants to classify the repair positions. The ligament was repaired using suture in a Krakow fashion placed through drill holes in the lateral capitellum, then secured against the posterior cortex. Elbow range of motion was documented for both flexion and ex- tension in all repair positions for each of the 10 cadaveric specimens. Statistical analysis was performed using an analysis of variance (ANOVA) and a Tukey-Kramer post hoc analysis to determine statistical significance. RESULTS: There was a statistically significant difference between elbow range of motion in each repair position and the native elbow in all but position 3, which was anterior and distal to the central IJS axis pin (8° loss of flexion and 6° loss of extension). Flexion was significantly different in only position 2 (15° loss), while extension was different in both position 1 (51° loss) and position 4 (42° loss). Total motion loss was significant for positions 1 (57°), 2 (16°), 4 (48°), and 5 (24°). CONCLUSIONS: When using an IJS elbow stabilizing device, since the axis pin occupies the anatomic origin of the lat- eral ulnar collateral ligament, the repair should be placed as close as possible to the isometric point in the anterior and distal quadrant of the lateral capitellum to maximize postoperative elbow range of motion.

Trial of ultrasound guided carpal tunnel release versus traditional open release (TUTOR).

BACKGROUND: Carpal tunnel release (CTR) is a surgical treatment option for patients with carpal tunnel syndrome (CTS) symptoms that are unresponsive to conservative treatment. Most patients experience symptomatic relief after CTR regardless of the surgical technique. However, direct comparisons of the safety and effectiveness between CTR surgical techniques are limited. The purpose of this randomized controlled trial is to compare the safety and effectiveness of CTR with ultrasound guidance (CTR-US) versus mini-open CTR (mOCTR) in subjects with symptomatic CTS. DESIGN AND METHODS: TUTOR (Trial of Ultrasound guided CTR versus Traditional Open Release) is a randomized controlled trial in which 120 subjects at up to 12 sites in the United States will be randomized (2:1) to receive CTR-US or mOCTR. The primary endpoint of the study is the percentage of patients who return to normal daily activities within 3 days of the procedure. Secondary endpoints of the study are median time to return to normal daily activities, percentage of patients who return to work within 3 days of the procedure, median time to return to work, Boston Carpal Tunnel Questionnaire Symptom Severity Scale (BCTQ-SSS) change score at 3 months, BCTQ Functional Status Scale (BCTQ-FSS) change score at 3 months, Numeric Pain Scale change score at 3 months, EuroQoL-5 Dimension 5-Level (EQ-5D-5L) change score at 3 months, and the incidence of device- or procedure-related adverse events at 3 months. Patient follow-up in this trial will continue for 1 year. ETHICS AND DISSEMINATION: This study was approved by a central institutional review board and ongoing trial oversight will be provided by a data safety monitoring board (DSMB). The authors intend to report the results of this trial at medical conferences and peer-reviewed journals. The outcomes of TUTOR will have important clinical and economic implications for all stakeholders involved in treating patients with CTS. STUDY REGISTRATION: ClinicalTrials.gov (https://clinicaltrials.gov): NCT05405218. LEVEL OF EVIDENCE: 1.

Does Use of a Night Extension Orthosis Improve Outcomes in Patients With Dupuytren Contracture Treated With Injectable Collagenase?

Purpose: Current prescribing information for the treatment of patients with Dupuytren contracture with injectable collagenase Clostridium histolyticum (CCH) recommends use of a night extension orthosis for 4 months after treatment. The present study examines whether this treatment improves the outcomes. Methods: Adult patients with Dupuytren contracture treated with CCH during the study period were eligible for inclusion. The patients were randomized to orthosis or no orthosis groups and were stratified based on the severity of contracture prior to randomization. The orthosis group was fitted postmanipulation with a hand-based custom orthosis that held the treated finger in maximal comfortable extension, and the patients were instructed to wear the orthosis at night for 3 months. The patients were assessed at 7-10 days, 30 days, and 90 days postmanipulation. Orthosis compliance was measured with a survey. The primary outcome measure was improvement in total active extension (TAE), defined as the sum of active metacarpophalangeal (MCP), proximal interphalangeal, and distal interphalangeal joint extension in the treated finger at 90 days after treatment. Secondary outcomes included total active flexion (TAF), Michigan Hand Questionnaire scores, patient satisfaction, and clinical success. Results: Twenty-six patients completed the study, 12 in the orthosis group and 14 in the no orthosis group. The majority of contractures (90%) were primarily through the MCP joint. The patients in both the groups demonstrated significant improvements in TAE at 90-day follow-up (orthosis P = .002, no orthosis P = .001) . The difference in improvement in the median TAE between the 2 groups was not significant (P = .40). There were no significant differences between groups for TAE, TAF, Michigan Hand Questionnaire scores, patient satisfaction, or clinical success at any of the time points assessed (P > .05). Conclusions: In patients with Dupuytren contracture with primarily MCP joint involvement, providing an orthosis after treatment with CCH may not offer a short-term benefit compared with CCH treatment alone in terms of TAE, TAF, or patient-reported outcome measures. Type of study/level of evidence: Therapeutic I.