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Many patients experience inadequate pain control due to limited options that are both efficacious and safe for treating moderate-to-severe acute pain; therefore, opioids are still frequently prescribed for their effectiveness despite known tolerability issues and safety concerns. Suzetrigine, an oral, non-opioid, offers a promising alternative by selectively inhibiting the voltage-gated sodium channel 1.8 (NaV1.8), a novel therapeutic target for pain management. Given the high selectivity of suzetrigine for NaV1.8 (does not bind to other sodium channels/receptors with CNS activity), suzetrigine does not have CNS side effects or addictive potential associated with opioids. In the largest randomized, controlled phase 3 trials in established acute pain models, suzetrigine monotherapy demonstrated statistically significant and clinically meaningful reduction in moderate-to-severe acute pain compared to placebo.BackgroundMany patients experience inadequate pain control due to limited options that are both efficacious and safe for treating moderate-to-severe acute pain; therefore, opioids are still frequently prescribed for their effectiveness despite known tolerability issues and safety concerns. Suzetrigine, an oral, non-opioid, offers a promising alternative by selectively inhibiting the voltage-gated sodium channel 1.8 (NaV1.8), a novel therapeutic target for pain management. Given the high selectivity of suzetrigine for NaV1.8 (does not bind to other sodium channels/receptors with CNS activity), suzetrigine does not have CNS side effects or addictive potential associated with opioids. In the largest randomized, controlled phase 3 trials in established acute pain models, suzetrigine monotherapy demonstrated statistically significant and clinically meaningful reduction in moderate-to-severe acute pain compared to placebo.To evaluate the safety and effectiveness of suzetrigine for the treatment of moderate-to-severe-acute surgical and non-surgical pain conditions, we conducted a phase 3, single-arm study in adults with moderate or severe acute pain on the verbal categorical rating scale and ≥4 on the numeric pain rating scale following surgical procedures or after presenting to a medical facility with moderate or severe acute pain of new origin. Participants received suzetrigine (100mg then 50mg every 12hrs) for 14 days or pain resolution, whichever came first. The primary endpoint was safety. The secondary endpoint was participant perception of suzetrigine's effectiveness in treating acute pain at the end of treatment using a patient global assessment.MethodsTo evaluate the safety and effectiveness of suzetrigine for the treatment of moderate-to-severe-acute surgical and non-surgical pain conditions, we conducted a phase 3, single-arm study in adults with moderate or severe acute pain on the verbal categorical rating scale and ≥4 on the numeric pain rating scale following surgical procedures or after presenting to a medical facility with moderate or severe acute pain of new origin. Participants received suzetrigine (100mg then 50mg every 12hrs) for 14 days or pain resolution, whichever came first. The primary endpoint was safety. The secondary endpoint was participant perception of suzetrigine's effectiveness in treating acute pain at the end of treatment using a patient global assessment.Suzetrigine was generally safe and well-tolerated in participants (N=256) with a range of surgical and non-surgical acute pain conditions; the maximum severity for most participants who had adverse events was mild (71 participants; 27.7%) or moderate (21 participants; 8.2%). Most participants (213 participants; 83.2%) rated suzetrigine's effectiveness for treating pain on a patient global assessment as good, very good, or excellent.ResultsSuzetrigine was generally safe and well-tolerated in participants (N=256) with a range of surgical and non-surgical acute pain conditions; the maximum severity for most participants who had adverse events was mild (71 participants; 27.7%) or moderate (21 participants; 8.2%). Most participants (213 participants; 83.2%) rated suzetrigine's effectiveness for treating pain on a patient global assessment as good, very good, or excellent.Suzetrigine provides a safe and effective non-opioid, non-addictive treatment with broad applicability for moderate-to-severe acute pain.ConclusionSuzetrigine provides a safe and effective non-opioid, non-addictive treatment with broad applicability for moderate-to-severe acute pain.NCT05661734.Clinicaltrialsgov RegistrationNCT05661734.

Control of salivary secretion in ticks involves autocrine dopamine activating two dopamine receptors: D1 and Invertebrate-specific D1-like dopamine receptors. In this study, we investigated Na/K-ATPase as an important component of the secretory process. Immunoreactivity for Na/K-ATPase revealed basal infolding of lamellate cells in type-I, abluminal interstitial (epithelial) cells in type-II and labyrinth-like infolding structures opening towards the lumen in type-III acini. Ouabain (10 μmol l −1 ), a specific inhibitor of Na/K-ATPase, abolished dopamine-induced salivary secretion by suppressing fluid transport in type III acini. At 1 μmol l −1 , ouabain, the secreted saliva was hyperosmotic. This suggests that ouabain also inhibits an ion resorptive function of Na/K-ATPase in the type I acini. Dopamine/ouabain were not involved in activation of protein secretion, while dopamine-induced saliva contained constitutively basal level of protein. We hypothesize that the dopamine-dependent primary saliva formation, mediated by Na/K-ATPase in type III and type II acini, is followed by a dopamine-independent resorptive function of Na/K-ATPase in type I acini located in the proximal end of the salivary duct.

•Knee pain patients have benefited from anesthetization of the peripatellar plexus.•Accurately identifying the peripatellar plexus can help reduce patient morbidity.•Accurately identifying the peripatellar plexus has clinical limitations.•Ultrasound is effective for the identification of peripatellar plexus contributions.•Ultrasound is effective for guided injection of peripatellar plexus contributions.

Background: Osteoarthritis (OA) is the leading cause of disability among US adults and most commonly affects the knee. Guidelines for knee OA treatment include behavioral, nonpharmacological, pharmacological, and surgical interventions. While emerging knee OA treatments show promise for pain control, data gaps remain regarding the efficacy, safety, comparative effectiveness, and real-world value of treatments. Objectives: The Innovations in Genicular Outcomes Registry (IGOR) is prospectively collecting real-world data to assess clinical effectiveness, safety, health-related quality of life, and healthcare resource utilization of knee OA treatments. Design: The IGOR is a prospective, observational, longitudinal, multicenter registry (NCT05495334) examining knee OA pain treatment outcomes at intervals up to 18 months after treatment. Methods and analysis: All clinical management decisions are made via shared decision-making involving both the physician and the patient. Index joint-directed treatments may include various intra-articular injections, oral opioid and nonopioid medications (including nonsteroidal anti-inflammatory drugs), cryo nerve blocks, radiofrequency ablations, novel treatment modalities, other physical therapy modalities (including muscle strengthening), and total knee arthroplasties. Patient-reported assessments along with physician-provided medical record data are recorded. Regular data quality assessments are conducted for each site, and an outside monitor ensures data quality and integrity. A steering committee ensures transparency and oversees administrative, legal, ethical, and scientific decisions. Treatment outcomes within and between therapies are compared. Ethics: Ethical approval was granted by Advarra, Inc. (protocol number, Pro00050981). Discussion: Data from the IGOR registry study will further elucidate the effectiveness, safety, and real-world value of knee OA treatments individually or in combination. Characterization of real-world treatment patterns will help better understand the impact of specific treatments. Trial registration: Clinicaltrials.gov, NCT05495334. Graphical abstract

BackgroundPolyethylene wear debris, and the resulting inflammatory response leading to osteolysis and loosening, is the primary mode of failure limiting the longevity of total hip replacements. Alternative bearing surfaces, including ceramic-on-polyethylene, have been investigated in an effort to decrease the amount of polyethylene wear debris. The purpose of this study was to evaluate the seventeen to twenty-one-year results of the use of ceramic-on-polyethylene total hip prostheses.MethodsSixty-four total hip prostheses were implanted with cement, by one surgeon, in fifty-six patients from 1978 to 1981. The average age at the index arthroplasty was sixty-nine years (range, fifty-one to eighty-four years). The components consisted of a cemented Charnley-Müller stem with a 32-mm modular alumina femoral head and a cemented all-polyethylene acetabular component. All patients who retained the index prosthesis were assessed clinically with use of Harris hip scores and were evaluated radiographically at the time of the latest follow-up.ResultsAt the time of this latest follow-up, of the original sixty-four implants, eighteen (28%) were still in place and five (8%) had been revised. The remaining forty-one implants were in patients who had died and were functioning well until the patient’s death. No patient was lost to follow-up. Of the eighteen hips with an intact prosthesis in the surviving patients, seven had an excellent clinical result; nine, a good result; and two, a fair result. One asymptomatic hip had definite radiographic evidence of femoral loosening. No hip had definite signs of acetabular loosening or evidence of osteolysis. Survivorship analysis revealed that the probability of survival of the prostheses without revision was 95% at five years, 95% at ten years, 89% at fifteen years, and 79% at twenty years. The mean linear and volumetric polyethylene wear rates were 0.034 mm/yr and 28 mm/yr, respectively. There were no fractures of the ceramic heads.ConclusionsOutstanding long-term clinical and radiographic results were attained despite the use of what are now considered substandard techniques (an inferior stem design, a 32-mm head, and first-generation cementing techniques). The wear rates in this study are lower than previously reported metal-on-polyethylene wear rates and are consistent with the lowest reported in vivo ceramic-on-polyethylene wear rates. These findings support the consideration of ceramic-on-polyethylene bearing surfaces in total hip arthroplasty.

Emerging technologies have given us a whole host of new ways for people to be creative. From the immersive worlds of AR/VR to the synthesis powers of largelanguage models and generative AI, these new tools hold the potential to reshape human expression and creativity. But how can we ensure that these new modalities are accessible to everyone, even those who aren’t able bodied? This thesis advocates for a human-centered approach to the development of many-modal systems. I will probe how our machines support, direct, or inhibit creativity as a mode of problem solving through 6 novel multimodal prototype interfaces and discuss how these systems support creativity for people who may otherwise be excluded. We will explore how multimodal systems allow people to interact according to their preferences and abilities, and how this flexibility creates space between modalities for accessible, rich, and creative computing. This includes discussing what we can learn about creativity by engaging people with disabilities in co-design, and how supporting this model of problem solving is imperative for designing future system interfaces that are inclusive and usable by all people

Background: Many patients experience inadequate pain control due to limited options that are both efficacious and safe for treating moderate-to-severe acute pain; therefore, opioids are still frequently prescribed for their effectiveness despite known tolerability issues and safety concerns. Suzetrigine, an oral, non-opioid, offers a promising alternative by selectively inhibiting the voltage-gated sodium channel 1.8 (NaV1.8), a novel therapeutic target for pain management. Given the high selectivity of suzetrigine for NaV1.8 (does not bind to other sodium channels/receptors with CNS activity), suzetrigine does not have CNS side effects or addictive potential associated with opioids. In the largest randomized, controlled phase 3 trials in established acute pain models, suzetrigine monotherapy demonstrated statistically significant and clinically meaningful reduction in moderate-to-severe acute pain compared to placebo. Methods: To evaluate the safety and effectiveness of suzetrigine for the treatment of moderate-to-severe-acute surgical and non-surgical pain conditions, we conducted a phase 3, single-arm study in adults with moderate or severe acute pain on the verbal categorical rating scale and [greater than or equal to]4 on the numeric pain rating scale following surgical procedures or after presenting to a medical facility with moderate or severe acute pain of new origin. Participants received suzetrigine (100mg then 50mg every 12hrs) for 14 days or pain resolution, whichever came first. The primary endpoint was safety. The secondary endpoint was participant perception of suzetrigine's effectiveness in treating acute pain at the end of treatment using a patient global assessment. Results: Suzetrigine was generally safe and well-tolerated in participants (N=256) with a range of surgical and non-surgical acute pain conditions; the maximum severity for most participants who had adverse events was mild (71 participants; 27.7%) or moderate (21 participants; 8.2%). Most participants (213 participants; 83.2%) rated suzetrigine's effectiveness for treating pain on a patient global assessment as good, very good, or excellent. Conclusion: Suzetrigine provides a safe and effective non-opioid, non-addictive treatment with broad applicability for moderate-to-severe acute pain. Clinicaltrials.gov Registration: NCT05661734. Keywords: suzetrigine, VX-548, non-opioid, NaV1.8 inhibitor, moderate-to-severe acute pain, surgical/nonsurgical acute pain

Many patients experience inadequate pain control due to limited options that are both efficacious and safe for treating moderate-to-severe acute pain; therefore, opioids are still frequently prescribed for their effectiveness despite known tolerability issues and safety concerns. Suzetrigine, an oral, non-opioid, offers a promising alternative by selectively inhibiting the voltage-gated sodium channel 1.8 (Na 1.8), a novel therapeutic target for pain management. Given the high selectivity of suzetrigine for Na 1.8 (does not bind to other sodium channels/receptors with CNS activity), suzetrigine does not have CNS side effects or addictive potential associated with opioids. In the largest randomized, controlled phase 3 trials in established acute pain models, suzetrigine monotherapy demonstrated statistically significant and clinically meaningful reduction in moderate-to-severe acute pain compared to placebo. To evaluate the safety and effectiveness of suzetrigine for the treatment of moderate-to-severe-acute surgical and non-surgical pain conditions, we conducted a phase 3, single-arm study in adults with moderate or severe acute pain on the verbal categorical rating scale and ≥4 on the numeric pain rating scale following surgical procedures or after presenting to a medical facility with moderate or severe acute pain of new origin. Participants received suzetrigine (100mg then 50mg every 12hrs) for 14 days or pain resolution, whichever came first. The primary endpoint was safety. The secondary endpoint was participant perception of suzetrigine's effectiveness in treating acute pain at the end of treatment using a patient global assessment. Suzetrigine was generally safe and well-tolerated in participants (N=256) with a range of surgical and non-surgical acute pain conditions; the maximum severity for most participants who had adverse events was mild (71 participants; 27.7%) or moderate (21 participants; 8.2%). Most participants (213 participants; 83.2%) rated suzetrigine's effectiveness for treating pain on a patient global assessment as good, very good, or excellent. Suzetrigine provides a safe and effective non-opioid, non-addictive treatment with broad applicability for moderate-to-severe acute pain. NCT05661734.

Advances in high dynamic range (HDR) lighting estimation from a single image have opened new possibilities for augmented reality (AR) applications. Predicting complex lighting environments from a single input image allows for the realistic rendering and compositing of virtual objects. In this work, we investigate the color robustness of such methods -- an often overlooked yet critical factor for achieving visual realism. While most evaluations conflate color with other lighting attributes (e.g., intensity, direction), we isolate color as the primary variable of interest. Rather than introducing a new lighting estimation algorithm, we explore whether simple adaptation techniques can enhance the color accuracy of existing models. Using a novel HDR dataset featuring diverse lighting colors, we systematically evaluate several adaptation strategies. Our results show that preprocessing the input image with a pre-trained white balance network improves color robustness, outperforming other strategies across all tested scenarios. Notably, this approach requires no retraining of the lighting estimation model. We further validate the generality of this finding by applying the technique to three state-of-the-art lighting estimation methods from recent literature.