Chronic Idiopathic Ulcers Mimicking Cecal Carcinoma: A Case Report.

Chronic idiopathic ulcers of the colon pose diagnostic challenges due to their elusive etiology and potential resemblance to other intestinal pathologies, such as cecal carcinoma. This case report outlines the clinical course of a 68-year-old female patient who presented to the emergency department (ED) with persistent right lower quadrant pain. Despite multiple hospital visits yielding varied diagnoses, a definitive diagnosis was only made following a laparoscopic partial colectomy, which revealed chronic idiopathic ulcers with transmural scarring and adhesions to adjacent small intestine loops. Histological examination demonstrated a substantial ulcer bed populated by inflammatory cells, including large stellate and spindled stromal cells within the granulation tissue, alongside lymphoid hyperplasia and scar tissue extending into the muscularis propria. The initial presentation of this case could easily be mistaken for appendicitis, diverticulitis, carcinoma, or irritable bowel syndrome, highlighting the significance of considering chronic idiopathic ulcers in the differential diagnosis of patients presenting with cecal masses.

Preoperative prescription opioid use as an independent predictor of 90-day mortality and adverse events in craniotomy and craniectomy patients.

OBJECTIVE: A growing body of literature suggests that preoperative opioid exposure is an independent predictor of poor outcomes in surgical patients. No outcomes data exist on preoperative opioid use and craniotomies/craniectomies. The objective of this study was to determine the impact of preoperative opioid use on 90-day adverse events after craniotomy or craniectomy. METHODS: A single-center retrospective cohort study of 2445 patients undergoing a craniotomy/craniectomy between January 1, 2013, and October 1, 2018, was conducted. Baseline demographics, pre- and postoperative opioid use (morphine milligram equivalents [MMEs]), and surgical metrics were recorded. Patients were categorized based on whether they took prescription opioids preoperatively, defined as within 1 month of surgery, or were opioid naive. The outcomes were mortality and adverse events 90 days after craniotomy/craniectomy. RESULTS: Overall, 26.6% of patients composed the preoperative opioid group. The median daily MME intake among this group was 34.6 (IQR 14.1-90) MMEs. Lower employment rates (p < 0.001), uninsured status (p = 0.016), and intravenous drug use (p = 0.006) were associated with preoperative opioid use. Preoperative opioid use was associated with increased venous thromboembolism (p = 0.001), acute kidney injury (p = 0.002), acute respiratory failure (p < 0.001), myocardial infarction (p = 0.002), delirium (p < 0.001), and infection (p < 0.001). Preoperative opioid use was an independent predictor of overall 90-day adverse events (OR 1.643, 95% CI 1.289-2.095; p < 0.001) and 90-day mortality (OR 1.690, 95% CI 1.254-2.277; p < 0.001). CONCLUSIONS: Preoperative opioid use was independently associated with 90-day postoperative adverse events and mortality. Opioid use increases vulnerability in craniotomy/craniectomy patients and necessitates close monitoring to improve outcomes.

X-ray imageable, drug-loaded hydrogel that forms at body temperature for image-guided, needle- based locoregional drug delivery.

Liver cancer ranks as the fifth leading cause of cancer-related death globally. Direct intratumoral injections of anti-cancer therapeutics may improve therapeutic efficacy and mitigate adverse effects compared to intravenous injections. Some challenges of intratumoral injections are that the liquid drug formulation may not remain localized and have unpredictable volumetric distribution. Thus, drug delivery varies widely, highly-dependent upon technique. An x-ray imageable poloxamer 407 (POL)-based drug delivery gel was developed and characterized, enabling real-time feedback. Utilizing three needle devices, POL or a control iodinated contrast solution were injected into an ex vivo bovine liver. The 3D distribution was assessed with cone beam computed tomography (CBCT). The 3D distribution of POL gels demonstrated localized spherical morphologies regardless of the injection rate. In addition, the gel 3D conformal distribution could be intentionally altered, depending on the injection technique. When doxorubicin (DOX) was loaded into the POL and injected, DOX distribution on optical imaging matched iodine distribution on CBCT suggesting spatial alignment of DOX and iodine localization in tissue. The controllability and localized deposition of this formulation may ultimately reduce the dependence on operator technique, reduce systemic side effects, and facilitate reproducibility across treatments, through more predictable standardized delivery.

Therapeutic targeting of cellular senescence in diabetic macular edema: preclinical and phase 1 trial results.

Compromised vascular endothelial barrier function is a salient feature of diabetic complications such as sight-threatening diabetic macular edema (DME). Current standards of care for DME manage aspects of the disease, but require frequent intravitreal administration and are poorly effective in large subsets of patients. Here we provide evidence that an elevated burden of senescent cells in the retina triggers cardinal features of DME pathology and conduct an initial test of senolytic therapy in patients with DME. In cell culture models, sustained hyperglycemia provoked cellular senescence in subsets of vascular endothelial cells displaying perturbed transendothelial junctions associated with poor barrier function and leading to micro-inflammation. Pharmacological elimination of senescent cells in a mouse model of DME reduces diabetes-induced retinal vascular leakage and preserves retinal function. We then conducted a phase 1 single ascending dose safety study of UBX1325 (foselutoclax), a senolytic small-molecule inhibitor of BCL-xL, in patients with advanced DME for whom anti-vascular endothelial growth factor therapy was no longer considered beneficial. The primary objective of assessment of safety and tolerability of UBX1325 was achieved. Collectively, our data suggest that therapeutic targeting of senescent cells in the diabetic retina with a BCL-xL inhibitor may provide a long-lasting, disease-modifying intervention for DME. This hypothesis will need to be verified in larger clinical trials. ClinicalTrials.gov identifier: NCT04537884 .

Olefin Difunctionalization for the Synthesis of Tetrahydroisoquinoline, Morpholine, Piperazine, and Azepane.

This report outlines a versatile strategy for synthesizing a diverse array of N-heterocycles. By the utilization of common olefins, this simple protocol facilitates their coupling with various bifunctional reagents. Furthermore, it can be integrated with C-H amination techniques to directly produce N-heterocycles in a multicomponent cascade coupling process. The unique bond disconnection logic employed in this process underscores its efficiency in achieving rapid simplification through cascade couplings.

Risk of infectious adverse events of venetoclax therapy for hematologic malignancies: a systematic review and meta-analysis of RCTs.

ABSTRACT: Venetoclax is a small molecule inhibitor of BCL-2 used in the treatment of acute myelogenous leukemia (AML) and chronic lymphocytic leukemia (CLL). Recent postmarketing studies of ibrutinib, another small molecule inhibitor, suggested that these agents may predispose to opportunistic infections. We sought to systematically review the randomized controlled trial (RCT) evidence of venetoclax to assess whether it predisposes patients to infectious adverse events (IAEs) and neutropenia. We systematically reviewed RCTs comparing venetoclax therapy with active or placebo controls for patients with hematologic malignancies. Data on IAEs and neutropenia were pooled by Bayesian meta-analysis, and we computed the probability of any increased risk (P[risk ratio (RR) > 1]) of IAEs or neutropenic complications. Seven RCTs were included, comprising 2067 patients. In CLL (n = 1032), there was a low probability of increased risk of high-grade (P[RR > 1] = 71.2%) and fatal IAEs (P[RR > 1] = 64.5%) and high-grade neutropenia (P[RR > 1] = 63.4%). There were insufficient data to perform a meta-analysis of IAEs in AML; however, 1 trial suggested an increased risk of IAEs with venetoclax. Furthermore, in AML (n = 642), venetoclax was associated with a high probability of increased risk of high-grade neutropenia (P[RR > 1] = 94.6%) and febrile neutropenia (P[RR > 1] = 90.6%). Our results suggest that venetoclax has a low probability of increased risk of IAEs or neutropenia in CLL. By contrast, there is likely increased risk of high-grade neutropenia and febrile neutropenia in AML. Importantly, our analyses did not identify any specific IAEs that would benefit from routine antimicrobial prophylaxis or pre-emptive testing.

Brain-Penetrating Peptide Shuttles across the Blood-Brain Barrier and Extracellular-like Space.

Systemic delivery of therapeutics into the brain is greatly impaired by multiple biological barriers─the blood-brain barrier (BBB) and the extracellular matrix (ECM) of the extracellular space. To address this problem, we developed a combinatorial approach to identify peptides that can shuttle and transport across both barriers. A cysteine-constrained heptapeptide M13 phage display library was iteratively panned against an established BBB model for three rounds to select for peptides that can transport across the barrier. Using next-generation DNA sequencing and in silico analysis, we identified peptides that were selectively enriched from successive rounds of panning for functional validation in vitro and in vivo. Select peptide-presenting phages exhibited efficient shuttling across the in vitro BBB model. Two clones, Pep-3 and Pep-9, exhibited higher specificity and efficiency of transcytosis than controls. We confirmed that peptides Pep-3 and Pep-9 demonstrated better diffusive transport through the extracellular matrix than gold standard nona-arginine and clinically trialed angiopep-2 peptides. In in vivo studies, we demonstrated that systemically administered Pep-3 and Pep-9 peptide-presenting phages penetrate the BBB and distribute into the brain parenchyma. In addition, free peptides Pep-3 and Pep-9 achieved higher accumulation in the brain than free angiopep-2 and may exhibit brain targeting. In summary, these in vitro and in vivo studies highlight that combinatorial phage display with a designed selection strategy can identify peptides as promising carriers, which are able to overcome the multiple biological barriers of the brain and shuttle different-sized molecules from small fluorophores to large macromolecules for improved delivery into the brain.

INDUCING REPRESENTATIONAL CHANGE IN THE HIPPOCAMPUS THROUGH REAL-TIME NEUROFEEDBACK.

When you perceive or remember one thing, other related things come to mind. This competition has consequences for how these items are later perceived, attended, or remembered. Such behavioral consequences result from changes in how much the neural representations of the items overlap, especially in the hippocampus. These changes can reflect increased (integration) or decreased (differentiation) overlap; previous studies have posited that the amount of coactivation between competing representations in cortex determines which will occur: high coactivation leads to hippocampal integration, medium coactivation leads to differentiation, and low coactivation is inert. However, those studies used indirect proxies for coactivation, by manipulating stimulus similarity or task demands. Here we induce coactivation of competing memories in visual cortex more directly using closed-loop neurofeedback from real-time fMRI. While viewing one object, participants were rewarded for implicitly activating the representation of another object as strongly as possible. Across multiple real-time fMRI training sessions, they succeeded in using the neurofeedback to induce coactivation. Compared with untrained objects, this coactivation led to behavioral and neural integration: The trained objects became harder for participants to discriminate in a categorical perception task and harder to decode from patterns of fMRI activity in the hippocampus.

Teledermatology in remote Indigenous populations: Lessons learned and paths to explore, an experience from Canada (Québec) and Australia.

Objective: Recent introduction of a provincially funded and administered teledermatology platform in Quebec presents a major opportunity to improve healthcare delivery to rural Indigenous communities where healthcare is suboptimal. In this study, we assessed approaches, challenges, solutions, and outcomes in implementing teledermatology in rural Indigenous communities of Australia and Canada. Methods: A narrative review was performed using journal articles and grey literatures to assess challenges encountered in Canadian and Australian teledermatology programs in rural Indigenous communities. We then conducted a focused search to identify solutions and outcomes to these challenges. We identified four main areas of focus for implementing teledermatology: financial, cultural, legal, and provider competency. Results: Main financial concerns included identifying the cost-to-benefit ratio of teledermatology and financial benefits of the store-and-forward system compared to videoconferencing. Delivery of teledermatology through culturally considerate services is crucial to mend the mistrust felt by Indigenous people toward mainstream health services. From a legal standpoint, patient confidentiality and physician liability must be considered. A uniform teledermatology platform and physician competency in both telemedicine and dermatology are needed to ensure standard of care. Conclusion: Teledermatology initiatives represent great opportunities to improve healthcare services to rural Indigenous populations.

Safety of COVID-19 mRNA vaccination and effects of SARS-CoV-2 infection in children and adults with mast cell disorders.

Mastocytosis is characterized by abnormal clonal mast cell proliferation. Given the paucity of data in patients with mastocytosis, it is crucial to assess the safety of COVID-19 vaccines in this population. We aimed to assess the risk of allergic reactions and the effect of COVID-19 infection among patients with mastocytosis. Participants were recruited from Canada and Israel between December 2021 and May 2022. Consenting participants were administered standardized questionnaires querying whether they were infected with COVID-19, if they received the first and second dose vaccines, and post-vaccination side effects including allergic reactions (urticaria/angioedema, current rash flaring, need for updosing medications, or respiratory symptoms) and common side effects including injection site reaction (ISR) and flu-like symptoms. Forty participants with mastocytosis were administered a standardized questionnaire (median age = 9, 59% male). Amongst all participants, 16 (39%) reported COVID-19 infection and most (75%) reported flu-like symptoms, 3 (19%) were asymptomatic, 1 suffered from shortness of breath/chest pain and 1 from facial flushing. Of the 25 participants who were eligible for vaccination (≥ 5 years old), 80% received a first-dose vaccine and 68% received a second-dose vaccine. Of those who received the first-dose vaccine, most (60%) remained asymptomatic, 20% developed flu-like symptoms, 20% had an ISR, and 1 patient had an allergic reaction (urticaria and swelling). Of those who received the second-dose vaccine, most (53%) were asymptomatic, and 1 had an allergic reaction. No significant difference was found between side effects of both vaccine doses. No reactions fulfilled the criteria for anaphylaxis in either dose. This study reveals that among patients with mastocytosis, COVID-19 vaccine and infection were well-tolerated in the majority of cases.

Improving Crew Overboard Recovery for Commercial Fishing in the Gulf of Mexico.

Occupational fatality rates in the commercial fishing industry in the United States remain more than 20 times higher than the national average. The burden of commercial fishing fatalities due to unintentional falls overboard is highest in the Gulf of Mexico (GOM) shrimp fishery. The objective of this quasi-experimental, pre-/post-test project design was disseminating recovery slings to GOM captains/deckhands, training in their use, and assessing the attitudes, beliefs, and intentions of fishermen in their adoption. Due to the COVID-19 pandemic, a land-based simulation was used to train commercial fishermen at three port locations in use of crew overboard (COB) recovery slings. A survey was developed to assess the attitudes, beliefs, and intentions of commercial fishermen in COB recovery. Purposive sampling was employed to recruit 30-50 fishermen at each location. Following pre-/post-training surveys, fishermen received one recovery sling per vessel along with a task list of instructions for use of the sling. A third survey and task list questions were performed at 12-18 months. There were 119 recovery slings and training in their use provided to 123 commercial shrimp fishing vessel owners/captains and deckhands along the Texas and Louisiana Gulf Coast. Repeated measures analysis of variance of the three surveys showed that positive change in normative beliefs was significant for the importance of quickly and safely maneuvering the vessel to the crew member. This change was most significant over the period from the initial training and receipt of the recovery sling by the vessel captain/deckhand, to the time of follow-up 12-18 months later (p = .03). Regarding control beliefs, training was associated with immediate statistically significant improved confidence that, with assistance, the fisherman would be able to use the sling and other equipment to hoist the COB (p = .02). However, this confidence waned significantly over time (p = .03). Attitudes and beliefs of commercial fishermen in the GOM can be favorably influenced toward a COB recovery device, as well as their confidence, and intention to use such devices. However, results show that attitudes and beliefs may wane over time, emphasizing the importance of repeated training and survival drills in this industry.

Successful treatment of acrodermatitis continua of Hallopeau with tildrakizumab: A case report.

Acrodermatitis continua of Hallopeau is a rare, localized variant of pustular psoriasis commonly associated with join disease and severe quality of life impairment. While there are no standard treatment guidelines, therapies used for psoriasis vulgaris are commonly tried. We report a case of severe acrodermatitis continua of Hallopeau in a patient with multiple comorbidities (advanced malignancy, recurrent empyema, psoriatic arthritis) where tildrakizumab lead to a rapid resolution of skin and joint disease which was maintained 1 year later. To date, there are only four cases reporting the use of IL-23 inhibitors class in acrodermatitis continua of Hallopeau and none for tildrakizumab. However, IL-23 inhibitors should be strongly considered among the treatment of choice for acrodermatitis continua of Hallopeau, especially in patients with ongoing malignancy and/or high risk of infections.

Combining Molecular and Radiomic Features for Risk Assessment in Breast Cancer.

Breast cancer risk is highly variable within the population and current research is leading the shift toward personalized medicine. By accurately assessing an individual woman's risk, we can reduce the risk of over/undertreatment by preventing unnecessary procedures or by elevating screening procedures. Breast density measured from conventional mammography has been established as one of the most dominant risk factors for breast cancer; however, it is currently limited by its ability to characterize more complex breast parenchymal patterns that have been shown to provide additional information to strengthen cancer risk models. Molecular factors ranging from high penetrance, or high likelihood that a mutation will show signs and symptoms of the disease, to combinations of gene mutations with low penetrance have shown promise for augmenting risk assessment. Although imaging biomarkers and molecular biomarkers have both individually demonstrated improved performance in risk assessment, few studies have evaluated them together. This review aims to highlight the current state of the art in breast cancer risk assessment using imaging and genetic biomarkers.

Tunable [3+2] and [4+2] annulations for pyrrolidine and piperidine synthesis.

N-heterocycles are privileged pharmaceutical scaffolds in drug discovery and development. We disclose here divergent intermolecular coupling strategies that can access diverse N-heterocycles directly from olefins. The radical-to-polar mechanistic switching is key for the divergent cyclization processes. These distinctive annulations result in the coupling of alkenes with simple bifunctional reagents for divergent N-heterocycle syntheses.

Differentiation and Integration of Competing Memories: A Neural Network Model.

What determines when neural representations of memories move together (integrate) or apart (differentiate)? Classic supervised learning models posit that, when two stimuli predict similar outcomes, their representations should integrate. However, these models have recently been challenged by studies showing that pairing two stimuli with a shared associate can sometimes cause differentiation, depending on the parameters of the study and the brain region being examined. Here, we provide a purely unsupervised neural network model that can explain these and other related findings. The model can exhibit integration or differentiation depending on the amount of activity allowed to spread to competitors - inactive memories are not modified, connections to moderately active competitors are weakened (leading to differentiation), and connections to highly active competitors are strengthened (leading to integration). The model also makes several novel predictions - most importantly, that differentiation will be rapid and asymmetric. Overall, these modeling results provide a computational explanation for a diverse set of seemingly contradictory empirical findings in the memory literature, as well as new insights into the dynamics at play during learning.

Impact of X-Ray Exposure From Computed Tomography on Wearable Insulin Delivery Devices.

BACKGROUND: To investigate the impact of radiation exposure from a computed tomography (CT) scanner on the functional integrity of a wearable insulin delivery system. METHODS: A total of 160 Omnipods and four personal diabetes managers (PDMs) were evenly divided into four groups: (1) control group (no radiation exposure), (2) typical radiation exposure group, (3) 4× typical radiation exposure group, and (4) scatter radiation group. Pods were attached to an anthropomorphic torso phantom on the abdomen (direct irradiation) or shoulder (scatter radiation) region. A third-generation dual-source CT scanner was used to scan the pods using either a typical exposure (used for routine CT abdominal study of a median size patient) or 4× typical exposure. A manufacturer-recommended 20-step functionality test was performed for all 160 Omnipods. RESULTS: The radiation dose (measured in volume CT Dose index) was 16 mGy for a typical exposure, and 64 mGy for 4× typical exposure. The scatter radiation is less than 0.1 mGy. All Pods passed the functionality test except one pod in the scatter radiation group, which sounded an alarm due to occlusion. The blockage to the fluid was due to a kink in the soft cannula, a mechanical issue not caused by the radiation exposure. CONCLUSIONS: This study suggests X-ray exposure levels used in radiological imaging procedures do not negatively impact the functional integrity of Omnipods. This finding may support the potential for the manufacturer to remove the warning that patients should remove the Pod for X-ray imaging procedures, which will have a huge impact on patient care.

Efficacy and Safety of Sonic Hedgehog Inhibitors in Basal Cell Carcinomas: An Updated Systematic Review and Meta-analysis (2009-2022).

BACKGROUND: Basal cell carcinoma (BCC) of the skin is the most common form of skin cancer in the United States. In life-threatening, advanced BCC, sonic hedgehog inhibitors (SSHis) remain a pre-eminent treatment option for locally advanced BCC and metastatic BCC. OBJECTIVE: In this updated systematic review and meta-analysis, we aimed to better characterize the efficacy and safety of SSHis by including final updates from pivotal clinical trials and additional new recent studies. METHODS: An electronic database search was performed for articles including clinical trials, prospective case series, and retrospective medical record reviews on human subjects. Overall response rates (ORRs) and complete response rates (CRRs) were the primary outcomes. For safety assessment, the prevalence of the following adverse effects was analyzed: muscle spasms, dysgeusia, alopecia, weight loss, fatigue, nausea, myalgias, vomiting, skin squamous cell carcinoma, increased creatine kinase, diarrhea, decreased appetite, and amenorrhea. Analyses were performed using R statistical software. Data were pooled using linear models with fixed effects meta-analysis for primary analyses, along with 95% confidence intervals (CIs) and p-values. Intermolecular differences were calculated using Fisher's exact test. RESULTS: A total of 22 studies (N = 2384 patients) were included in the meta-analysis: 19 studies assessing both efficacy and safety, 2 studies assessing safety only, and 1 study assessing efficacy only. Overall, the pooled ORR for all patients was 64.9% (95% CI 48.2-81.6%), implicating there is at least a partial response (z = 7.60, p < 0.0001) in most patients receiving SSHis. The ORR for vismodegib was 68.5% and 50.1% for sonidegib. The most common adverse effects for vismodegib and sonidegib were muscle spasms (70.5% and 61.0%, respectively), dysgeusia (58.4% and 48.6%, respectively), and alopecia (59.9% and 51.1%, respectively). Patients were likely to experience weight loss (35.1%, p < 0.0001) from vismodegib. Alternatively, patients taking sonidegib experienced more nausea, diarrhea, increased creatine kinase levels, and decreased appetite compared with those receiving vismodegib. CONCLUSION: SSHis are an effective treatment for advanced BCC disease. Given the high discontinuation rates, management of patient expectations is warranted for compliance and achieving long-term efficacy. It is essential to stay updated with the latest discoveries on the efficacy and safety of SSHis.

Clinical Implementation of the Omnipod 5 Automated Insulin Delivery System: Key Considerations for Training and Onboarding People With Diabetes.

Automated insulin delivery (AID) systems, which connect an insulin pump, continuous glucose monitoring system, and software algorithm to automate insulin delivery based on real-time glycemic data, hold promise for improving outcomes and reducing therapeutic burden for people with diabetes. This article reviews the features of the Omnipod 5 Automated Insulin Delivery System and how it compares to other AID systems available on or currently under review for the U.S. market. It also provides practical guidance for clinicians on how to effectively train and onboard people with diabetes on the Omnipod 5 System, including how to personalize therapy and optimize glycemia. Many people with diabetes receive their diabetes care in primary care settings rather than in a diabetes specialty clinic. Therefore, it is important that primary care providers have access to resources to support the adoption of AID technologies such as the Omnipod 5 System.