Long-term Efficacy of Corticosteroid Injection for Carpal Tunnel Syndrome: A Systematic Review.

Carpal tunnel syndrome (CTS) is a debilitating condition that can cause significant morbidity. Corticosteroid injection (CI) is a popular treatment for CTS. Short-term benefits of CI for CTS have been reported, but there is little evidence on long-term outcomes. We performed a systematic review in the PubMed/MEDLINE and Cochrane Library databases to identify studies which reported outcomes of CI for CTS with at least 1-year follow-up. We identified 20 total studies and extracted data on outcomes such as number of patients needing eventual surgery or reinjection, complications, and functional scores. In included studies, 41.6% of patients underwent eventual carpal tunnel release surgery (CTRS), 29% underwent reinjection, there were no major and approximately 34/1133 (3.0%) minor complications, and median/mean time from CI to eventual CTRS ranged from 128 to 446 days. There was disparity on the long-term efficacy of CI for functional outcomes. The evidence indicates that CI is a very low risk procedure that has potential to improve symptoms enough to either prevent or, in most cases, delay the need for further reintervention. However, our conclusions are limited by the heterogeneity of available studies. There is a need for further, high-quality research on this topic.

Cadaver Study on Transoral Thyroid Chondrolaryngoplasty and Transoral Sistrunk Operation, Possibility from Transoral Thyroidectomy.

OBJECTIVE: Transoral approaches in surgery are gaining global popularity. Transoral endoscopic and robotic thyroidectomies are well established due to the benefit of being truly scarless. Thyroid chondrolaryngoplasty reduces protrusion of the thyroid notch in transgender patients. The Sistrunk operation involves removal of the thyroglossal cyst and the central portion of the hyoid bone. In this cadaveric study, we developed a transoral thyroidectomy approach and assessed the feasibility of applying this technique to thyroid chondrolaryngoplasty and Sistrunk operation with the proper usage of a special endoscopic burr. METHODS: We performed surgery using the transoral vestibular approach with 13 fresh-frozen human cadavers. Unlike transoral thyroid surgery, which requires high-resolution detailed anatomical view, this technique uses a 5-mm 30-degree endoscope with a 5-mm central port. A smaller central port can reduce the risk of mental nerve paresthesia. A special endoscopic burr for functional endoscopic sinus surgery is used to thin the thyroid notch cartilage and cut the central portion of the hyoid bone. RESULTS: We successfully performed transoral thyroid chondrolaryngoplasty and transoral Sistrunk operation in 13 cadavers. CONCLUSION: Transoral chondrolaryngoplasty and transoral Sistrunk operation are feasible for transgender or thyroglossal cyst patients. It offers the additional benefit of being a scarless surgery and could play a promising role in minimally invasive thyroid surgeries. Proper use of an endoscopic drilling burr to thin thyroid notch cartilage and cutting the central portion of the hyoid bone can make transoral thyroid chondrolaryngoplasty and transoral Sistrunk operation safe and feasible .

Modulation of taxane binding to tubulin curved and straight conformations by systematic 3'N modification provides for improved microtubule binding, persistent cytotoxicity and in vivo potency.

The taxane class of microtubule stabilizers are some of the most effective and widely used chemotherapeutics. The anticancer activity of taxanes arises from their ability to induce tubulin assembly by selectively recognizing the curved (c-) conformation in unassembled tubulin as compared to the straight (s-) conformation in assembled tubulin. We first designed and synthesized a series of 3'N-modified taxanes bearing covalent groups. Instead of discovering covalent taxanes, we found a series of non-covalent taxanes 2, in which the 3'N side chain was found to be essential for cytotoxicity due to its role in locking tubulin in the s-conformation. A representative compound bearing an acrylamide moiety (2h) exhibited increased binding affinity to the unassembled tubulin c-conformation and less cytotoxicity than paclitaxel. Further exploration of chemical space around 2h afforded a new series 3, in which derivatives such as 3l bind more tightly to both the s- and c-conformations of tubulin compared to paclitaxel, leading to more efficient promotion of tubulin polymerization and a greater persistence of in vitro efficacy against breast cancer cells after drug washout. Although 3l also had improved in vivo potency as compared to paclitaxel, it was also associated with increased systemic toxicity that required localized, intratumoral injection to observe potent and prolonged antitumor efficacy.

An anti-HER2 biparatopic antibody that induces unique HER2 clustering and complement-dependent cytotoxicity.

Human epidermal growth factor receptor 2 (HER2) is a receptor tyrosine kinase that plays an oncogenic role in breast, gastric and other solid tumors. However, anti-HER2 therapies are only currently approved for the treatment of breast and gastric/gastric esophageal junction cancers and treatment resistance remains a problem. Here, we engineer an anti-HER2 IgG1 bispecific, biparatopic antibody (Ab), zanidatamab, with unique and enhanced functionalities compared to both trastuzumab and the combination of trastuzumab plus pertuzumab (tras + pert). Zanidatamab binds adjacent HER2 molecules in trans and initiates distinct HER2 reorganization, as shown by polarized cell surface HER2 caps and large HER2 clusters, not observed with trastuzumab or tras + pert. Moreover, zanidatamab, but not trastuzumab nor tras + pert, elicit potent complement-dependent cytotoxicity (CDC) against high HER2-expressing tumor cells in vitro. Zanidatamab also mediates HER2 internalization and downregulation, inhibition of both cell signaling and tumor growth, antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP), and also shows superior in vivo antitumor activity compared to tras + pert in a HER2-expressing xenograft model. Collectively, we show that zanidatamab has multiple and distinct mechanisms of action derived from the structural effects of biparatopic HER2 engagement.

The Combination of Fractional Tendon Lengthening and the Wide Awake, Local Anesthesia, No Tourniquet Technique for Secondary Tendon Reconstruction.

Rupture is a major concern after primary flexor tendon repair. The predominant treatment for rupture of the primary repair is immediate surgical exploration and repeat repair. However, repeat repair is challenging, including achieving ideal tension in the flexor mechanism. Further, immediate repeat repair is associated with poor outcomes, particularly in the small finger. As such, there is a need to improve both the technique and outcomes of repeat repair of primary flexor tendon rupture. We present a case of primary flexor tendon repair rupture treated with a novel combination of fractional tendon lengthening and the wide awake, local anesthesia, no tourniquet technique. A combination of these techniques has multiple benefits. An intraoperative, dynamic assessment of the digits enables immediate optimization of the repair. Further, these techniques allow for better intraoperative patient education and communication, increasing the likelihood of adherence to postoperative therapy and better overall outcomes.

The Treatment of Complex Extremity Wounds Using External Tissue Expansion: A Case Series.

SUMMARY: The goal of wound reconstruction is the approximation of soft tissue and re-establishment of an acceptable appearance with minimal risk of complications. For large wound closure in the extremities, skin graft and flap reconstruction are common treatments but are associated with a variety of complications. Comparatively, tissue expansion can provide the opportunity to reconstruct large wounds with native, durable, and sensate tissue without significant donor site morbidity. External tissue expansion is less invasive and avoids complications associated with internal expansion. The authors treated 11 patients with varying extremity wound types and sizes with an external tissue expansion device. Patient age ranged from 18 to 68 years with an average age of 43.7 years (SD, ± 13.1 years). Average wound surface area was approximately 235 cm 2 (SD, ± 135.3 cm 2 ). Devices were affixed and left for 7 to 11 days before closure of the wounds. Outcomes were assessed at 2 to 36 weeks postoperative follow-up. All wounds were fully closed after treatment without need for secondary reconstructive procedures. No patient experienced major complications. All patients demonstrated intact sensation within the area of reconstruction equivalent to surrounding tissues. External tissue expansion, an excellent treatment option in extremity reconstruction, is efficacious and associated with lower complication rates compared with internal tissue expansion, skin grafts, and flap reconstruction. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

How Are Radial Height and Radial Shortening Defined in the Treatment of Distal Radius Fractures? A Critical Review.

BACKGROUND: Radial height is a radiographic parameter used to guide the treatment of distal radius fractures. However, it is often used synonymously with other terms, and there are substantial discrepancies in its measurement/definition. These discrepancies can alter the measurement of radial height and affect treatment decisions. The purpose of this review is to identify the different definitions of radial height in the literature relevant to distal radius fractures. METHODS: A literature review was conducted in the PubMed/MEDLINE database from inception to 2022. Full-length, English-language studies that pertained to distal radius fractures and reported radial height as a recorded measurement were included. The method of radial height measurement (definition) was extracted from included studies. Level of evidence was determined by the Oxford Centre for Evidence-based Medicine Levels of Evidence tool. RESULTS: A total of 385 studies were identified. Of these, 183 (47.5%) did not provide a definition for radial height. Of the studies that defined radial height, 50.9% (103/202) measured radial height from the radial styloid to the distal ulna, 10.9% (22/202) measured from the radial styloid to the distal radius, and 29.2% (59/202) were "other" definitions. CONCLUSIONS: There is substantial discrepancy in the way that radial height is measured and reported. We advocate for a standardized measurement of radial height (synonymous with radial length) from the radial styloid to the distal ulnar articular surface. Radial shortening is a different measurement and requires comparison with a reference value.

Sperm DNA methylome abnormalities occur both pre- and post-treatment in men with Hodgkin disease and testicular cancer.

BACKGROUND: Combination chemotherapy has contributed to increased survival from Hodgkin disease (HD) and testicular cancer (TC). However, questions concerning the quality of spermatozoa after treatment have arisen. While studies have shown evidence of DNA damage and aneuploidy in spermatozoa years following anticancer treatment, the sperm epigenome has received little attention. Our objectives here were to determine the impact of HD and TC, as well as their treatments, on sperm DNA methylation. Semen samples were collected from community controls (CC) and from men undergoing treatment for HD or TC, both before initiation of chemotherapy and at multiple times post-treatment. Sperm DNA methylation was assessed using genome-wide and locus-specific approaches. RESULTS: Imprinted gene methylation was not affected in the sperm of HD or TC men, before or after treatment. Prior to treatment, using Illumina HumanMethylation450 BeadChip (450 K) arrays, a subset of 500 probes was able to distinguish sperm samples from TC, HD and CC subjects; differences between groups persisted post-treatment. Comparing altered sperm methylation between HD or TC patients versus CC men, twice as many sites were affected in TC versus HD men; for both groups, the most affected CpGs were hypomethylated. For TC patients, the promoter region of GDF2 contained the largest region of differential methylation. To assess alterations in DNA methylation over time/post-chemotherapy, serial samples from individual patients were compared. With restriction landmark genome scanning and 450 K array analyses, some patients who underwent chemotherapy showed increased alterations in DNA methylation, up to 2 to 3 years post-treatment, when compared to the CC cohort. Similarly, a higher-resolution human sperm-specific assay that includes assessment of environmentally sensitive regions, or "dynamic sites," also demonstrated persistently altered sperm DNA methylation in cancer patients post-treatment and suggested preferential susceptibility of "dynamic" CpG sites. CONCLUSIONS: Distinct sperm DNA methylation signatures were present pre-treatment in men with HD and TC and may help explain increases in birth defects reported in recent clinical studies. Epigenetic defects in spermatozoa of some cancer survivors were evident even up to 2 years post-treatment. Abnormalities in the sperm epigenome both pre- and post-chemotherapy may contribute to detrimental effects on future reproductive health.

Continuous Passive Elongation Through an External Fixator: A Versatile and Beneficial Adjunct Technique to Treat Severe and Recurrent Cases of Dupuytren Contracture.

Dupuytren disease and its associated digit contracture often negatively impact the quality of life for patients. Severe cases of Dupuytren contracture and symptom recurrence are both difficult for hand surgeons to treat. Improved treatment options are therefore needed. One method is continuous passive elongation (CPE). In CPE, a device is affixed to the digit, which applies a continuous extending force to pull the affected finger out of flexion. Multiple external fixators used to induce CPE have been reported. However, a low-profile, hand-specific external fixator, the DigiFix, provides benefits over previously reported devices. We present the technique of CPE using DigiFix as a beneficial and versatile adjunct treatment for severe and recurrent cases of Dupuytren contracture.

Longitudinal Tear of the Central Slip Causing Painful and Unusual Snapping of the Finger: A Case Report.

The most common cause for catching or snapping in the finger is stenosing tenosynovitis, that is, trigger finger. Although less common, snapping can also occur as a result of extensor mechanism injury. Among these injuries, sagittal band rupture is most common and leads to snapping at the metacarpophalangeal joint. Snapping at the proximal interphalangeal (PIP) joint is rare with only 4 reported cases; reported mechanisms of PIP joint snapping include retinacular ligament injury or tendon impingement. We present a unique case of painful finger snapping at the PIP joint as a result of longitudinal tear of the central slip, leading to sudden subluxation of one-half of the central slip and conjoint lateral band with flexion of the PIP joint.

Targeting the tubulin C-terminal tail by charged small molecules.

The disordered tubulin C-terminal tail (CTT), which possesses a higher degree of heterogeneity, is the target for the interaction of many proteins and cellular components. Compared to the seven well-described binding sites of microtubule-targeting agents (MTAs) that localize on the globular tubulin core, tubulin CTT is far less explored. Therefore, tubulin CTT can be regarded as a novel site for the development of MTAs with distinct biochemical and cell biological properties. Here, we designed and synthesized linear and cyclic peptides containing multiple arginines (RRR), which are complementary to multiple acidic residues in tubulin CTT. Some of them showed moderate induction and promotion of tubulin polymerization. The most potent macrocyclic compound 1f was found to bind to tubulin CTT and thus exert its bioactivity. Such RRR containing compounds represent a starting point for the discovery of tubulin CTT-targeting agents with therapeutic potential.

The Microtubule Destabilizer Eribulin Synergizes with STING Agonists to Promote Antitumor Efficacy in Triple-Negative Breast Cancer Models.

Eribulin is a microtubule destabilizer used in the treatment of triple-negative breast cancer (TNBC). Eribulin and other microtubule targeted drugs, such as the taxanes, have shared antimitotic effects, but differ in their mechanism of microtubule disruption, leading to diverse effects on cellular signaling and trafficking. Herein, we demonstrate that eribulin is unique from paclitaxel in its ability to enhance expression of the immunogenic cytokine interferon beta (IFNß) in combination with STING agonists in both immune cells and TNBC models, including profound synergism with ADU-S100 and E7766, which are currently undergoing clinical trials. The mechanism by which eribulin enhances STING signaling is downstream of microtubule disruption and independent of the eribulin-dependent release of mitochondrial DNA. Eribulin did not override the requirement of ER exit for STING activation and did not inhibit subsequent STING degradation; however, eribulin significantly enhanced IRF3 phosphorylation and IFNß production downstream of the RNA sensing pathway that converges on this transcription factor. Additionally, we found that eribulin enhanced the population of activated CD4+ T-cells in vivo when combined with either a STING agonist or tumor, demonstrating the ability to function as an immune adjuvant. We further interrogated the combination of eribulin with ADU-S100 in the MMTV-PyVT spontaneous murine mammary tumor model where we observed significant antitumor efficacy with combination treatment. Together, our findings demonstrate that microtubule targeted chemotherapeutics have distinct immunological effects and that eribulin's ability to enhance innate immune sensing pathways supports its use in combination with immunotherapies, such as STING agonists, for the more effective treatment of TNBC and other malignancies.

External tissue expansion to salvage failed scalp and forehead reconstruction: a case report.

The reconstruction of forehead and scalp defects is a difficult task. Common reconstructive methods are associated with multiple complications and may fail, requiring a difficult second surgery. We present the use of external tissue expansion as a method to achieve effective closure of a failed scalp and forehead reconstruction.

Advanced Paternal Age and Future Generations.

Paternal age at conception has been increasing. In this review, we first present the results from the major mammalian animal models used to establish that increasing paternal age does affect progeny outcome. These models provide several major advantages including the possibility to assess multi- transgenerational effects of paternal age on progeny in a relatively short time window. We then present the clinical observations relating advanced paternal age to fertility and effects on offspring with respect to perinatal health, cancer risk, genetic diseases, and neurodevelopmental effects. An overview of the potential mechanism operating in altering germ cells in advanced age is presented. This is followed by an analysis of the current state of management of reproductive risks associated with advanced paternal age. The numerous challenges associated with developing effective, practical strategies to mitigate the impact of advanced paternal age are outlined along with an approach on how to move forward with this important clinical quandary.

Evaluation of a Mobile Health App Offering Fertility Information to Male Patients With Cancer: Usability Study.

BACKGROUND: Cancer and its treatment can adversely affect male fertility. Although sperm banking is an effective fertility preservation method, there is an unmet need for information and support surrounding these issues. OBJECTIVE: This usability study evaluates a mobile health app providing male patients with cancer with credible information about the impact of cancer and its treatment on fertility and fertility preservation. METHODS: Participants were recruited by a market research firm. Eligibility criteria were men who were 18-45 years of age, identified as male, diagnosed with new or recurring cancer within 1 year, not in fertility treatment, able to read and write in English or French, and had internet access. App usage was tracked for 2 weeks. After app use, participants provided qualitative feedback about their experiences using the app as well as quantitative data regarding their sperm banking decisions, perceived change in fertility knowledge, evaluation of the app's information on the Information Assessment Method, and the app's quality on the user version of the Mobile App Rating Scale. RESULTS: The sample included 40 men aged 27-45 years. Approximately 68% (27/40) indicated that no one had previously spoken to them about the impact of cancer on fertility, and 85% (34/40) had not received information on fertility preservation. Approximately 83% (33/40) found the app's information relevant, and 85% (34/40) said that it increased their fertility knowledge. Approximately 23% (9/40) made a decision about sperm banking after using the app. Participants rated the app's quality highly, with mean scores (out of 5) of 4.14 for information, 4.06 for functionality, 3.84 for aesthetics, and 3.63 for engagement. CONCLUSIONS: The app proved to be useful for male patients with cancer, suggesting that mobile health resources could be beneficial to incorporate into clinical care to enable shared decision-making about fertility.

Re-evaluation of the Fijianolide/Laulimalide Chemotype Suggests an Alternate Mechanism of Action for C-15/C-20 Analogs.

Herein, we report on naturally derived microtubule stabilizers with activity against triple negative breast cancer (TNBC) cell lines, including paclitaxel, fijianolide B/laulimalide (3), fijianolide B di-acetate (4), and two new semisynthetic analogs of 3, which include fijianolide J (5) and fijianolide L (6). Similar to paclitaxel, compound 3 demonstrated classic microtubule stabilizing activity with potent (GI50 = 0.7-17 nM) antiproliferative efficacy among the five molecularly distinct TNBC cell lines. Alternatively, compounds 5 or 6, generated from oxidation of C-20 or C-15 and C-20 respectively, resulted in a unique profile with reduced potency (GI50 = 4-9 µM), but improved efficacy in some lines, suggesting a distinct mechanism of action. The C-15, C-20 di-acetate, and dioxo modifications on 4 and 6 resulted in compounds devoid of classic microtubule stabilizing activity in biochemical assays. While 4 also had no detectable effect on cellular microtubules, 6 promoted a reorganization of the cytoskeleton resulting in an accumulation of microtubules at the cell periphery. Compound 5, with a single C-20 oxo substitution, displayed a mixed phenotype, sharing properties of 3 and 6. These results demonstrate the importance of the C-15/C-20 chiral centers, which appear to be required for the potent microtubule stabilizing activity of this chemotype and that oxidation of these sites promotes unanticipated cytoskeletal alterations that are distinct from classic microtubule stabilization, likely through a distinct mechanism of action.

External Tissue Expansion in Complex Extremity Reconstruction.

Skin grafting and flap-based reconstruction have been the conventional treatments for complex extremity wounds. However, these methods can be associated with relatively high complication rates and involve increasing levels of complexity. External tissue expansion has recently emerged as an attractive alternative to its conventional counterparts. It is a technically simple and low-morbidity technique for complex wound reconstruction. This article provides a review of internal and external tissue expansion with a focus on the evolution, indications, and recent successes of external expansion for soft tissue coverage.

Synostosis of the interphalangeal joint: an uncommon cause of post-fracture digital stiffness.

Loss of motion and stiffness after fracture of the digits are most commonly a result of soft tissue contracture and adhesions. However, stiffness can also have a bony etiology. We present a case of synostosis of the thumb interphalangeal joint after non-operative treatment of a closed fracture.

Chronic Nicotine Exposure Minimally Affects Rat Supraspinatus Tendon Properties and Bone Microstructure.

Cigarette smoking is the largest cause of preventable deaths, and a known risk factor for musculoskeletal issues including rotator cuff tendon tears. Tendon degeneration is believed to be due in part to changes in tendon cell health and collagen structure. Several studies have demonstrated that exposure to nicotine negatively impacts tendon healing, but surprisingly, nicotine exposure was shown to increase rat supraspinatus tendon stiffness. In order to address this seeming contradiction, the objective of this study was to comprehensively investigate the effects of long-term (18 weeks) exposure of nicotine on tendon-to-bone microstructural properties in a rat model. We hypothesized that long term subcutaneous nicotine delivery would lead to diminished tendon mechanical properties, decreased bone microstructure in the humeral head, and altered tendon cell morphology compared to age-matched control rats receiving saline. Results demonstrated a small decrease in tendon size and stiffness, with decreased cell density in the tendon midsubstance. However, no differences were found in the enthesis fibrocartilage or in the underlying subchondral or trabecular bone. In conclusion, our study revealed limited effects of nicotine on the homeostatic condition of the supraspinatus tendon, enthesis, and underlying bone. Future studies are needed to ascertain effects of other components of tobacco products.

Surgery Performed by Supervised Trainees Does not Affect Outcome in First Metatarsophalangeal Joint (MTPJ) Arthrodesis.

First metatarsophalangeal joint (MTPJ) arthrodesis is an index procedure for orthopedic trainees in the United Kingdom. There is an absence of evidence as to the outcome of surgery when performed by supervised trainees. The aim of this study is to compare the incidence of fusion, complication rate and radiographic outcomes in first MTPJ arthrodesis performed by supervised orthopedic trainees with consultants. This is a retrospective cohort study of 117 patients undergoing first MTPJ arthrodesis from August 2015 to December 2017 in our institute for hallux valgus (HV) deformity with first MPTJ arthrosis or for hallux rigidus. Patients were followed to a minimum of 1-year postsurgery and were given an open appointment thereafter. In the hallux rigidus group, there was no significant difference between the complication rate (p = .477), incidence of fusion (p = .663), postoperatively HVA (p = .763), and postoperative intermetatarsal angle (p = .539) between trainees and consultants. There was a significant difference in mean tourniquet time (p = .563) between trainees and consultants. In the hallux valgus group, there was no significant difference in the complication rate (p = .519), incidence of fusion (p = .786), tourniquet time (p = .075), postoperative HVA (p = .423), and postoperative intermetatarsal angle (p = .143) between the trainees and consultants. This is the first MTPJ fusion series that demonstrates good results can be achieved by supervised trainees performing the procedure. This would suggest that first MTPJ arthrodesis remains an opportunity for trainees to continue learning to perform under supervision whilst ensuring no change in outcome for the patient.