A patent review of MAPK inhibitors (2018 - present).

INTRODUCTION: The mitogen-activated protein kinase (MAPK) family consist of p38 MAP kinases, c-Jun N-terminal kinases (JNKs) and extracellular signal-regulated kinases (ERKs). They are involved in a multitude of diseases, including inflammatory, autoimmune, neurodegenerative, and metabolic diseases as well as cancer. In recent years, further developments in the field of MAPK-inhibitors have been reported, including an isoform or downstream target selective inhibition of MAPKs as well as target protein degradation approaches. AREAS COVERED: This review summarizes newly patented MAPK-inhibitors that were claimed between 2018 and early 2023. Presented are the patents as well as their corresponding publications, the storyline of development, and clinical trials involving these compounds. This article elaborates a total of 27 patents, which were identified using established search engines. EXPERT OPINION: Although industrial research on MAPK-inhibitors has been ongoing for more than 20 years, novel clinical trials of MAPK-inhibitors as potential drug candidates are still being conducted in the period under review. Recently reported inhibitors show an excellent selectivity profile and are even achieving selectivity between closely related isoforms. This progression offers the possibility to eliminate unwanted side effects and may finally lead to the approval of the first MAPK-inhibitor.

Ultrasonic Energy and Data Transfer through a Metal-Liquid Multi-Layer Channel Enhanced by Automatic Gain and Carrier Control.

Ultrasonic communication and power transfer are attractive solutions when conventional electromagnetic-based or wired connections are unfeasible. Most ultrasonic communication applications concern a single-solid barrier. Nevertheless, some relevant scenarios can be composed of several fluid-solid media, through which communication and power transfer are intended. Due to its multi-layer nature, insertion loss and, consequently, the system efficiency considerably decrease. This paper presents an ultrasonic system capable of simultaneously power transferring and transmitting data through a set of two flat steel plates separated by a fluid layer using a pair of co-axially aligned piezoelectric transducers on opposite sides of the barrier. The system is based on frequency modulation and adopts a novel technique for automatic gain and automatic carrier control. The modems used herein were developed specifically for this application, rendering the system able to transfer data at a rate of 19,200 bps, using the frequency shift keying (FSK) modulation scheme and simultaneously transferring 66 mW of power through two flat steel plates (5 mm) separated by a fluid layer (100 mm), which completely supplied a pressure and temperature sensor. The proposed automatic gain control allowed a higher data transmission rate and the automatic carrier control reduced power consumption. The former reduced the transmission error from 12% to 5%, while the latter reduced the global power consumption from 2.6 W to 1.2 W. The proposed system is promising for monitoring applications such as oil wellbore structural health monitoring systems.

A method for polyclonal antigen-specific T cell-targeted genome editing (TarGET) for adoptive cell transfer applications.

Adoptive cell therapy of donor-derived, antigen-specific T cells expressing native T cell receptors (TCRs) is a powerful strategy to fight viral infections in immunocompromised patients. Determining the fate of T cells following patient infusion hinges on the ability to track them in vivo. While this is possible by genetic labeling of parent cells, the applicability of this approach has been limited by the non-specificity of the edited T cells. Here, we devised a method for CRISPR-targeted genome integration of a barcoded gene into Epstein-Barr virus-antigen-stimulated T cells and demonstrated its use for exclusively identifying expanded virus-specific cell lineages. Our method facilitated the enrichment of antigen-specific T cells, which then mediated improved cytotoxicity against Epstein-Barr virus-transformed target cells. Single-cell and deep sequencing for lineage tracing revealed the expansion profile of specific T cell clones and their corresponding gene expression signature. This approach has the potential to enhance the traceability and the monitoring capabilities during immunotherapeutic T cell regimens.

Does Biological Sex Matter in Lyme Disease? The Need for Sex-Disaggregated Data in Persistent Illness.

Background: Biological sex should be included as an important variable in clinical research studies to identify outcome differences between men and women. Very few Lyme disease studies were designed to consider sex-based differences or gender bias as an important component of the research design. Methods: To assess sex-based differences in Lyme disease patients who were clinically diagnosed and reported remaining ill for six or more months after receiving antibiotic treatment, we analyzed self-reported clinical data from 2170 patients in the MyLymeData patient registry. We also reviewed previous Lyme disease studies for distribution of patients by biological sex according to stage of illness, data source, and definition of disease used as enrollment criteria. Results: In MyLymeData, women reported more tick-borne coinfections, worse symptoms, longer diagnostic delays, more misdiagnoses, and worse functional impairment than men. No differences were reported in antibiotic treatment response or side effects. In our review, of clinical research trials and data sources, we identified a smaller percentage of women in studies of acute Lyme disease and a larger percentage of women in studies of persistent illness. Samples and data sources that were more reflective of patients seen in clinical practice had a higher percentage of women than randomized controlled trials and post-treatment Lyme disease studies. Conclusion: Our results indicate that biological sex should be integrated into Lyme disease research as a distinct variable. Future Lyme disease studies should include sex-based disaggregated data to illuminate differences that may exist between men and women with persistent illness.

A Review of the Recommendations and Strength of Evidence for Clinical Practice Guidelines on the Management of Small Renal Masses.

Introduction: With the rise in the detection of incidental small renal masses (SRM), the management paradigm for these patients has become an issue of increasing concern. We aim to identify areas of consensus, controversy, and opportunities for improvement among recently published guidelines and assess the strength of evidence for the management of SRMs. Methods: We reviewed practice guidelines for SRMs promulgated by the American Urological Association, European Association of Urology, National Comprehensive Cancer Network, American Society of Clinical Oncology, European Society for Medical Oncology, and the Chinese Society of Clinical Oncology. Levels of evidence and strength of recommendations for evaluation, management and follow-up were analyzed with regard to consensus, conflict, and neglect. Results: There is consensus among guidelines for the initial evaluation and treatment of SRMs; however, discrepancies exist with regard to indications for active surveillance, thermal ablation, and timing/method of follow-up after treatment. Routine renal mass biopsy is not recommended by any guideline. Overwhelmingly, guideline statements are based on low to moderate levels of evidence; only 23% of the reviewed guidelines were based on high-level evidence, 38% based on moderate-level, and 39% on low-level evidence or expert opinion. Conclusions: Despite all six guidelines sharing a consensus on most management topics regarding SRMs, the ongoing lack of high-level evidence precludes gold standard recommendations in the areas of diagnosis, treatment, and follow-up. More high-quality studies are needed to develop a stronger, data-supported universal guideline for the management of SRMs.

Do non-bovine domestic animals produce A2 milk?: an in silico analysis.

A2 milk is an easily digestible product since it has only A2 beta-casein. In cattle, the A1 and A2 alleles are found in the population and the A2 milk is produced from A2A2 animals. Little is known about these alleles in other domestic dairy species. The present study aims to analyze sequence of genetic material available on public databases and quantify the animals genotyped. Eight domestic species were analyzed. There is strong evidence that domestic non-bovine species only carry A2 beta-casein. The data reported here for goats already confirm it due to the large number of animals genotyped as well as buffaloes. It means that they naturally produce A2 milk and no selection must be done. Thus, the fact that A2 milk is easier to digest can be used to add value to dairy product of these species. It helps to conquer new markets. It also improves people's health and breeder profitability.

Porcine Bladder Replacement with a Bilayer Silk Fibroin Enhanced Prosthetic Reservoir: A Feasibility Study.

Introduction: The creation of synthetic reservoirs for bladder replacement has been limited by challenges of interfacing synthetic materials and native tissue. We sought to overcome this challenge by utilizing a novel bilayer silk fibroin scaffold (BLSF) as an intermediary toward the development of an acellular prosthetic reservoir. Methods: Under institutionally approved protocols, 3D-printed reservoirs were implanted in six juvenile female pigs after cystectomy. BLSF was attached to the in situ prosthetic reservoir serving as an intermediary to native ureteral and urethral tissue anastomoses. Our first protocol allowed four pigs to be survived up to 7 days, and the second protocol allowed two pigs to be survived for up to 1 year. At the first sign of functional decline or the end of the study period, the animals were euthanized, and kidneys, ureters, prosthetic bladder, and urethra were harvested en bloc for histopathology analysis. Results: The first two pigs had anastomotic urine leaks because of design flaws resulting in early termination. The third pig had acute renal failure resulting in early termination. The artificial bladder design was modified in subsequent iterations. The fourth pig survived for 7 days and, upon autopsy, had intact urethral and ureteral anastomoses. The fifth and sixth pigs survived for 11 and 12 weeks, respectively, before they were sacrificed because of failure to thrive. One animal developed an enteric fistula. The other animal had an intact anastomosis, and the BLFS was identified at the ureteral and urethral anastomoses on histopathologic analysis. Conclusions: Replacing the porcine bladder with a prosthetic bladder was achieved for up to 3 months, the second longest survival period for a nonbiologic bladder alternative. BLSF was used for the first time to create an interface between synthetic material and biologic tissue by allowing ingrowth of urothelium onto the acellular alloplastic bladder.

Mechanical and gas adsorption properties of graphene and graphynes under biaxial strain.

The exceptional properties of two-dimensional (2D) solids have motivated extensive research, which revealed the possibility of controlling many characteristics of these materials through strain. For instance, previous investigations demonstrated that compressive deformation could be used to direct the chemisorption of atomic hydrogen and oxygen. Still, to our knowledge, there is no work detailing how strain affects the adsorption isotherms of 2D materials and the adsorption properties of materials such as the graphynes, which are monolayers composed of sp and sp[Formula: see text] carbon atoms. In the present work, we analyze how biaxial tensile deformation changes the adsorption properties of four 2D materials (graphene, [Formula: see text]-graphyne, [Formula: see text]-graphyne, and [Formula: see text]-graphyne). To achieve this, we perform Monte Carlo Grand Canonical calculations to obtain the adsorption isotherms of H[Formula: see text], CO[Formula: see text], and CH[Formula: see text] on the monolayers with and without strain. And, to apply the deformation, we carry out Molecular Dynamics simulations. We find a substantial reduction in the amount of gas adsorbed on the monolayers for nearly all gas-solid combinations. This is particularly true for graphene, where 14.5% strain reduces the quantity of H[Formula: see text]/CO[Formula: see text]/CH[Formula: see text] by 44.7/64.1/41.7% at P [Formula: see text] 1 atm. To understand the results, we calculate adsorption enthalpies and analyze the gas distribution above the monolayers. We also characterize the mechanical properties of the considered solids under biaxial deformation. Finally, a comparison of pore sizes with the kinetic diameters of various gases suggests applications for the graphynes, with and without strain, in gas separation.

speedingCARs: accelerating the engineering of CAR T cells by signaling domain shuffling and single-cell sequencing.

Chimeric antigen receptors (CARs) consist of an antigen-binding region fused to intracellular signaling domains, enabling customized T cell responses against targets. Despite their major role in T cell activation, effector function and persistence, only a small set of immune signaling domains have been explored. Here we present speedingCARs, an integrated method for engineering CAR T cells via signaling domain shuffling and pooled functional screening. Leveraging the inherent modularity of natural signaling domains, we generate a library of 180 unique CAR variants genomically integrated into primary human T cells by CRISPR-Cas9. In vitro tumor cell co-culture, followed by single-cell RNA sequencing (scRNA-seq) and single-cell CAR sequencing (scCAR-seq), enables high-throughput screening for identifying several variants with tumor killing properties and T cell phenotypes markedly different from standard CARs. Mapping of the CAR scRNA-seq data onto that of tumor infiltrating lymphocytes further helps guide the selection of variants. These results thus help expand the CAR signaling domain combination space, and supports speedingCARs as a tool for the engineering of CARs for potential therapeutic development.

Effects of Avermectins on the Environment Based on Its Toxicity to Plants and Soil Invertebrates-a Review.

Avermectins are pharmaceutical drugs widely used mainly in livestock to combat both ectoparasites and endoparasites. Drugs belonging to this family include ivermectin, abamectin, doramectin, selamectin, eprinomectin, and emamectin benzoate, and they share similar chemical characteristics. When administered to livestock, between 80 and 98% of the drug is estimated to leave the body without being metabolized in feces, thus reaching the soil. For this reason, concern for avermectin contamination in soil is increasing, and researchers are focused on estimating the effects on non-target organisms, such as plants and soil invertebrates. This review aimed to compile and discuss updated data of avermectin toxicity on non-target organisms to better comprehend its effect on the environment. Effects on plants are scarcely studied, since they were not believed to absorb these drugs. However, recent studies suggest that plants can be negatively affected. Regarding soil invertebrates, negative effects such as increased mortality and reduced reproduction are best known to dung-beetles. Recently, some studies have also suggested that earthworms, springtails, and enchytraeids can be adversely affected by avermectin exposure. Since ivermectin was the first avermectin marketed, most of the data refers to this product. According to new data on scientific literature, avermectins can now be considered harmful to non-target organisms, and its prudent use is recommended in order to reduce negative effects on the environment. For future investigations, inclusion of avermectins other than ivermectin, as well as field and "omics" studies is suggested.

Environmentally realistic concentrations of eprinomectin induce phytotoxic and genotoxic effects in Allium cepa.

Eprinomectin, a veterinary drug within the family of avermectins, is widely used in the agricultural sector to combat a variety of parasites, mainly nematodes. However, only 10% of the drug is metabolized in the organism, so large quantities of the drug are released into the environment through urine and/or feces. Soil is the first and main environmental compartment to be contaminated by it, and nontargeted organisms can be affected. Thus, the present study aims to evaluate the phytotoxicity (through the evaluation of germination, root development, and germination speed) and genotoxicity (through an assessment of the induction of micronuclei and chromosomal aberrations) of eprinomectin. For the analyses, Allium cepa seeds were germinated in soil contaminated with a range of concentrations of eprinomectin: from 0.5 to 62.5 µg/g for the genotoxicity test and from 0.5 to 128.0 µg/g for the phytotoxicity test. The results showed that seed germination was not affected, but root development was affected at concentrations of 0.5 µg/g, 1.0 µg/g, 4.0 µg/g, 8.0 µg/g, 64.0 µg/g, and 128.0 µg/g, and germination speed was significantly changed at concentrations of 1.0 µg/g, 4.0 µg/g, 16.0 µg/g, 32.0 µg/g, and 64.0 µg/g. Significant differences in the mitotic index and genotoxicity index were observed only at concentrations of 2.5 µg/g and 12.5 µg/g, respectively. Only the 0.5 µg/g concentration did not show significant induction of micronuclei in the meristematic cells, but the damage observed at other concentrations did not persist in F1 cells. According to the results, eprinomectin is both phytotoxic and genotoxic, so the release of eprinomectin into the environment should be minimized.

Prospective, Randomized Comparison of Dual-Lumen vs Single-Lumen Flexible Ureteroscopes in Proximal Ureteral and Renal Stone Management.

Introduction: We sought to compare the safety, efficacy, efficiency, and surgeon experience during upper urinary tract stone management with single-lumen (SLFU) vs dual-lumen flexible ureteroscopes (DLFU). Materials and Methods: Seventy-nine patients with proximal ureteral or renal stone burden <2 cm were randomized to a SLFU or DLFU. We recorded times for ureteroscopy (URS), laser lithotripsy, stone basketing, as well as intraoperative and postoperative complications. The rate of stone clearance and stone free status were calculated using CT imaging. Surgeons completed a survey after each procedure rating various metrics regarding ureteroscope performance. Results: Thirty-five patients from the single-lumen group and 44 patients from the dual-lumen group had comparable median URS time (37 vs 35 minutes, p = 0.984) and basketing time (12 vs 19 minutes; p = 0.584). Median lithotripsy time was decreased in the dual-lumen group (single: 6 vs dual: 2 minutes, p = 0.017). The stone clearance rate was superior in the dual-lumen group (single: 3.7 vs dual: 7.1 mm3/min, p = 0.025). The absolute stone-free rate (SFR) was superior for the dual-lumen group (single: 26% vs dual: 48%, p = 0.045). No differences in intraoperative (single: 0% vs dual: 2%; p = 0.375) and postoperative complications (single: 7% vs dual: 11%, p = 0.474) were observed. Surgeons' ratings of the dual-lumen ureteroscope was superior for visibility, comfort, ease of use, and overall performance. Conclusions: The use of the dual-lumen ureteroscope in patients with renal and proximal ureteral stones <2 cm provided shorter lithotripsy time, higher stone clearance rates, improved SFR, and superior surgeon ratings when compared with SLFUs.

Factors Associated with Ruptured Ectopic Pregnancy: A 10-Year Review at a District Hospital in Ghana.

Background: Approximately 1-2% of all pregnancies are ectopic. Despite a decline in ectopic pregnancy-related mortality, there is still a paucity of information on the factors associated with clinical presentation and outcomes in Sub-Saharan Africa which is essential in determining the most appropriate treatment modalities. Methods: We performed a ten-year retrospective chart review of cases of ectopic pregnancies managed at the Lekma hospital and assessed them for peculiar risk factors, clinical presentation, and outcomes. Associations between patients' sociodemographic characteristics, clinical presentation, and treatment outcome were evaluated using multiple logistic regression and reported as adjusted odds ratios (AOR). The confidence interval (CI) was set at 95%, and a p value <0.05 were considered significant. Results: Over the ten-year period, there were 115 ectopic pregnancies and 14,450 deliveries (7.9/1,000). The mean age ± standard deviation of the 115 patients was 27.61 ± 5.56. More than half of the patients were single (59/115, 51.3%). The majority (71.3%) of the patients presented with a ruptured ectopic pregnancy. After adjusting for covariates, the odds of an ectopic pregnancy presenting as ruptured among single patients was 2.63 times higher than that of married patients (AOR = 3.63, 95% CI: 1.33-9.93, p=0.01). Ectopic pregnancies located in the isthmic region of the tube had a 77% lower odds of presenting as ruptured than those located in the ampullary region (AOR = 0.23, 95% CI: 0.07-0.74, p=0.01). The odds of rupturing were 1.69 times increased for every additional week after the missed period (AOR = 2.69, 95% CI: 1.56-4.64, p < 0.01). No mortalities were reported as a result of an ectopic pregnancy. Conclusion: Most of the cases of ectopic pregnancy presented ruptured. Marital status and period of amenorrhoea were significantly associated with rupture.

Multidisciplinary Approach and Outcomes of Pretreatment Small (cT1a) Renal Mass Biopsy: Single-Center Experience.

Purpose: We evaluated our experience of a multidisciplinary approach to renal mass biopsy (RMB) for small renal masses (SRMs) employing in-office ultrasound (US)-guided biopsy by urology (24%), CT, or US biopsy by interventional radiology (IR) (79%), and endoscopic ultrasound (EUS)-guided biopsy by gastroenterology (GI) (4%). Materials and Methods: A single-institution retrospective review of patients who underwent RMB for SRM from May 2013 to August 2019 was conducted. Data regarding patient demographics, tumor characteristics, biopsy technique, histopathology, and management were collected. Diagnostic rates, concordance with final pathology, complications, and outcomes were analyzed. Results: Of the 192 biopsies reviewed, 63% biopsies were malignant, 20% were benign, and 17% were nondiagnostic. Based on biopsy results, 71 patients (37%) elected active surveillance. Thirty-eight (20%) patients underwent cryoablation, 56 (29%) underwent partial nephrectomy, 14 (7%) underwent radical nephrectomy, and the remaining patients were treated elsewhere. The rate of surgery for benign pathology after pretreatment RMB was 3%. The concordance rate between biopsy and final pathology was 99% for malignancy, 96% for specific pathology subtype, and 85% for renal cell carcinoma grade. Median time from diagnosis to definitive treatment was 97 days (urology: 76, IR: 110 and GI: 54, p = 0.002). Three (1.6%) Clavien I complications were reported. Conclusion: Our multidisciplinary approach to RMB for clinical stage T1a demonstrated favorable safety and diagnostic rates, which effectively directed management strategies and minimized surgery for benign disease. Urologist-performed office biopsies significantly shortened the time from diagnosis to definitive treatment. Our experience with GI EUS biopsy has demonstrated feasibility and safety for tumors that were otherwise not accessible percutaneously.

SARS-CoV-2 reactive and neutralizing antibodies discovered by single-cell sequencing of plasma cells and mammalian display.

Characterization of COVID-19 antibodies has largely focused on memory B cells; however, it is the antibody-secreting plasma cells that are directly responsible for the production of serum antibodies, which play a critical role in resolving SARS-CoV-2 infection. Little is known about the specificity of plasma cells, largely because plasma cells lack surface antibody expression, thereby complicating their screening. Here, we describe a technology pipeline that integrates single-cell antibody repertoire sequencing and mammalian display to interrogate the specificity of plasma cells from 16 convalescent patients. Single-cell sequencing allows us to profile antibody repertoire features and identify expanded clonal lineages. Mammalian display screening is used to reveal that 43 antibodies (of 132 candidates) derived from expanded plasma cell lineages are specific to SARS-CoV-2 antigens, including antibodies with high affinity to the SARS-CoV-2 receptor-binding domain (RBD) that exhibit potent neutralization and broad binding to the RBD of SARS-CoV-2 variants (of concern/interest).

Patient-reported outcomes in HCC: A scoping review by the Practice Metrics Committee of the American Association for the Study of Liver Diseases.

BACKGROUND AND AIMS: HCC is a leading cause of mortality in patients with advanced liver disease and is associated with significant morbidity. Despite multiple available curative and palliative treatments, there is a lack of systematic evaluation of patient-reported outcomes (PROs) in HCC. APPROACH AND RESULTS: The American Association for the Study of Liver Diseases Practice Metrics Committee conducted a scoping review of PROs in HCC from 1990 to 2021 to (1) synthesize the evidence on PROs in HCC and (2) provide recommendations on incorporating PROs into clinical practice and quality improvement efforts. A total of 63 studies met inclusion criteria investigating factors associated with PROs, the relationship between PROs and survival, and associations between HCC therapy and PROs. Studies recruited heterogeneous populations, and most were cross-sectional. Poor PROs were associated with worse prognosis after adjusting for clinical factors and with more advanced disease stage, although some studies showed better PROs in patients with HCC compared to those with cirrhosis. Locoregional and systemic therapies were generally associated with a high symptom burden; however, some studies showed lower symptom burden for transarterial radiotherapy and radiation therapy. Qualitative studies identified additional symptoms not routinely assessed with structured questionnaires. Gaps in the literature include lack of integration of PROs into clinical care to guide HCC treatment decisions, unknown impact of HCC on caregivers, and the effect of palliative or supportive care quality of life and health outcomes. CONCLUSION: Evidence supports assessment of PROs in HCC; however, clinical implementation and the impact of PRO measurement on quality of care and longitudinal outcomes need future investigation.

Maintenance of Wellness in Patients With Obsessive-Compulsive Disorder Who Discontinue Medication After Exposure/Response Prevention Augmentation: A Randomized Clinical Trial.

IMPORTANCE: Serotonin reuptake inhibitors (SRIs) are the only medications approved for obsessive-compulsive disorder (OCD), yet most patients taking SRIs exhibit significant symptoms. Adding exposure/response prevention (EX/RP) therapy improves symptoms, but it is unknown whether patients maintain wellness after discontinuing SRIs. OBJECTIVE: To assess whether patients with OCD who are taking SRIs and have attained wellness after EX/RP augmentation can discontinue their SRI with noninferior outcomes compared with those who continue their SRI therapy. DESIGN, SETTING, AND PARTICIPANTS: A 24-week, double-blind, randomized clinical trial was performed from May 3, 2013, to June 25, 2018. The trial took place at US academic medical centers. Participants included 137 adults with a principal diagnosis of OCD (≥1 year) who were taking an SRI (≥12 weeks), had at least moderate symptoms (defined as Yale-Brown Obsessive-Compulsive Scale [Y-BOCS] score ≥18 points), and received as many as 25 sessions of EX/RP therapy. Those who attained wellness (Y-BOCS score ≤14 points; 103 patients [75.2%]) were study eligible. Data were analyzed from June 29, 2019, to October 2, 2021. INTERVENTION: Participants were randomly assigned either to receive taper to placebo (taper group) or to continue their SRI (continuation group) and monitored for 24 weeks. MAIN OUTCOME AND MEASURES: The Y-BOCS score (range, 0-40 points) was the primary outcome; the Hamilton Depression Rating Scale (HDRS; range, 0-52 points) and the Quality-of-Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF; range, 0%-100%) scores were secondary outcomes. Outcomes were assessed at 8 time points by independent evaluators who were blinded to randomization. The taper regimen was hypothesized to be noninferior to continuation at 24 weeks using a 1-sided α value of .05. RESULTS: A total of 101 patients (mean [SD] age, 31.0 [11.2] years; 55 women [54.5%]) participated in the trial: 51 patients (50.5%) in the taper group and 50 patients (49.5%) in the continuation group. At 24 weeks, patients in the taper group had noninferior results compared with patients in the continuation group (mean [SD] Y-BOCS score: taper group, 11.47 [6.56] points; continuation group: 11.51 [5.97] points; difference, -0.04 points; 1-sided 95% CI, -∞ to 2.09 points [below the noninferiority margin of 3.0 points]; mean [SD] HDRS score: taper group, 5.69 [3.84] points; continuation group, 4.61 [3.46] points; difference, 1.08 points; 1-sided 95% CI, -∞ to 2.28 points [below the noninferiority margin of 2.5 points]; mean [SD] Q-LES-Q-SF score: taper group, 68.01% [15.28%]; continuation group, 70.01% [15.59%]; difference, 2.00%; 1-sided 95% CI, -∞ to 6.83 [below the noninferiority margin of 7.75]). However, the taper group had higher rates of clinical worsening (23 of 51 [45%] vs 12 of 50 [24%]; P = .04). CONCLUSIONS AND RELEVANCE: Results of this randomized clinical trial show that patients with OCD who achieve wellness after EX/RP therapy could, on average, discontinue their SRI with noninferior outcomes compared with those who continued their SRI. Those who tapered the SRI had higher clinical worsening rates. Future research should evaluate if SRI half-life alters these rates. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01686087.

Ex Vivo Renal Stone Dusting: Impact of Laser Modality, Ureteral Access Sheath, and Suction on Total Stone Clearance.

Introduction and Objectives: Conventional renal stone dusting is challenging; the holmium (Ho:YAG) laser and holmium with MOSES effect (Ho:YAG-MOSES) fail to uniformly produce fragments ≤100 µm (i.e., dust). The superpulse thulium fiber laser (sTFL) may more effectively render uroliths into "dust," and may thus improve stone-free rates. Accordingly, we performed ex vivo evaluations with all three laser modalities, assessing stone fragments and stone clearance. Methods: Seventy-two ex vivo porcine kidney-ureter models were divided into 12 groups of 6: laser type (Ho:YAG, Ho:YAG-MOSES, sTFL), ureteroscope with and without applied suction, and the presence or absence of a 14F ureteral access sheath (UAS). Calcium oxalate stones were preweighed and implanted into each kidney via a pyelotomy. Stones were treated at 16W using dusting settings of 0.4J × 40Hz (Ho:YAG), 0.2J × 80Hz (Ho:YAG-MOSES), and 0.2J × 80Hz (sTFL) for up to 20 minutes. No stone basketing was performed. Kidneys were bivalved and residual fragments were collected, dried, weighed, and sieved to determine fragment size and stone clearance. Results: Initial stone mass (mg), procedure time (seconds), and laser energy expenditure (kJ) were similar in all 12 groups. The greatest stone clearance was seen with sTFL + suction + UAS (94%) compared with a conventional technique (Ho:YAG + no suction + no UAS) (65%, p < 0.01). The use of sTFL provided greater stone clearance than Ho:YAG or Ho:YAG-MOSES. Aspiration improved stone clearance for sTFL (p = 0.01), but not for Ho:YAG or Ho:YAG-MOSES, consistent with the creation of smaller fragments with sTFL. Presence of a 14F UAS improved stone clearance in all scenarios (p < 0.01). Conclusions: In this ex vivo study, stone clearance was optimized under the following conditions: sTFL, 14F UAS, and aspiration. This combination resulted in 94% of stone fragments being cleared; the 6% remaining fragments were all <2 mm. In all scenarios, deployment of a 14F UAS improved stone clearance.

Quality measures in HCC care by the Practice Metrics Committee of the American Association for the Study of Liver Diseases.

The burden of HCC is substantial. To address gaps in HCC care, the American Association for the Study of Liver Diseases (AASLD) Practice Metrics Committee (PMC) aimed to develop a standard set of process-based measures and patient-reported outcomes (PROs) along the HCC care continuum. We identified candidate process and outcomes measures for HCC care based on structured literature review. A 13-member panel with content expertise across the HCC care continuum evaluated candidate measures on importance and performance gap using a modified Delphi approach (two rounds of rating) to define the final set of measures. Candidate PROs based on a structured scoping review were ranked by 74 patients with HCC across 7 diverse institutions. Out of 135 measures, 29 measures made the final set. These covered surveillance (6 measures), diagnosis (6 measures), staging (2 measures), treatment (10 measures), and outcomes (5 measures). Examples included the use of ultrasound (± alpha-fetoprotein [AFP]) every 6 months, need for surveillance in high-risk populations, diagnostic testing for patients with a new AFP elevation, multidisciplinary liver tumor board (MLTB) review of Liver Imaging-Reporting and Data System 4 lesions, standard evaluation at diagnosis, treatment recommendations based on Barcelona Clinic Liver Cancer staging, MLTB discussion of treatment options, appropriate referral for evaluation of liver transplantation candidacy, and role of palliative therapy. PROs include those related to pain, anxiety, fear of treatment, and uncertainty about the best individual treatment and the future. The AASLD PMC has developed a set of explicit quality measures in HCC care to help bridge the gap between guideline recommendations and measurable processes and outcomes. Measurement and subsequent implementation of these metrics could be a central step in the improvement of patient care and outcomes in this high-risk population.

A rational blueprint for the design of chemically-controlled protein switches.

Small-molecule responsive protein switches are crucial components to control synthetic cellular activities. However, the repertoire of small-molecule protein switches is insufficient for many applications, including those in the translational spaces, where properties such as safety, immunogenicity, drug half-life, and drug side-effects are critical. Here, we present a computational protein design strategy to repurpose drug-inhibited protein-protein interactions as OFF- and ON-switches. The designed binders and drug-receptors form chemically-disruptable heterodimers (CDH) which dissociate in the presence of small molecules. To design ON-switches, we converted the CDHs into a multi-domain architecture which we refer to as activation by inhibitor release switches (AIR) that incorporate a rationally designed drug-insensitive receptor protein. CDHs and AIRs showed excellent performance as drug responsive switches to control combinations of synthetic circuits in mammalian cells. This approach effectively expands the chemical space and logic responses in living cells and provides a blueprint to develop new ON- and OFF-switches.