Molecular Characteristics of Cisplatin-Induced Ototoxicity and Therapeutic Interventions.

Cisplatin is a commonly used chemotherapeutic agent with proven efficacy in treating various malignancies, including testicular, ovarian, cervical, breast, bladder, head and neck, and lung cancer. Cisplatin is also used to treat tumors in children, such as neuroblastoma, osteosarcoma, and hepatoblastoma. However, its clinical use is limited by severe side effects, including ototoxicity, nephrotoxicity, neurotoxicity, hepatotoxicity, gastrointestinal toxicity, and retinal toxicity. Cisplatin-induced ototoxicity manifests as irreversible, bilateral, high-frequency sensorineural hearing loss in 40-60% of adults and in up to 60% of children. Hearing loss can lead to social isolation, depression, and cognitive decline in adults, and speech and language developmental delays in children. Cisplatin causes hair cell death by forming DNA adducts, mitochondrial dysfunction, oxidative stress, and inflammation, culminating in programmed cell death by apoptosis, necroptosis, pyroptosis, or ferroptosis. Contemporary medical interventions for cisplatin ototoxicity are limited to prosthetic devices, such as hearing aids, but these have significant limitations because the cochlea remains damaged. Recently, the U.S. Food and Drug Administration (FDA) approved the first therapy, sodium thiosulfate, to prevent cisplatin-induced hearing loss in pediatric patients with localized, non-metastatic solid tumors. Other pharmacological treatments for cisplatin ototoxicity are in various stages of preclinical and clinical development. This narrative review aims to highlight the molecular mechanisms involved in cisplatin-induced ototoxicity, focusing on cochlear inflammation, and shed light on potential antioxidant and anti-inflammatory therapeutic interventions to prevent or mitigate the ototoxic effects of cisplatin. We conducted a comprehensive literature search (Google Scholar, PubMed) focusing on publications in the last five years.

Role of mitochondrial dysfunction and oxidative stress in sensorineural hearing loss.

Sensorineural hearing loss (SNHL) can either be genetically inherited or acquired as a result of aging, noise exposure, or ototoxic drugs. Although the precise pathophysiological mechanisms underlying SNHL remain unclear, an overwhelming body of evidence implicates mitochondrial dysfunction and oxidative stress playing a central etiological role. With its high metabolic demands, the cochlea, particularly the sensory hair cells, stria vascularis, and spiral ganglion neurons, is vulnerable to the damaging effects of mitochondrial reactive oxygen species (ROS). Mitochondrial dysfunction and consequent oxidative stress in cochlear cells can be caused by inherited mitochondrial DNA (mtDNA) mutations (hereditary hearing loss and aminoglycoside-induced ototoxicity), accumulation of acquired mtDNA mutations with age (age-related hearing loss), mitochondrial overdrive and calcium dysregulation (noise-induced hearing loss and cisplatin-induced ototoxicity), or accumulation of ototoxic drugs within hair cell mitochondria (drug-induced hearing loss). In this review, we provide an overview of our current knowledge on the role of mitochondrial dysfunction and oxidative stress in the development of SNHL caused by genetic mutations, aging, exposure to excessive noise, and ototoxic drugs. We also explore the advancements in antioxidant therapies for the different forms of acquired SNHL that are being evaluated in preclinical and clinical studies.

Which Components of the Simple Shoulder Test Show Improvement After Scapulothoracic Fusion for Recalcitrant Scapular Winging? Clinical Results at a Minimum of 5 Years of Follow-up.

BACKGROUND: Scapular winging is an uncommon but important cause of shoulder pain and disability. Surgical management can include soft tissue procedures such as split pectoralis major transfer, the Eden-Lange procedure, or a triple tendon transfer. When these procedures do not alleviate symptomatic winging or are inappropriate, scapulothoracic fusion is an alternative, but data on its longer-term effectiveness are sparse. QUESTIONS/PURPOSES: (1) What changes in outcome scores were observed (VAS, Single Assessment Numeric Evaluation [SANE], and Simple Shoulder Test [SST] scores), and what proportion of the patients improved by an amount larger than the minimum clinically important difference (MCID) for the outcome tool in question? (2) Which components of the SST are patients able to perform at a minimum of 5 years? (3) What complications occurred after surgery? METHODS: We performed a retrospective study in a single, large, urban referral medical center of patients who underwent scapulothoracic fusion. Between January 2011 and November 2016, 15 patients underwent scapulothoracic fusion to treat symptomatic scapular winging. Only patients with nondystrophic etiology were included in the analysis (n = 13). Of the 13 remaining patients, one patient was lost to follow-up and another patient died during data collection, leaving 11 patients for the final analysis. Six patients had brachial plexus injuries affecting multiple nerve roots and periscapular muscles, and five had persistent symptoms despite prior tendon transfer. The median age of the patients was 43 years (range 20 to 67 years), and there were six male and five female patients. All patients had a minimum of 5 years of follow-up. There was a median follow-up of 79 months (range 61 to 128 months). The VAS pain score (range 0 to 10, higher scores represent more pain; MCID = 2), SST score (range 0 to 12, higher scores represent less pain and better shoulder function; MCID = 2.3), and SANE score (range 0 to 100, higher scores represent better shoulder function; MCID = 28) were recorded before surgery and at the most recent follow-up. We compared scores from before surgery with those taken at the most recent follow-up and ascertained the proportion of patients whose improvement exceeded the MCID. The number of patients achieving fusion (as confirmed by a CT image), complications, and reoperations was recorded via a record review as well as direct patient query by telephone. RESULTS: The median VAS pain score improved from 7 (range 3 to 10) preoperatively to 3 (range 2 to 5) at the latest follow-up (p < 0.001). The median SANE score improved from 30 (range 0 to 60) preoperatively to 65 (range 40 to 85) at the latest follow-up (p < 0.001). The median SST score improved from 0 (range 0 to 9) to 8 (range 5 to 10) at the latest follow-up (p < 0.001). Ten of 11 patients had improvements exceeding the MCID for VAS, six of 11 had improvements for SANE scores, and nine of 11 had improvements for SST. Preoperative to postoperative improvements in these components of the SST were seen (responses of "yes"): comfort at rest (three of 11 improved to 11 of 11; p < 0.001), sleep comfortably (three of 11 improved to 11 of 11; p < 0.001), place coin on shelf (two of 11 improved to 10 of 11; p < 0.001), lift 1 pound above shoulder (two of 11 improved to eight of 11; p = 0.03), and carry 20 pounds with the arm at side (one of 11 improved to nine of 11; p < 0.001). All 11 patients had successful fusion noted on CT images. There were three complications (progression of glenohumeral arthritis, broken wires, and perioperative chest tube placement) and one reoperation for progression of glenohumeral arthritis with subsequent total shoulder arthroplasty. CONCLUSION: Patients with recalcitrant symptomatic scapular winging often undergo an exhaustive course of clinical examinations, diagnostic tests, physical therapy, and multiple surgical procedures. Those with brachial plexus palsy with involvement of multiple nerves may continue to have symptoms despite nonoperative management and subsequent soft tissue tendon transfers. Scapulothoracic fusion could be considered for patients with persistent pain and decreased function because of recalcitrant scapular winging who are either not candidates for the procedure or have persistent symptoms despite prior soft tissue procedures. LEVEL OF EVIDENCE: Level IV, therapeutic study.

The minimal clinically important differences of the Simple Shoulder Test are different for different arthroplasty types.

BACKGROUND: Preoperative and postoperative patient self-reported measures are the key to understanding the benefit of shoulder arthroplasty for patients with different diagnoses and having different surgical approaches. The minimal clinically important difference (MCID) for patient-reported outcomes such as the Simple Shoulder Test (SST) is often used to document the amount of improvement that is of importance to the patient; however, the MCID may differ for different types of shoulder arthroplasty. The objective of this study was to report the MCID of the SST and the MCID of the percentage of maximal possible improvement (%MPI) for 5 different arthroplasty types. METHODS: Eight hundred eighty-seven patients undergoing shoulder arthroplasty with preoperative SST scores, 2-year postoperative SST scores, and patient satisfaction were included. The sample comprised 368 patients undergoing anatomic total shoulder arthroplasty (aTSA), 330 patients undergoing ream-and-run arthroplasty (R&R), 80 patients undergoing reverse total shoulder arthroplasty (rTSA), 53 patients undergoing cuff tear arthropathy arthroplasty, and 56 patients undergoing hemiarthroplasty. For each type of arthroplasty, the anchor-based method was used for calculating the MCID for both absolute SST scores and %MPI. RESULTS: Significant improvements in SST values were seen for all arthroplasty types. The MCID for SST change was 2.3 overall but ranged from 1.6 for aTSA, to 2.6 for R&R, to 3.7 for rTSA. The MCID for %MPI was 32% overall but ranged from 22% for aTSA to 42% for hemiarthroplasty. The percentage of patients exceeding the MCID threshold was highest for aTSA at 96% and lowest for hemiarthroplasty at 61%. CONCLUSION: The same MCID value may not be appropriate for different types of shoulder arthroplasty. This study reports MCID thresholds that can be used when assessing the effectiveness for each of the common types of shoulder arthroplasty.

The Safe and Effective Use of Plant-Based Diets with Guidelines for Health Professionals.

Plant-based diets, defined here as including both vegan and lacto-ovo-vegetarian diets, are growing in popularity throughout the Western world for various reasons, including concerns for human health and the health of the planet. Plant-based diets are more environmentally sustainable than meat-based diets and have a reduced environmental impact, including producing lower levels of greenhouse gas emissions. Dietary guidelines are normally formulated to enhance the health of society, reduce the risk of chronic diseases, and prevent nutritional deficiencies. We reviewed the scientific data on plant-based diets to summarize their preventative and therapeutic role in cardiovascular disease, cancer, diabetes, obesity, and osteoporosis. Consuming plant-based diets is safe and effective for all stages of the life cycle, from pregnancy and lactation, to childhood, to old age. Plant-based diets, which are high in fiber and polyphenolics, are also associated with a diverse gut microbiota, producing metabolites that have anti-inflammatory functions that may help manage disease processes. Concerns about the adequate intake of a number of nutrients, including vitamin B12, calcium, vitamin D, iron, zinc, and omega-3 fats, are discussed. The use of fortified foods and/or supplements as well as appropriate food choices are outlined for each nutrient. Finally, guidelines are suggested for health professionals working with clients consuming plant-based diets.

Imaging update on soft tissue sarcoma.

Soft tissue sarcomas (STS) are rare tumours presenting as soft tissue lumps. Ultrasound is often the primary modality for the initial assessment, with MRI the mainstay for lesion characterisation. PET/CT along with other emerging MRI sequences are used in certain situations as an adjunct and problem solving tool in STS staging and assessment of disease recurrence. Recent advances include the promise of whole body MRI, hybrid PET/MRI, diffusion weighted imaging, dynamic contrast enhanced MRI and advances in artificial intelligence. This article discusses current concepts in extremity STS imaging and highlights recent advances.

Phosphaturic mesenchymal tumors: radiological aspects and suggested imaging pathway.

Phosphaturic mesenchymal tumors (PMTs) are rare mesenchymal neoplasms of soft tissue or bone origin that can give rise to a challenge in diagnostic imaging. These tumors are frequently associated with tumor-induced osteomalacia, also called oncogenic osteomalacia, which is a rare paraneoplastic syndrome characterized by ectopic secretion of fibroblast growth factor 23, a hormone that regulates serum phosphate level. PMTs show polymorphic features on both radiological findings and histological examination, causing problems in diagnosis owing to their similarity with other mesenchymal tumors. Thus, this paper aims to describe radiological aspects of PMTs and suggest an imaging pathway for accurate diagnosis throughout the evidence from the literature review.

Unicortical sternal graft reconstruction for anterior sternoclavicular joint instability.

Sternoclavicular joint (SCJ) injury represents 3%-5% of all shoulder girdle injuries, yet can produce significant pain and disability. While conservative management improves symptoms in most cases, surgical intervention may be indicated for patients with symptoms recalcitrant to nonoperative treatment. A wide range of surgical stabilisation techniques is documented in the literature; however, the scarcity of SCJ pathology has hindered development of a 'gold standard'.We present a minimalistic medial clavicle osteoplasty and SCJ reconstruction using semitendinosus autograft anchored with unicortical sternal tunnels in the 54 years old with chronic SCJ instability. This technique can be performed safely, resulting in joint stability and pain reduction, while avoiding risks and complications noted in the literature with other techniques.

Mirogabalin as a Novel Gabapentinoid for the Treatment of Chronic Pain Conditions: An Analysis of Current Evidence.

Neuropathic pain is a challenge for physicians to treat and often requires a multimodal approach with both pharmacologic and lifestyle interventions. Mirogabalin, a potent, selective ligand of the α2δ-1 and α2δ-2 subunits of voltage-gated calcium channels (VGCCs), provides analgesia by inhibiting neurotransmitter release at the presynaptic end of the neuron. Mirogabalin offers more sustained analgesia than its gabapentinoid counterparts in addition to a wider safety margin for adverse events. Recent clinical trials of mirogabalin have demonstrated both efficacy and tolerability of the drug for the treatment of diabetic peripheral neuropathic pain and postherpetic neuralgia, leading to its approval in Japan. While still not yet FDA approved, mirogabalin is still in its infancy and offers potential into the treatment of neuropathic pain and its associated comorbidities.

Non-neoplastic Soft Tissue Tumors and Tumor-like Lesions.

Clinicians are commonly faced with patients presenting with a solitary palpable soft tissue mass. Most soft tissue lesions are benign, and not every mass is due to a neoplastic process. Many pathologies can mimic a malignant tumor. Despite appropriate clinicoradiologic assessment, these lesions can be mistaken for a soft tissue sarcoma and can lead to multiple investigations or an intervention, inconveniencing patients and leading to an increased health care cost. With the relevant clinical history, clinical examination, and specific imaging characteristics, the diagnosis can be narrowed. We present a pictorial review of soft tissue sarcoma mimics with guidance on appropriate differential diagnoses.

Ream and run and total shoulder: patient and shoulder characteristics in five hundred forty-four concurrent cases.

PURPOSE: Total shoulder (TSA) is commonly used to treat arthritic shoulders with intact rotator cuffs; however, some patients choose a ream and run (RnR) to avoid the potential risks and limitations of a prosthetic glenoid component. Little is known about how patients selecting each of these two procedures compare and contrast. METHODS: We analyzed the patient characteristics, shoulder characteristics, and two year clinical outcomes of 544 patients having RnR or TSA at the same institution during the same six year period. RESULTS: Patients selecting the RnR were more likely to be male (92.0% vs. 47.0%), younger (58 ± 9 vs. 67 ± 10 years), married (83.2% vs. 66.8%), from outside of our state (51.7% vs. 21.7%), commercially insured (59.1% vs. 25.2%), and to have type B2 glenoids (46.0% vs. 27.8%) as well as greater glenoid retroversion (19 ± 11 vs. 15 ± 11 degrees) (p < .001). The average two year SST score for the RnRs was 10.0 ± 2.6 vs. 9.5 ± 2.7 for the TSAs. The percent of maximum possible improvement (%MPI) for the RnRs averaged 72 ± 39% vs. 73 ± 29% for the TSAs. Patients with work-related shoulder problems had lower two year SSTs and lower %MPIs. Younger patients having TSAs did less well than older patients. Female patients having RnRs did less well than those having TSAs (p < 0.001). CONCLUSIONS: This investigation highlights important characteristics of patients selecting the RnR and the TSA for glenohumeral arthritis. Excellent outcomes can be achieved for appropriately selected patients having either procedure.

Patient Outcomes Following Micropulse Transscleral Cyclophotocoagulation: Intermediate-term Results.

PURPOSE: To report the safety and efficacy outcomes following micropulse transscleral cyclophotocoagulation (MPTSCPC) procedure in patients with uncontrolled glaucoma. MATERIALS AND METHODS: Longitudinal retrospective cohort, multicenter study. Patients with different types of glaucoma who underwent MPTSCPC with P3 probe between July 2015 and May 2017. Patients were treated by different glaucoma specialists from 5 different locations (Tulane Study Group). Data on preoperative characteristics, surgical procedure(s) performed, and postoperative outcomes were collected and analyzed. Statistical analysis using logistic regression and Kaplan-Meier analysis was performed with Stata software. Intraoperative and postoperative complications, intraocular pressure, visual acuity, need for incisional glaucoma surgery, need for repeat micropulse, and number of topical medications were studied. RESULTS: One hundred ninety-seven eyes from 161 patients were included. Median follow-up was 12 months [interquartile range (IQR), 6 to 14]. Glaucoma diagnosis included 141 primary open-angle glaucoma (POAG), 8 neovascular glaucoma, and 12 others. The total success rate was 71%. Two percent (4 patients) developed postoperative cystoid macular edema. Preoperative mean intraocular pressure (SD) was 22±9 and 16±6 mm Hg at last follow-up (P<0.001). Median preoperative logMAR visual acuity (IQR) was 0.4 (0.2 to 1.0) and 0.3 (0.2 to 1.0) at last follow-up (P=0.65, Wilcoxon signed-rank test). Median number (IQR) of topical medications was 3 (1 to 4) preoperative and 2 (1 to 3) at last follow-up (P<0.001). Kaplan-Meier analysis indicated 90% of patients free from repeat MPTSCPC at 12 months. Multivariable logistic regression identified 3 significant independent predictors of total success: diagnosis (P=0.011) (POAG), previous glaucoma surgery (P=0.003), and other concurrent procedures (P=0.013). CONCLUSIONS: Our large longitudinal cohort study has provided evidence that MPTSCPC is a safe and generally effective option in the treatment of POAG up to 12 months.

Comparison of surgical outcomes between canaloplasty and trabeculectomy with mitomycin C at 2-year follow-up: A longitudinal cohort study.

PURPOSE: To compare operative outcomes of patients after canaloplasty and trabeculectomy with mitomycin C (MMC) through 2-year follow-up. METHODS: We included 31 eyes of 31 patients with primary open-angle glaucoma (POAG) who underwent canaloplasty and 37 eyes of 37 patients with POAG who underwent trabeculectomy with MMC with 24 months of postoperative follow-up. All surgeries were performed by a single surgeon between January 2005 and May 2011. Failure was defined as intraocular pressure (IOP> 18 or <4 mmHg at 2 years), second operative procedure, or loss of light perception. Change in IOP, visual acuity (VA), glaucoma medications, and complication rates at 24 months were analyzed. RESULTS: Caucasians made up to half of the patients included in this study (58% vs. 43%) while the rest where either African Americans (32% vs. 43%) or Hispanic (10% vs. 14%) patients between the canaloplasty and trabeculectomy group. Both groups showed significant reduction in IOP from baseline at 24 months. Trabeculectomy patients had a greater mean reduction of IOP compared to canaloplasty patients (12.2 ± 12 vs. 4.7 ± 7.5, P = 0.003) and also achieved lower IOP at 24 months (12.2 ± 4.1 vs. 14.9 ± 6.0, P = 0.03). Postoperative glaucoma medication use was less in the trabeculectomy group (n = 0, interquartile range [IQR] 0-2) compared to those in whom canaloplasty was performed (n = 2, IQR 0-3, P = 0.02). VA showed no statistical change in either group over 2 years. Overall failure rates at 2 years were comparable between the two groups: 32% for trabeculectomy and 26% for canaloplasty (P = 0.6). Subgroup analysis revealed a lower failure rate in Caucasions (15%) when compared to Blacks (42%) and Hispanics/others (50%, P = 0.03). CONCLUSION: Canaloplasty and trabeculectomy both achieved significant reduction in IOP with comparable success rates. Trabeculectomy can achieve a greater reduction in IOP while requiring fewer medications however is associated with more intensive postoperative care and frequent interventions. Pigmented populations have worse outcomes compared to Caucasians.

Stereocontrolled Semisyntheses of Elliptone and 12aß-Hydroxyelliptone.

Operationally simple, stereocontrolled semisyntheses of the anticancer rotenoids elliptone and 12aß-hydroxyelliptone, isolated from Derris elliptica and Derris trifoliata, respectively, are described. Inspired by the work of Singhal, elliptone was prepared from rotenone via a dihydroxylation-oxidative cleavage, chemoselective Baeyer-Villiger oxidation, and acid-catalyzed elimination sequence. Elaboration of elliptone to 12aß-hydroxyelliptone was achieved via a diastereoselective chromium-mediated Étard-like hydroxylation. The semisynthesis of elliptone constitutes an improvement over previous methods in terms of safety, scalability, and yield, while the first synthesis of 12aß-hydroxyelliptone is also described.

Is the Simple Shoulder Test a valid outcome instrument for shoulder arthroplasty?

BACKGROUND: The Simple Shoulder Test (SST) is a brief, inexpensive, and widely used patient-reported outcome tool, but it has not been rigorously evaluated for patients having shoulder arthroplasty. The goal of this study was to rigorously evaluate the validity of the SST for outcome assessment in shoulder arthroplasty using a systematic review of the literature and an analysis of its properties in a series of 408 surgical cases. METHODS: SST scores, 36-Item Short Form Health Survey scores, and satisfaction scores were collected preoperatively and 2 years postoperatively. Responsiveness was assessed by comparing preoperative and 2-year postoperative scores. Criterion validity was determined by correlating the SST with the 36-Item Short Form Health Survey. Construct validity was tested through 5 clinical hypotheses regarding satisfaction, comorbidities, insurance status, previous failed surgery, and narcotic use. RESULTS: Scores after arthroplasty improved from 3.9 ± 2.8 to 10.2 ± 2.3 (P < .001). The change in SST correlated strongly with patient satisfaction (P < .001). The SST had large Cohen's d effect sizes and standardized response means. Criterion validity was supported by significant differences between satisfied and unsatisfied patients, those with more severe and less severe comorbidities, those with workers' compensation or Medicaid and other types of insurance, those with and without previous failed shoulder surgery, and those taking and those not taking narcotic pain medication before surgery (P < .005). CONCLUSION: These data combined with a systematic review of the literature demonstrate that the SST is a valid and responsive patient-reported outcome measure for assessing the outcomes of shoulder arthroplasty.

Risk Factors for Chronic Diseases and Multimorbidity in a Primary Care Context of Central Argentina: A Web-Based Interactive and Cross-Sectional Study.

Global health agencies estimate an increase of chronic diseases in South America. Nevertheless, few studies have investigated chronic diseases and their risk factors in the perspective of multimorbidity. This research aimed to identify these aspects in a primary health care setting of central Argentina. The Pan America version of the STEP wise approach surveillance (STEPS) instrument of the World Health Organization was applied to 1044 participants, 365 men and 679 women, with a mean age of 43 years. High prevalence of overweight (33.5%), obesity (35.2%), central obesity (54%), dyslipidemia (43.5%), metabolic syndrome (21.1%), low intake of fruit and vegetables (91.8%), low levels of physical activity (71.5%), risky alcohol consumption (28%), and smoking (22.5%) were detected. Hypertension and diabetes were the most prevalent chronic conditions and the total prevalence of multimorbidity was 33.1%, with 2, 3, 4, 5 and 6 chronic conditions found in 19.9%, 9.1%, 2.6%, 1.1% and 0.4% of the population, respectively. Multimorbidity affected 6.4% of the young, 31.7% of the adults, and 60.6% of the elderly, and was more prevalent among women, and in participants with lower levels of education. Having multimorbidity was significantly associated with obesity, central obesity, and higher concentrations of total blood cholesterol, low-density lipoprotein cholesterol, triglycerides, and glucose. A website was made available to the participants in order to share the experimental results and health-promoting information.

Mitochondrial protein Fus1/Tusc2 in premature aging and age-related pathologies: critical roles of calcium and energy homeostasis.

Decreased energy production and increased oxidative stress are considered to be major contributors to aging and aging-associated pathologies. The role of mitochondrial calcium homeostasis has also been highlighted as an important factor affecting different pathological conditions. Here, we present evidence that loss of a small mitochondrial protein Fus1 that maintains mitochondrial homeostasis results in premature aging, aging-associated pathologies, and decreased survival. We showed that Fus1KO mice develop multiple early aging signs including lordokyphosis, lack of vigor, inability to accumulate fat, reduced ability to tolerate stress, and premature death. Other prominent pathological changes included low sperm counts, compromised ability of adult stem cells to repopulate tissues, and chronic inflammation. At the molecular level, we demonstrated that mitochondria of Fus1 KO cells have low reserve respiratory capacity (the ability to produce extra energy during sudden energy demanding situations), and show significantly altered dynamics of cellular calcium response.Our recent studies on early hearing and memory loss in Fus1 KO mice combined with the new data presented here suggest that calcium and energy homeostasis controlled by Fus1 may be at the core of its aging-regulating activities. Thus, Fus1 protein and Fus1-dependent pathways and processes may represent new tools and targets for anti-aging strategies.