Auditory and tactile gap discrimination by observers with normal and impaired hearing

Temporal processing ability for the senses of hearing and touch was examined through the measurement of gap-duration discrimination thresholds (GDDTs) employing the same low-frequency sinusoidal stimuli in both modalities. GDDTs were measured in three groups of observers (normal-hearing, hearing-impaired, and normal-hearing with simulated hearing loss) covering an age range of 21–69 yr. GDDTs for a baseline gap of 6 ms were measured for four different combinations of 100-ms leading and trailing markers (250–250, 250–400, 400–250, and 400–400 Hz). Auditory measurements were obtained for monaural presentation over headphones and tactile measurements were obtained using sinusoidal vibrations presented to the left middle finger. The auditory GDDTs of the hearing-impaired listeners, which were larger than those of the normal-hearing observers, were well-reproduced in the listeners with simulated loss. The magnitude of the GDDT was generally independent of modality and showed effects of age in both modalities. The use of different-frequency compared to same-frequency markers led to a greater deterioration in auditory GDDTs compared to tactile GDDTs and may reflect differences in bandwidth properties between the two sensory systems.National Institute on Deafness and Other Communication Disorders (U.S.) (Grant R01 DC000117

HIV-1 Inhibits Autophagy in Bystander Macrophage/Monocytic Cells through Src-Akt and STAT3

Autophagy is a homeostatic mechanism of lysosomal degradation. Defective autophagy has been linked to various disorders such as impaired control of pathogens and neurodegeneration. Autophagy is regulated by a complex array of signaling pathways that act upstream of autophagy proteins. Little is known about the role of altered regulatory signaling in disorders associated with defective autophagy. In particular, it is not known if pathogens inhibit autophagy by modulation of upstream regulatory pathways. Cells infected with HIV-1 blocked rapamycin-induced autophagy and CD40-induced autophagic killing of Toxoplasma gondii in bystander (non-HIV-1 infected) macrophage/monocytic cells. Blockade of autophagy was dependent on Src-Akt and STAT3 triggered by HIV-1 Tat and IL-10. Neutralization of the upstream receptors VEGFR, β-integrin or CXCR4, as well as of HIV-1 Tat or IL-10 restored autophagy in macrophage/monocytic cells exposed to HIV-1-infected cells. Defective autophagic killing of T. gondii was detected in monocyte-derived macrophages from a subset of HIV-1+ patients. This defect was also reverted by neutralization of Tat or IL-10. These studies revealed that a pathogen can impair autophagy in non-infected cells by activating counter-regulatory pathways. The fact that pharmacologic manipulation of cell signaling restored autophagy in cells exposed to HIV-1-infected cells raises the possibility of therapeutic manipulation of cell signaling to restore autophagy in HIV-1 infection

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Can Artificial Intelligence Pass the American Board of Orthopaedic Surgery Examination? Orthopaedic Residents Versus ChatGPT.

BACKGROUND: Advances in neural networks, deep learning, and artificial intelligence (AI) have progressed recently. Previous deep learning AI has been structured around domain-specific areas that are trained on dataset-specific areas of interest that yield high accuracy and precision. A new AI model using large language models (LLM) and nonspecific domain areas, ChatGPT (OpenAI), has gained attention. Although AI has demonstrated proficiency in managing vast amounts of data, implementation of that knowledge remains a challenge. QUESTIONS/PURPOSES: (1) What percentage of Orthopaedic In-Training Examination questions can a generative, pretrained transformer chatbot (ChatGPT) answer correctly? (2) How does that percentage compare with results achieved by orthopaedic residents of different levels, and if scoring lower than the 10th percentile relative to 5th-year residents is likely to correspond to a failing American Board of Orthopaedic Surgery score, is this LLM likely to pass the orthopaedic surgery written boards? (3) Does increasing question taxonomy affect the LLM\u27s ability to select the correct answer choices? METHODS: This study randomly selected 400 of 3840 publicly available questions based on the Orthopaedic In-Training Examination and compared the mean score with that of residents who took the test over a 5-year period. Questions with figures, diagrams, or charts were excluded, including five questions the LLM could not provide an answer for, resulting in 207 questions administered with raw score recorded. The LLM\u27s answer results were compared with the Orthopaedic In-Training Examination ranking of orthopaedic surgery residents. Based on the findings of an earlier study, a pass-fail cutoff was set at the 10th percentile. Questions answered were then categorized based on the Buckwalter taxonomy of recall, which deals with increasingly complex levels of interpretation and application of knowledge; comparison was made of the LLM\u27s performance across taxonomic levels and was analyzed using a chi-square test. RESULTS: ChatGPT selected the correct answer 47% (97 of 207) of the time, and 53% (110 of 207) of the time it answered incorrectly. Based on prior Orthopaedic In-Training Examination testing, the LLM scored in the 40th percentile for postgraduate year (PGY) 1s, the eighth percentile for PGY2s, and the first percentile for PGY3s, PGY4s, and PGY5s; based on the latter finding (and using a predefined cutoff of the 10th percentile of PGY5s as the threshold for a passing score), it seems unlikely that the LLM would pass the written board examination. The LLM\u27s performance decreased as question taxonomy level increased (it answered 54% [54 of 101] of Tax 1 questions correctly, 51% [18 of 35] of Tax 2 questions correctly, and 34% [24 of 71] of Tax 3 questions correctly; p = 0.034). CONCLUSION: Although this general-domain LLM has a low likelihood of passing the orthopaedic surgery board examination, testing performance and knowledge are comparable to that of a first-year orthopaedic surgery resident. The LLM\u27s ability to provide accurate answers declines with increasing question taxonomy and complexity, indicating a deficiency in implementing knowledge. CLINICAL RELEVANCE: Current AI appears to perform better at knowledge and interpretation-based inquires, and based on this study and other areas of opportunity, it may become an additional tool for orthopaedic learning and education

Local bio-absorbable antibiotic delivery in calcium sulfate beads in hip and knee arthroplasty

Antibiotic-impregnated calcium sulfate (AICS) beads have been used for prevention and treatment of periprosthetic joint infections. We evaluated post-operative complications following the use of AICS beads. 56 patients undergoing complex primary or revision hip or knee arthroplasty received antibiotic calcium sulfate beads. Primary outcomes were wound complication rates. Secondary outcomes included reoperation and reinfection rates. One case (1.7%) of persistent wound drainage occurred requiring surgical irrigation and a poly-exchange. No post-operative infections were seen. Use of 100% pure calcium sulfate AICS beads may help reduce post-operative wound complications. AICS appears to be a safe adjunct tool in local antibiotic delivery

Etiology, Evaluation, and Management of Dislocation After Primary Total Hip Arthroplasty.

The rate of dislocation after primary total hip arthroplasty has decreased, but given the high volume of total hip arthroplasty procedures that are performed, dislocation remains a common complication. The etiology of dislocation after total hip arthroplasty is multifactorial and depends on the patient's characteristics as well as the orthopaedic surgeon's operative techniques and decisions regarding implants. A detailed assessment of the patient, preoperative planning, a thorough understanding of the anatomy, proper surgical technique, and knowledge of the biomechanics of the implant decrease the likelihood of dislocations following total hip arthroplasty. The advent of new techniques and procedures has further reduced the occurrence of dislocation following total hip arthroplasty. However, should dislocation occur, primary management or revision total hip arthroplasty techniques provide excellent results to salvage the mobility and function of the hip

Total Hip Instability and the Spinopelvic Link.

Purpose of reviewAdvances in technology, implant design, and surgical technique have lowered the dislocation rate in primary total hip arthroplasty (THA). Despite these advances, there remain a large number of instability episodes without a known etiology. Recent research suggests that the pelvic and lumbar spine interrelationship may be the explanation in prosthetic dislocations without a known cause. In this review, we describe the biomechanics, measurements, diagnoses, classification, management, and outcomes of total hip and revision total hip instability as it relates to spinopelvic alignment.Recent findingsAs a person goes from standing to sitting, lumbar lordosis decreases, and the sacrum and entire pelvis tilts posteriorly with sacrum and coccyx rotating posterior-inferiorly, resulting in increased acetabular cup anteversion to accommodate femoral flexion. A fused spine and associated fixed acetabulum can result in abnormal pelvic femoral motion, impingement, and dislocation. Classifying the spinopelvic mechanics by sacral motion based on sitting and standing lateral radiographs provides an understanding of how the acetabulum behaves in space. This information helps appropriate cup positioning, reducing the risk of femoral side impingement and subsequent dislocation. Surgical techniques to consider in the spinopelvic at-risk patient are positioning considerations in acetabular cup inclination and anteversion, high offset femoral stems, high offset acetabular liners, dual mobility articulations, and removal of impinging structures. Future research is needed to define the safest order of operation in concomitant hip and spine pathology, the effects on pelvic femoral biomechanics in spine surgery, and whether preoperative and intraoperative management strategies have a long-term beneficial effect on the dislocation rate

Total knee arthroplasty after Hauser procedure: beware of the patellar tendon!

Preoperative planning is a fundamental element in total knee arthroplasty (TKA). A previous surgery that must be recognized and identified preoperatively is the Hauser procedure, a posteromedialization of the tibial tubercle for recurrent patellar instability. Here, we describe 2 case reports in patients with previous Hauser surgeries. The first TKA surgery was complicated from a standard medial peripatellar approach resulting in complete transection of the patellar tendon during standard arthrotomy. The tendon was repaired, and the arthroplasty was aborted. For the second case, correct preoperative identification of the Hauser procedure was performed. The second TKA surgery was performed using a lateral peripatellar arthrotomy with excellent exposure, resulting in a successful operation. Here, we highlight the importance of an accurate history, physical and radiographic examination, and the recommendation of an alternative TKA approach to help avoid the serious intraoperative complication of a patellar tendon laceration