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Ototoxicity is among the adverse events related to cancer treatment that can have far-reaching consequences and negative impacts on quality-of-life for cancer patients and survivors of all ages. Ototoxicity management (OtoM) comprises the prevention, diagnosis, monitoring, and treatment, including rehabilitation and therapeutic intervention, of individuals who experience hearing loss, tinnitus, or balance/vestibular difficulties following exposures to ototoxic agents, including platinum chemotherapy (cisplatin, carboplatin) and cranial radiation. Despite the well-established physical, socioeconomic, and psychological consequences of hearing and balance dysfunction, there are no widely adopted standards for clinical management of cancer treatment-related ototoxicity. Consensus recommendations and a roadmap are needed to guide development of effective and feasible OtoM programs, direct research efforts, address the needs of caregivers and patients at all stages of cancer care and survivorship. Here we review current evidence and propose near-term to longer-term goals to advance OtoM in five strategic areas: (1) beneficiary awareness, empowerment, and engagement, (2) workforce enhancement, (3) program development, (4) policy, funding, and sustainability, and (5) research and evaluation. The goal is to identify needs and establish a roadmap to guide worldwide adoption of standardized OtoM for cancer treatment and improved outcomes for patients and survivors.

Point of care ultrasound (POCUS) has been a constantly evolving and growing tool utilized by emergency medicine and intensive care practitioners. Ultrasound use for the assessment and management of critically ill patients has been available for several decades with the focused assessment with sonography in trauma (FAST) exam being one of the first widely adopted POCUS protocols. This along with other established protocols has made an impact on the care delivered to critically ill patients. This narrative review will cover some of the history of POCUS in the emergency department, brief considerations for machines and infrastructure, and current uses including in trauma, shock/hypotension, cardiac arrest, dyspnea, abdomen, vascular, and procedural guidance. Furthermore, it will provide a review of the evidence supporting its efficacy in managing critically ill patients and future directions.

OBJECTIVES: The objectives of our systematic review and meta-analyses were to determine the diagnostic accuracy of central venous oxygen saturation (Scvo 2) in estimating mixed venous oxygen saturation (Svo 2) and cardiac index in critically ill patients. DATA SOURCES: A systematic search using MEDLINE, Cochrane Central Register of Controlled Trials, and Embase was completed on May 6, 2024. STUDY SELECTION: Studies of patients in the ICU for whom Scvo 2 and at least one reference standard test was performed (thermodilution and/or Svo 2) were included. DATA EXTRACTION: Individual patient data were used to calculate the pooled intraclass correlation coefficient (ICC) for Svo 2 and Spearman correlation for cardiac index. The Quality Assessment of Diagnostic Accuracy Studies-2 and Grading Recommendations Assessment, Development, and Evaluation tools were used for the risk of bias and certainty of evidence assessments. DATA SYNTHESIS: Of 3427 studies, a total of 18 studies with 1971 patients were identified. We meta-analyzed 16 studies (1335 patients) that used Svo 2 as a reference and three studies (166 patients) that used thermodilution as reference. The ICC for reference Svo 2 was 0.83 (95% CI, 0.75–0.89) with a mean difference of 2.98% toward Scvo 2. The Spearman rank correlation for reference cardiac index is 0.47 (95% CI, 0.46–0.48; p < 0.0001). CONCLUSIONS: There is moderate reliability for Scvo 2 in predicting Svo 2 in critical care patients with variability based on sampling site and presence of sepsis. There is limited evidence on the independent use of Scvo 2 in predicting cardiac index.

DddA-derived cytosine base editors (DdCBEs) enable the targeted introduction of C•G-to-T•A conversions in mitochondrial DNA (mtDNA). DdCBEs work in pairs, with each arm composed of a transcription activator-like effector (TALE), a split double-stranded DNA deaminase half, and a uracil glycosylase inhibitor. This pioneering technology has helped improve our understanding of cellular processes involving mtDNA and has paved the way for the development of models and therapies for genetic disorders caused by pathogenic mtDNA variants. Nonetheless, given the intrinsic properties of TALE proteins, several target sites in human mtDNA are predicted to remain out of reach to DdCBEs and other TALE-based technologies. Specifically, due to the conventional requirement for a thymine immediately upstream of the TALE target sequences ( i.e. , the 5′-T constraint), over 150 loci in the human mitochondrial genome are presumed to be inaccessible to DdCBEs. Previous attempts at circumventing this requirement, either by developing monomeric DdCBEs or utilizing DNA-binding domains alternative to TALEs, have resulted in suboptimal specificity profiles with reduced therapeutic potential. Here, aiming to challenge and elucidate the relevance of the 5′-T constraint in the context of DdCBE-mediated mtDNA editing, and to expand the range of motifs that are editable by this technology, we generated DdCBEs containing TALE proteins engineered to recognize all 5′ bases. These modified DdCBEs are herein referred to as αDdCBEs. Notably, 5′-T-noncompliant canonical DdCBEs efficiently edited mtDNA at diverse loci. However, they were frequently outperformed by αDdCBEs, which exhibited significant improvements in activity and specificity, regardless of the most 5′ bases of their TALE binding sites. Furthermore, we showed that αDdCBEs are compatible with the enhanced DddA tox variants DddA6 and DddA11, and we validated TALE shifting with αDdCBEs as an effective approach to optimize base editing outcomes. Overall, αDdCBEs enable efficient, specific, and unconstrained mitochondrial base editing.

Objectives: Radial tears of the meniscus are increasingly treated with repair instead of partial meniscectomy, with satisfactory short-term clinical outcomes. There remains a paucity of mid- and long-term outcomes data for this preservation technique. The purpose of this study was to 1) evaluate the mid- to long-term clinical outcomes and reoperation rate of radial meniscal repair versus bucket-handle meniscal repair and 2) evaluate the outcomes of both surgeries overtime. We hypothesized that radial repair would provide similar outcomes and reoperation rates to that of bucket-handle meniscal repair in this propensity-matched cohort. Methods: A previously identified cohort of radial meniscal tears without concurrent root injuries undergoing surgical repair at a single institution between 2011 and 2015 were reviewed. Inclusion criteria was patients undergoing repair of full-thickness radial tears. Exclusion criteria were patients who had 1) not consented for research follow-up, 2) <2 year of follow-up, 3) high-grade (Outerbridge grade 3 or 4) chondromalacia, 4) knee dislocations or combined anterior cruciate ligament and posterior cruciate ligament injuries, 5) repair of posterior meniscal root tears, and 6) repair of partial radial tears. Propensity matching was performed based on age at surgery, sex, laterality, body mass index (BMI), and concomitant anterior cruciate ligament reconstruction (ACLR) using a comparison pool of 70 bucket-handle meniscal repairs (BHMR). Reoperation-free survival rates, Tegner Activity Score, visual analog scale (VAS) for pain, and International Knee Documentation Committee (IKDC) scores were analyzed. Results: Twenty-four patients (18 males, 6 females, age 22.8 ± 11.9 years, BMI 26.5 ± 5.8) with radial meniscal repair were included in this study. Eighteen of these patients were successfully propensity matched to 18 bucket-handle meniscal tears for an overall mean follow-up of 10.2 ± 1.7 years (range, 7.3-13.5) (Table 1). The 24 radial tear repairs demonstrated significant and durable postoperative improvements at mean 10.2 years across VAS at rest (3.0 ± 2.5 vs 0.5 ± 1.0, p < 0.001), VAS for pain at use (5.8 ± 2.9 vs 1.4 ± 1.9, p < 0.001) Tegner (2.6 ± 1.4 vs 6.8 ± 2.0, p < 0.001) and IKDC (39.8 ± 12.3 vs 84.1 ± 16.5, p < 0.001) (Table 1). Of patients not undergoing reoperation (19), 100% reported being “Satisfied” 4/19 (21%) or “Very Satisfied” 15/19 (79%). When the 18 radial tear repairs were compared to the 18 BHMT repairs, there was no significant difference across VAS for pain at rest (0.6 ± 1.2 vs 0.3 ± 0.7, p = 0.48), VAS for pain at use (1.6 ± 2.1 vs 1.1 ± 1.3, p = 0.48) Tegner (6.9 ± 2.2 vs 6.4 ± 2.1, p = 0.51) and IKDC (83.4 ± 17.4 vs 82.1 ± 14.1, p = 0.83) (Table 2). Importantly, survival without reoperation rates were not statistically different between the 2 groups at 10-year follow-up (14/18 (78%) vs 16/18 (89%), p = 0.37) (Figure 1). There was no significant difference between clinical outcomes (Tegner and IKDC) at final follow-up in the radial repair group as compared to the 4-year mid-term outcomes (p = 0.58 and 0.19 respectively). For the BHMR group, Tegner scores were not significantly different (p = 0.60) compared with their 4-year timepoint; however, IKDC scores at the final timepoint were significantly lower 93.4 ± 3.4 vs 82.1 ± 14.1 (p = 0.01). Notably, both the radial repair and bucket-handle repairs groups reported final follow-up Tegner scores that were not significantly different from their preinjury Tegner scores (p = 0.70 for the radial group and p = 0.62 for the bucket-handle group). Conclusions: At mean 10-year follow-up, significant clinical improvements and high rates of satisfaction were observed for radial meniscal tear repair. When propensity matched, radial and BHMR demonstrated durable improvements in postoperative VAS for pain, IKDC, and Tegner scores, as well as similar, acceptable reoperation rates. [Figure: see text]

Objectives: Medial meniscus posterior root tears (MMPRTs) render the meniscus essentially non-functional, resulting in increased peak contact pressures, reduced forced dissipation, and increased risk of early osteoarthritis. Transtibial root repair has shown promise at restoring meniscus function and improving clinical outcomes; however, a paucity of literature exists evaluating the prognostic clinical and radiographic factors for poor outcomes following isolated meniscus root repair. The purpose of this study was to 1) describe the patient reported clinical outcomes after isolated MMPRT repair at minimum 2-year follow-up, 2) determine the retear and conversion to arthroplasty rates, and 3) identify prognostic factors for clinical outcomes and International Knee Documentation Committee (IKDC) Patient Acceptable Symptom State (PASS) achievement. Methods: Isolated MMPRT repairs from 2010-2020 at three institutions in Rochester, MN; Jacksonville, FL; and Phoenix, AZ were followed prospectively for postoperative Tegner Activity Scale, Visual Analog Scale (VAS) for pain, IKDC, Forgotten Joint Score (FJS), subjective improvement and knee preference, and subsequent surgeries at minimum 2-year follow up. PASS for IKDC was set at 69. Demographics, injury characteristics, and surgical details were collected. Results: Eighty-four patients were included in this study (age: 49.7 ± 11.0 years [range: 13-76]; sex: 75.0% female; BMI: 31.6 ± 6.9 kg/m 2 [MH1] ). Forty-five patients (53.6%) had BMI >30 kg/m 2 , and 14 patients (16.7%) reported a history of active smoking (Table 1). Mean medial compartment Outerbridge grade was 2.0 ± 1.1, with 73.8% of patients having grade ≥2 changes. Mean preinjury Tegner score, preoperative VAS at rest, and preoperative VAS with use were 4.6 ± 2.4, 3.6 ± 2.7, and 6.5 ± 2.5, respectively. At final follow-up (mean 3.9 ± 2.0 years), mean Tegner score was 4.3 ± 1.8, mean VAS at rest was 1.2 ± 2.0, and mean VAS with use was 2.3 ± 2.2. There was no significant difference in preinjury vs. postoperative Tegner scores (p = 0.208), and preinjury Tegner was significantly positively correlated with postoperative Tegner (p < 0.001). Significant (p < 0.001) postoperative improvements in both VAS at rest and with use were observed. Mean postoperative IKDC score was 73.3 ± 17.0, and mean FJS was 59.6 ± 27.9 at final follow-up. When asked to rate their knee at final follow-up compared to before surgery on a scale from 0-5 (0 = “significantly worse”, 1 = “mildly worse”, 3 = “unchanged”, 4 = “mildly improved”, 5 = “significantly improved”), the mean score 4.6 ± 0.8. Forty-one patients (74.5%) reported significant improvement, 8 (14.5%) reported mild improvement, 3 (5.5%) reported no change, and 3 (5.5%) reported mild worsening. No patients reported significant worsening. When asked which knee they preferred, 13 patients (26.0%) reported preferring their operated knee, compared to 18 (36.0%) who preferred their nonoperated knee. The remaining 19 patients (38.0%) had no preference for one knee over the other. A summary of all patient reported outcomes is reported in Table 2. At the time of final follow-up, 16 (19.0%) of patients had reached a clinical endpoint. Twenty-nine patients (34.5%) underwent postoperative MRIs at an average of 1.5 ± 1.7 years (range: 0.3-5.9 years) after surgery[MH1] . Twelve of the MRIs (41.4%) were ordered for evaluation of continued pain, while 7 (24.1%) were ordered for new pain or injury, and 10 (34.5%) were ordered for research purposes. Five patients (6.0%) had MRI-confirmed retears of the MMPRT repair at an average of 1.1 ± 1.3 years (range: 0.3-3.4) after surgery[HMMP2] , one of which was in an asymptomatic patient who received a follow-up MRI for research purposes. No patients underwent revision MMPRT repair surgery, and 7 patients (8.3%) progressed to arthroplasty (6 TKA, 1 UKA) at an average of 3.4 ± 4.3 years (range 0.6-12.6), one of whom also sustained a root retear. Therefore, the surgical failure was noted in 11 patients, corresponding to a surgical failure rate of 13.1% in this cohort. Of note, three of the five patients with MRI-confirmed retears had not received any further surgical intervention[MH3] [BA(M4] at the time of final follow-up 2.7, 3.8, and 8.5 years after surgery. Additionally, there were six non-MMPRT revision, non-arthroplasty subsequent surgeries in five patients, and there were three patients (3.6%) who sustained new medial meniscus tears 2.8-, 3.6-, and 5.9-years postoperatively, respectively. A concise summary of clinical endpoints can be found in Table 3 and Table 4. Significantly more females experienced surgical failures than males (17.5% vs. 0%, p = 0.040), and significantly more patients with medial compartment Outerbridge grades ≥2 experienced surgical failure than those with grades <2 (17.7% vs. 0%, p = 0.034). Additionally, patients who failed did have significantly higher mean KL grades than those who did not (1.4 ± 0.9 vs. 0.7 ± 0.7, p = 0.012). There were no other significant differences in the demographic or pathologic characteristics of patients who experienced surgical failure and those who did not. Of note, 37% of patients failed to achieve IKDC PASS, with smoking status associated with a 15-point reduction in IKDC (p=0.010) Conclusions: Patients undergoing transtibial root repair demonstrate restoration of pre-injury activity levels, significant clinical improvements in pain and function, and low surgical failure rates at minimum 2-year follow-up, with 89% of patients reporting subjective improvement after surgery. However, only 63% of patients were able to achieve PASS thresholds, suggesting that while effective, additional research on root repair technical and clinical optimization is warranted.

Objectives: Hip arthroscopy is rapidly advancing, with literature increasingly reporting positive outcomes at short- and mid-term follow-up; however, available long-term data remains limited. The purpose of this study is to evaluate long-term outcomes of primary hip arthroscopy at minimum 10-year follow-up at two academic centers by describing patient-reported outcomes (PROs) and determining reoperation, revision, and total hip arthroplasty (THA) rates. Methods: Primary hip arthroscopies performed between January 1988 and April 2013 at 2 academic centers were evaluated for postoperative PROs including Visual Analogue Scale (VAS), Tegner Activity Scale score, Hip Outcome Score Activities of Daily Living and Sport Scale (HOS-ADL/HOS-SS), modified Harris Hip Score (mHHS), Nonarthritic Hip Score (NAHS), 12-item International Hip Outcome Tool (iHOT-12), surgery satisfaction, function, and reoperations. Results: Two-hundred ninety-four primary hip arthroscopies with a mean age of 40±14 years; 66% female; and a mean body mass index (BMI) of 27±6 kg/m 2 were followed for mean 12±3 years (range: 10-24). Labral debridement and repair were performed in 41% and 59% of patients, respectively. All patients underwent interportal capsulotomy and 2% underwent T-capsulotomy. Eleven percent of patients underwent capsular repair. At final follow-up, patients reported mean VAS at rest of 2±2, with use of 3±3, iHOT-12 of 68±27, NAHS of 81±18, mHHS of 79±17, HOS-ADL of 82±19, and HOS-SS of 74±25. Mean surgical satisfaction was 8.4±2.4 (Table 1). Sixty-five hips (23%) underwent THA and 33 (11%) underwent revision arthroscopy (Table 2). Risk factors for THA included older age (p<0.001), higher BMI (p<0.001), lower lateral center-edge angle (p=0.039), larger alpha angle (p=0.001), higher Tönnis grade (p=0.011), labral debridement (p=0.004), and capsular nonrepair (p=0.030). Patients undergoing combined labral and capsular repair demonstrated a THA conversion rate of 3% compared to 31% for patients undergoing combined labral debridement and capsular nonrepair (p=0.006) (Table 3). Labral repair trended towards increased 10-year THA-free survival (84% vs. 77%, p=0.085) while capsular repair demonstrated significantly increased 10-year THA-free survival (97% vs 79%, p=0.032) (Figure 1). Conclusions: At minimum 10-year follow-up, patients undergoing primary hip arthroscopy demonstrated high rates of satisfaction and acceptable outcome scores. In total, 11% of patients underwent revision hip arthroscopic surgery with a THA conversion rate of 23%. Conversion to THA was associated with patient factors including older age and higher Tönnis grade as well as potentially modifiable surgical factors including labral debridement and capsular nonrepair.

Introduction: Transcribing disordered speech can be useful when diagnosing motor speech disorders such as primary progressive apraxia of speech (PPAOS), who have sound additions, deletions, and substitutions, or distortions and/or slow, segmented speech. Since transcribing speech can be a laborious process and requires an experienced listener, using automatic speech recognition (ASR) systems for diagnosis and treatment monitoring is appealing. This study evaluated the efficacy of a readily available ASR system (wav2vec 2.0) in transcribing speech of PPAOS patients to determine if the word error rate (WER) output by the ASR can differentiate between healthy speech and PPAOS and/or among its subtypes, whether WER correlates with AOS severity, and how the ASR's errors compare to those noted in manual transcriptions. Method: Forty-five patients with PPAOS and 22 healthy controls were recorded repeating 13 words, 3 times each, which were transcribed manually and using wav2vec 2.0. The WER and phonetic and prosodic speech errors were compared between groups, and ASR results were compared against manual transcriptions. Results: Mean overall WER was 0.88 for patients and 0.33 for controls. WER significantly correlated with AOS severity and accurately distinguished between patients and controls but not between AOS subtypes. The phonetic and prosodic errors from the ASR transcriptions were also unable to distinguish between subtypes, whereas errors calculated from human transcriptions were. There was poor agreement in the number of phonetic and prosodic errors between the ASR and human transcriptions. Conclusions: This study demonstrates that ASR can be useful in differentiating healthy from disordered speech and evaluating PPAOS severity but does not distinguish PPAOS subtypes. ASR transcriptions showed weak agreement with human transcriptions; thus, ASR may be a useful tool for the transcription of speech in PPAOS, but the research questions posed must be carefully considered within the context of its limitations. Supplemental Material: https://doi.org/10.23641/asha.26359417

Abstract Intrinsic resistance to targeted therapeutics in PTEN-deficient glioblastoma (GBM) is mediated by redundant signaling networks that sustain critical metabolic functions. Here, we demonstrate that coordinated inhibition of the ribosomal protein S6 kinase 1 (S6K1) and the receptor tyrosine kinase AXL using LY-2584702 and BMS-777607 can overcome network redundancy to reduce GBM tumor growth. This combination of S6K1 and AXL inhibition suppressed glucose flux to pyrimidine biosynthesis. Genetic inactivation studies to map the signaling network indicated that both S6K1 and S6K2 transmit growth signals in PTEN-deficient GBM. Kinome-wide ATP binding analysis in inhibitor-treated cells revealed that LY-2584702 directly inhibited S6K1, and substrate phosphorylation studies showed that BMS-777607 inactivation of upstream AXL collaborated to reduce S6K2-mediated signal transduction. Thus, combination targeting of S6K1 and AXL provides a kinase-directed therapeutic approach that circumvents signal transduction redundancy to interrupt metabolic function and reduce growth of PTEN-deficient GBM. Significance: Therapy for glioblastoma would be advanced by incorporating molecularly targeted kinase-directed agents, similar to standard of care strategies in other tumor types. Here, we identify a kinase targeting approach to inhibit the metabolism and growth of glioblastoma.