Peptide-mimetic treatment of Pseudomonas aeruginosa in a mouse model of respiratory infection.

The rise of drug resistance has become a global crisis, with >1 million deaths due to resistant bacterial infections each year. Pseudomonas aeruginosa, in particular, remains a serious problem with limited solutions due to complex resistance mechanisms that now lead to more than 32,000 multidrug-resistant (MDR) infections and over 2000 deaths in the U.S. annually. While the emergence of resistant bacteria has become ominously common, identification of useful new drug classes has been limited over the past over 40 years. We found that a potential novel therapeutic, the peptide-mimetic TM5, is effective at killing P. aeruginosa and displays sufficiently low toxicity in mammalian cells to allow for use in treatment of infections. Interestingly, TM5 kills P. aeruginosa more rapidly than traditional antibiotics, within 30-60 min in vitro, and is effective against a range of clinical isolates, including extensively drug resistant strains. In vivo, TM5 significantly reduced bacterial load in the lungs within 24 h compared to untreated mice and demonstrated few adverse effects. Taken together, these observations suggest that TM5 shows promise as an alternative therapy for MDR P. aeruginosa respiratory infections.

Sigmoid Volvulus in the Setting of Type 4 Hiatal Hernia: An Uncommon Presentation and Literature Review.

Hiatal hernias occur when intra-abdominal contents protrude into the diaphragmatic opening. Of the four classifications, Type 4 hiatal hernias are the most rare and severe. They develop from herniation of the gastroesophageal junction and abdominal viscera other than the stomach into the thoracic cavity. The resulting increase in intrathoracic pressure can cause a wide variety of symptoms on presentation and potentially lead to misdiagnosis. We present a rare case in which a 78-year-old woman presented with nonspecific symptoms and was diagnosed with incarcerated Type 4 hiatal hernia with sigmoid volvulus. We also report a literature review from 2015 to emphasize the importance of recognizing diverse symptomatic presentations in complex Type 4 hiatal hernias and the need for a comprehensive evaluation, as early detection and prompt intervention are essential in preventing life-threatening complications.

Real-world assessment of longitudinal opioid use and healthcare resource utilization in patients undergoing colorectal resection.

Liposomal bupivacaine (LB) has been used in multimodal pain management regimens to improve postsurgical analgesia. This retrospective cohort analysis assessed clinical and economic outcomes of LB vs non-LB analgesia in minimally invasive colorectal resection surgery using real-world patient data from the IQVIA linkage claims databases. Patients who received LB were 1:1 matched to patients who did not receive LB (non-LB) via propensity scores. Outcomes included opioid use during the perioperative (2 weeks before surgery to 2 weeks after discharge), continued (>2 weeks to 3 months after discharge), and persistent (>3 months to 6 months after discharge) periods and healthcare resource utilization (HRU) during the first 3 months after discharge. Mean opioid consumption was lower in the LB (n = 4397) versus non-LB (n = 4397) cohort perioperatively (483 vs 538 morphine milligram equivalents [MMEs]; P = 0.001) and after discharge within ∼3 months (222 vs 328 MMEs; P < 0.0001) and 3-6 months (245 vs 384 MMEs; P < 0.0001). The LB cohort had shorter mean length of stay (5.2 vs 5.7 days; P < 0.0001) and fewer inpatient readmissions (odds ratio [OR], 0.71; P < 0.0001), emergency department visits (OR, 0.78; P < 0.0001), and outpatient/office visits (OR, 0.91; P = 0.028) than the non-LB cohort 3 months after discharge. These data suggest use of LB in minimally invasive colorectal resection surgery may reduce perioperative and postdischarge opioid use as well as HRU. Although additional studies are needed to confirm these findings, this analysis provides valuable real-world data from large claims databases to evaluate clinical and economic outcomes that complement other types of retrospective and prospective studies.

Improved Pain and Function With Triamcinolone Acetonide Extended-Release and Cryoneurolysis for Knee Osteoarthritis: Use of a New Real-World Registry.

BACKGROUND: Knee osteoarthritis (OA) affects 19% of American adults aged more than 45 years and costs $27+ billion annually. A wide range of nonoperative treatment options are available. This study compared 6 treatments: cryoneurolysis with deep genicular nerve block (Cryo-Deep/Both), cryoneurolysis with superficial nerve block (Cryo-Superficial), intra-articular hyaluronic acid (IA-HA) injections, nonsteroidal anti-inflammatory drug injections (IA-NSAIDs), IA-corticosteroids (IA-CS) injections, or IA-triamcinolone extended release (IA-TA-ER) injections over 4 months for: (1) pain severity and analgesic use; and (2) physical function (from Knee Injury and Osteoarthritis Outcome Score for Joint Replacement). METHODS: Patients who had unilateral knee OA and received nonoperative intervention were enrolled in the Innovations in Genicular Outcomes Research registry, a novel, multicenter real-world registry, between September 2021 and February 2024. A total of 480 patients were enrolled. Both pain and functional outcomes were assessed at baseline, weekly, and monthly, which were analyzed by overall trend, magnitude changes pretreatment to post-treatment, and distribution-based minimally clinically important difference (MCID) score. Multivariate linear regressions with adjustments for 7 confounding factors were used to compare follow-up outcomes among 6 treatment groups. RESULTS: Use of IA-TA-ER injections was associated with the lowest pain, greatest pain reduction, and highest prevalence of patients achieving MCID relative to other treatments (P < .001). Deep/Both-Cryo and IA-CS were associated with a higher prevalence of achieving MCID than IA-HA, IA-NSAIDs, and Cryo-Superficial (P ≤ .001). Use of IA-TA-ER was also associated with the greatest functional score, improvement from baseline, and highest prevalence of patients achieving MCID than other treatments (P ≤ .003). CONCLUSIONS: The IA-TA-ER appears to outperform other treatments in terms of pain relief and functional improvement for up to 4 months following treatment. In addition, outcomes in the novel cryoneurolysis and conventional IA-CS were similar to one another and better than those in IA-HA and IA-NSAIDs.

Liposomal Bupivacaine Analgesia in Deep Inferior Epigastric Perforator Flap Breast Reconstruction: A Retrospective Cohort Study.

Background: Liposomal bupivacaine (LB) can be used for postsurgical analgesia after breast reconstruction. We examined real-world clinical and economic benefits of LB versus bupivacaine after deep inferior epigastric perforator (DIEP) flap breast reconstruction. Methods: This retrospective cohort study used the IQVIA claims databases to identify patients undergoing primary DIEP flap breast reconstruction in 2016-2019. Patients receiving LB and those receiving bupivacaine were compared to assess opioid utilization in morphine milligram equivalents (MMEs) and healthcare resource utilization during perioperative (2 weeks before surgery to 2 weeks after discharge) and 6-month postdischarge periods. A generalized linear mixed-effects model and inverse probability of treatment weighting method were performed. Results: Weighted baseline characteristics were similar between cohorts (LB, n = 669; bupivacaine, n = 348). The LB cohort received significantly fewer mean MMEs versus the bupivacaine cohort during the perioperative (395 versus 512 MMEs; rate ratio [RR], 0.771 [95% confidence interval (CI), 0.677-0.879]; P = 0.0001), 72 hours after surgery (63 versus 140 MMEs; RR, 0.449 [95% CI, 0.347-0.581]; P < 0.0001), and inpatient (154 versus 303 MMEs; RR, 0.508 [95% CI, 0.411-0.629]; P < 0.0001) periods; postdischarge filled opioid prescriptions were comparable. The LB cohort was less likely to have all-cause inpatient readmission (odds ratio, 0.670 [95% CI, 0.452-0.993]; P = 0.046) and outpatient clinic/office visits (odds ratio, 0.885 [95% CI, 0.785-0.999]; P = 0.048) 3 months after discharge than the bupivacaine cohort; other all-cause healthcare resource utilization outcomes were not different. Conclusions: LB was associated with fewer perioperative MMEs and all-cause 3-month inpatient readmissions and outpatient clinic/office visits than bupivacaine in patients undergoing DIEP flap breast reconstruction.

Cryoneurolysis Associated With Improved Pain, Function, and Sleep in Patients Following total Knee Arthroplasty: Use of a New Real-World Registry.

BACKGROUND: Total knee arthroplasty (TKA) is performed on approximately 790,000 patients annually in the United States and is projected to increase to 1.5 million by 2050. This study aimed at assessing the use of preoperative cryoneurolysis on patients undergoing TKA by analyzing: (1) pain severity; (2) opioid use; (3) functional status; and (4) sleep disturbance (SD) over 6 months following discharge. METHODS: Patients enrolled in the Innovations in Genicular Outcomes Registry between September 2021 and February 2024 were followed for 6 months. Our analyses included patients undergoing unilateral primary TKA with no preoperative opioid prescription, who either received cryoneurolysis, or did not. Baseline patient demographics were collected before TKA and tabulated. Pain management was assessed via the Brief Pain Inventory-Short Form instrument for pain severity. SD was measured using the patient-reported outcomes measurement information system questionnaire. Each outcome measure was assessed prior to TKA, weekly, and at monthly follow-up. Data were analyzed by a generalized linear mixed-effect regression model to compare cryoneurolysis versus control patients, with a P < .05 as significant. RESULTS: There were 80 patients who were treated with preoperative cryoneurolysis, while 60 control patients did not have treatment. Patients receiving cryoneurolysis experienced significantly lower pain severity and SD over the 6-month follow-up than control patients (P = .046). Cryoneurolysis was also associated with a trend toward greater functional improvement that did not reach statistical significance (P = .061). Further, patients who underwent cryoneurolysis were 72% less likely than control group patients to take opioids over 6 months following discharge (P < .001). CONCLUSIONS: Preoperative cryoneurolysis therapy in opioid-naive patients undergoing TKA is associated with improved pain, decreased opioid use, and improved SD for 6 months postoperatively. Cryoneurolysis, a nonopioid pain relief modality administered preoperatively, demonstrated substantial benefits in patients who underwent TKA.

Effects of liposomal bupivacaine on opioid use and healthcare resource utilization after outpatient spine surgery: a real-world assessment.

BACKGROUND CONTEXT: Perioperative pain management affects cost and outcomes in elective spine surgery. PURPOSE: This study investigated the association between liposomal bupivacaine (LB) and outpatient spine surgery outcomes, including perioperative, postoperative, and postdischarge opioid use and healthcare resource utilization. STUDY DESIGN: This was a retrospective comparative study. PATIENT SAMPLE: Eligibility criteria included adults with ≥6 months of continuous data before and after outpatient spine procedures including discectomy, laminectomy, or lumbar fusion. Patients receiving LB were matched 1:3 to patients receiving non-LB analgesia by propensity scores. OUTCOME MEASURES: Outcomes included (1) opioid use in morphine milligram equivalents (MMEs) during the perioperative and postdischarge periods and (2) postdischarge readmission and emergency department (ED) visits up to 3 months after surgery. Generalized linear mixed-effects modeling with appropriate distributions was used for analysis. METHODS: Deidentified data from the IQVIA linkage claims databases (2016-2019) were used for the analysis. This study was funded by Pacira BioSciences, Inc. RESULTS: In total, 381 patients received LB and 1143 patients received non-LB analgesia. Baseline characteristics were well balanced after propensity score matching. The LB cohort used fewer MMEs versus the non-LB cohort before discharge (80 vs 132 MMEs [mean difference, -52 MMEs; p=.0041]). Following discharge, there was a nonsignificant reduction in opioid use in the LB cohort versus the non-LB cohort within 90 days (429 vs 480 MMEs [mean difference, -50 MMEs; p=.289]) and from >90 days to 180 days (349 vs 381 MMEs [mean difference, -31 MMEs; p=.507]). The LB cohort had significantly lower rates of ED visits at 2 months after discharge versus the non-LB cohort (3.9% vs 7.6% [odds ratio, 0.50; p=.015]). Postdischarge readmission rates did not differ between cohorts. CONCLUSIONS: Use of LB for outpatient spine surgery was associated with reduced opioid use at the hospital and nonsignificant reduction in opioid use at all postoperative timepoints examined through 90 days after surgery versus non-LB analgesia. ED visit rates were significantly lower at 60 days after discharge. These findings support reduced cost and improved quality metrics in patients treated with LB versus non-LB analgesia for outpatient spine surgery.

Quality-of-Life Outcomes in Oral Cancer Patients Reconstructed With Double Free Flaps: A Preoperative and Postoperative Assessment.

PURPOSE: This study aimed to evaluate quality of life (QOL) in patients with locally advanced oral cancer who underwent surgical resection followed by simultaneous double free flap reconstruction. METHODS: Institutional database was reviewed from 2015 to 2021 and prospectively collected University of Washington Quality of Life data that were extracted for patients who met the inclusion criteria. Mean, composite, and best percentage scores were computed. Wilcoxon signed rank test was used to analyze differences between groups. RESULTS: Thirteen patients completed the assessment, all of them being male with a mean follow-up of 2.2 ± 1.2 years. Most common double free flap combination was fibula osteoseptocutaneous flap and anterolateral thigh flap (n = 11). Improvement in pain ( P = 0.01) domain score with decline in speech ( P = 0.01) and taste ( P = 0.02) was noted along with an overall decline in QOL ( P = 0.001) after cancer diagnosis. A decrease in physical function was seen postoperatively. Chewing and saliva were the most cited postoperative patient-reported domain affecting QOL. CONCLUSIONS: In double free flap reconstructed patients, in the postoperative phase, pain scores improved, whereas speech and taste scores declined. The overall health-related QOL declined compared with before cancer diagnosis.

Sequential free fibula transfers: Quality of life and systematic review.

BACKGROUND: Successive osteoseptocutaneous fibula transfers for jaws reconstruction are rare but important options. This study contributes patient-reported and clinical outcomes, as well as systematically reviews all existing reports. METHODS: All sequential fibula transfers performed by the senior author were reviewed from a prospectively managed database, including University of Washington quality of life (UWQoL). Systematic review was conducted in PubMed and Cochrane databases for similar publications. RESULTS: Eighteen patients (average age 51.5 years) received sequential fibulas (mean 4.7 years between reconstructions). Secondary fibulas more often had benign indications (72.2% vs. 33.3%, p = .04), most commonly osteoradionecrosis (38.9%). At a mean follow-up of 30.5 months, the average interincisal distance increased from 21.8 to 27.6 mm, and 92.3% tolerated an oral diet following the second fibula. Eight patients completed the UW-QoL before and after the second fibula, and three prior to the first fibula. Composite physical function was significantly decreased from 96.7 prefibula reconstruction to 63.3 following the first (p < .001) and 64.2 after the second fibula (p < .001). There were no differences in other domains. The systematic review yielded six articles reporting 56 patients (mean 39 months between fibulas). Secondary fibulas were performed for repeat malignancy (45%) and osteoreadionecrosis (39%), resulting in elevated tube feeding from 20% following the first to 39% following the second, but overall high quality of life in two studies. CONCLUSIONS: Sequential osteoseptocutaneous fibula reconstructions of jaws are often performed for benign indications such as osteoradionecrosis. Overall function and QoL are comparable with those following the first fibula transfer.

International Skin Imaging Collaboration-Designated Diagnoses (ISIC-DX): Consensus terminology for lesion diagnostic labeling.

BACKGROUND: A common terminology for diagnosis is critically important for clinical communication, education, research and artificial intelligence. Prevailing lexicons are limited in fully representing skin neoplasms. OBJECTIVES: To achieve expert consensus on diagnostic terms for skin neoplasms and their hierarchical mapping. METHODS: Diagnostic terms were extracted from textbooks, publications and extant diagnostic codes. Terms were hierarchically mapped to super-categories (e.g. 'benign') and cellular/tissue-differentiation categories (e.g. 'melanocytic'), and appended with pertinent-modifiers and synonyms. These terms were evaluated using a modified-Delphi consensus approach. Experts from the International-Skin-Imaging-Collaboration (ISIC) were surveyed on agreement with terms and their hierarchical mapping; they could suggest modifying, deleting or adding terms. Consensus threshold was >75% for the initial rounds and >50% for the final round. RESULTS: Eighteen experts completed all Delphi rounds. Of 379 terms, 356 (94%) reached consensus in round one. Eleven of 226 (5%) benign-category terms, 6/140 (4%) malignant-category terms and 6/13 (46%) indeterminate-category terms did not reach initial agreement. Following three rounds, final consensus consisted of 362 terms mapped to 3 super-categories and 41 cellular/tissue-differentiation categories. CONCLUSIONS: We have created, agreed upon, and made public a taxonomy for skin neoplasms and their hierarchical mapping. Further study will be needed to evaluate the utility and completeness of the lexicon.

Newer Pharmacologic Treatments in Adults With Type 2 Diabetes: A Clinical Guideline From the American College of Physicians.

DESCRIPTION: The American College of Physicians (ACP) developed this clinical guideline to update recommendations on newer pharmacologic treatments of type 2 diabetes. This clinical guideline is based on the best available evidence for effectiveness, comparative benefits and harms, consideration of patients' values and preferences, and costs. METHODS: This clinical guideline is based on a systematic review of the effectiveness and harms of newer pharmacologic treatments of type 2 diabetes, including glucagon-like peptide-1 (GLP-1) agonists, a GLP-1 agonist and glucose-dependent insulinotropic polypeptide agonist, sodium-glucose cotransporter-2 (SGLT-2) inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitors, and long-acting insulins, used either as monotherapy or in combination with other medications. The Clinical Guidelines Committee prioritized the following outcomes, which were evaluated using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach: all-cause mortality, major adverse cardiovascular events, myocardial infarction, stroke, hospitalization for congestive heart failure, progression of chronic kidney disease, serious adverse events, and severe hypoglycemia. Weight loss, as measured by percentage of participants who achieved at least 10% total body weight loss, was a prioritized outcome, but data were insufficient for network meta-analysis and were not rated with GRADE. AUDIENCE AND PATIENT POPULATION: The audience for this clinical guideline is physicians and other clinicians. The population is nonpregnant adults with type 2 diabetes. RECOMMENDATION 1: ACP recommends adding a sodium-glucose cotransporter-2 (SGLT-2) inhibitor or glucagon-like peptide-1 (GLP-1) agonist to metformin and lifestyle modifications in adults with type 2 diabetes and inadequate glycemic control (strong recommendation; high-certainty evidence). • Use an SGLT-2 inhibitor to reduce the risk for all-cause mortality, major adverse cardiovascular events, progression of chronic kidney disease, and hospitalization due to congestive heart failure. • Use a GLP-1 agonist to reduce the risk for all-cause mortality, major adverse cardiovascular events, and stroke. RECOMMENDATION 2: ACP recommends against adding a dipeptidyl peptidase-4 (DPP-4) inhibitor to metformin and lifestyle modifications in adults with type 2 diabetes and inadequate glycemic control to reduce morbidity and all-cause mortality (strong recommendation; high-certainty evidence).

Antiviral Effect of Antimicrobial Peptoid TM9 and Murine Model of Respiratory Coronavirus Infection.

New antiviral agents are essential to improving treatment and control of SARS-CoV-2 infections that can lead to the disease COVID-19. Antimicrobial peptoids are sequence-specific oligo-N-substituted glycine peptidomimetics that emulate the structure and function of natural antimicrobial peptides but are resistant to proteases. We demonstrate antiviral activity of a new peptoid (TM9) against the coronavirus, murine hepatitis virus (MHV), as a closely related model for the structure and antiviral susceptibility profile of SARS-CoV-2. This peptoid mimics the human cathelicidin LL-37, which has also been shown to have antimicrobial and antiviral activity. In this study, TM9 was effective against three murine coronavirus strains, demonstrating that the therapeutic window is large enough to allow the use of TM9 for treatment. All three isolates of MHV generated infection in mice after 15 min of exposure by aerosol using the Madison aerosol chamber, and all three viral strains could be isolated from the lungs throughout the 5-day observation period post-infection, with the peak titers on day 2. MHV-A59 and MHV-A59-GFP were also isolated from the liver, heart, spleen, olfactory bulbs, and brain. These data demonstrate that MHV serves as a valuable natural murine model of coronavirus pathogenesis in multiple organs, including the brain.

Development of a Health Equity Framework for the US Preventive Services Task Force.

Importance: Clinical practice guidelines can play an important role in mitigating health inequities. The US Preventive Services Task Force (USPSTF) has prioritized addressing health equity and racism in its recommendations. Objective: To develop a framework that would allow the USPSTF to incorporate a health equity lens that spans the entirety of its recommendation-making process. Evidence Review: Key guidance, policy, and explanatory frameworks related to health equity were identified, and their recommendations and findings were mapped to current USPSTF methods. USPSTF members as well as staff from multiple entities supporting the USPSTF portfolio were consulted. Based on all the gathered information, a draft health equity framework and checklist were developed; they were then circulated to the USPSTF's key partners for input and review. Findings: An equity framework was developed that could be applied to all phases of the recommendation process: (1) topic nomination, selection, and prioritization; (2) development of the work plan; (3) evidence review; (4) evidence deliberation; (5) development of the recommendation statement; and (6) dissemination of recommendations. For each phase, several considerations and checklist items to address are presented. These items include using health equity as a prioritization criterion and engaging a diverse group of stakeholders at the earliest phases in identifying topics for recommendations; developing necessary equity-relevant questions (eg, beyond effectiveness and harms) to address during the protocol phase; using methods in synthesizing the evidence and contextual issues in the evidence review related to specific populations experiencing a disproportionate burden of disease; and examining the magnitude and certainty of net benefit, implementation considerations, risk assessment, and evidence gaps through an equity lens when developing evidence-based recommendations. Conclusions and Relevance: Executing this entire framework and checklist as described will be challenging and will take additional time and resources. Nonetheless, whether adopted in its entirety or in parts, this framework offers guidance to the USPSTF, as well as other evidence-based guideline entities, in its mission to develop a more transparent, consistent, and intentional approach to addressing health equity in its recommendations.

Simulations of multiple breeding strategy scenarios in common bean for assessing genomic selection accuracy and model updating.

The aim of this study was to evaluate the accuracy of the ridge regression best linear unbiased prediction model across different traits, parent population sizes, and breeding strategies when estimating breeding values in common bean (Phaseolus vulgaris). Genomic selection was implemented to make selections within a breeding cycle and compared across five different breeding strategies (single seed descent, mass selection, pedigree method, modified pedigree method, and bulk breeding) following 10 breeding cycles. The model was trained on a simulated population of recombinant inbreds genotyped for 1010 single nucleotide polymorphism markers including 38 known quantitative trait loci identified in the literature. These QTL included 11 for seed yield, eight for white mold disease incidence, and 19 for days to flowering. Simulation results revealed that realized accuracies fluctuate depending on the factors investigated: trait genetic architecture, breeding strategy, and the number of initial parents used to begin the first breeding cycle. Trait architecture and breeding strategy appeared to have a larger impact on accuracy than the initial number of parents. Generally, maximum accuracies (in terms of the correlation between true and estimated breeding value) were consistently achieved under a mass selection strategy, pedigree method, and single seed descent method depending on the simulation parameters being tested. This study also investigated model updating, which involves retraining the prediction model with a new set of genotypes and phenotypes that have a closer relation to the population being tested. While it has been repeatedly shown that model updating generally improves prediction accuracy, it benefited some breeding strategies more than others. For low heritability traits (e.g., yield), conventional phenotype-based selection methods showed consistent rates of genetic gain, but genetic gain under genomic selection reached a plateau after fewer cycles. This plateauing is likely a cause of faster fixation of alleles and a diminishing of genetic variance when selections are made based on estimated breeding value as opposed to phenotype.