Cancer incidence, type, and survival after bariatric surgery.

BACKGROUND: Many types of cancer have been found to be associated with being overweight or obese. Literature has demonstrated a reduction in cancer risk in patients who have undergone bariatric surgery. OBJECTIVES: To compare the incidence and types of new cancer diagnoses, cumulative cancer incidence, cancer risk, and overall survival in patients with obesity who underwent bariatric surgery with that of those who did not. SETTING: Community-based academic medical center. METHODS: We retrospectively compared the rates and types of new incident cancers in a bariatric surgery cohort (Bariatric group) with those of a non-surgical cohort (Comparison group). The Comparison group was chosen from patients who had a clinic visit in our health system within 30 days of each bariatric surgical operation and matched on age, sex, and body mass index. Patients who had a cancer diagnosis prior to having bariatric surgery were excluded from the Bariatric group and patients who had a cancer diagnosis prior to the clinic visit on which they were matched were excluded from the Comparison group. Relative risk of cancer by type was calculated. Chi-square and Fisher exact tests were used for categorical data analysis, and Wilcoxon rank-sum for continuous data. The Kaplan Meier estimator with the log-rank test was used to compare overall survival between groups, while competing risks survival analysis with the Gray test for equality was used to compare cancer incidence in the Surgery group with that in the Comparison group. RESULTS: After matching, the Bariatric group had 1593 patients and the Comparison group had 2156. The Bariatric and Comparison groups had 82 and 222 new incident cancer cases, respectively (P < .001). The 10-year incidence of any new cancer in the Bariatric group was 6.5%, compared with an incidence of 12.1% in the Comparison group (P < .001). Relative risk of cancer in the Bariatric group was lower than that of the Comparison group, with the greatest differences in endometrial (88.8%), kidney (77.4%), thyroid (72.9%), and ductal carcinoma in situ (71.2%) cancers. The 10-year overall survival rate was higher in the Bariatric group than in the Comparison group, 93.3% versus 80.6%, respectively (P < .001). CONCLUSIONS: Bariatric surgery reduces the risk for developing cancer and offers survival advantage when compared with similar patients who do not undergo bariatric surgery.

Friendly Kisses Can Be Deadly: Capnocytophaga canimorsus Bacteremia in an Asplenic Patient Exposed to Canine Saliva.

The differential diagnosis for febrile asplenic patients must always include opportunistic infections. Capnocytophaga canimorsus is one such infection. In this report, we discuss the case of a 73-year-old woman with a medical history significant for splenectomy for splenic sarcoma with prophylactic vaccination for pneumococcus who presented with rigors, emesis, and abdominal pain. Initial vital signs were 39.6°C (103.3°F), 166/70 mmHg, 92 bpm, and 95% SpO2 on room air. A physical examination revealed mild epigastric tenderness. Initial labs and imaging were unremarkable. Eight hours after the presentation, she became hypotensive. Repeat labs revealed leukopenia with 51% bands, hemoglobin 11.0 g/dL down from 13.9 g/dL, platelets 74 K/µL trending down to 15 K/µL, PT 23.5 sec., aPTT 60.3 sec., D-dimer greater than 20 µg/mL, fibrinogen 190 mg/dL, LDH 1515 IU/L, haptoglobin less than 20 mg/dL, and creatinine 1.84 mg/dL. A peripheral smear showed schistocytes. Blood cultures identified gram-negative rods and Capnocytophaga canimorsus. After further questioning, she recalled her dog licking an abrasion on her left index finger. Four days after the presentation, she developed a purpuric rash on her bilateral hands and feet with areas of Nikolsky's negative bullae along the dorsum of her left foot. She also developed acute renal failure requiring renal replacement therapy and hemodialysis. Capnocytophaga canimorsus is an encapsulated facultative anaerobic gram-negative bacillus. Infection can result in bacteremia and sepsis and carries a high mortality rate, even with treatment. Those with hyposplenism/asplenia are particularly susceptible to infection and can deteriorate quickly, as seen in this case. Although this infection is rare, our case highlights how all asplenic patients must be assessed and treated for encapsulated bacterial infections when presenting with an acute febrile illness, regardless of initial laboratory analysis.

Synthesis and Optimization of 1-Substituted Imidazo[4,5-c]quinoline TLR7 Agonists.

TLR7 agonists have significant therapeutic potential in a variety of oncology and autoimmune applications. We recently reported a potent TLR7 selective agonist 1 that could be delivered by antibody-drug conjugate (ADC) technology to elicit potent anticancer activity. Herein we report synthetic chemistry and structure-activity relationship studies to develop TLR7 agonists with improved potency for next-generation ADC efforts. We found that the addition of hydrophobic acyl tails to parent compound 1 generally resulted in retained or improved TLR7 agonist activity without sacrificing the permeability or the selectivity over TLR8. In contrast, the addition of a simple alkyl tail at the same position resulted in a dramatic loss in potency. Molecular modeling was performed to provide a rationale for this dramatic loss in potency. We ultimately identified compounds 17b, 16b, and 16d as highly potent TLR7 agonists that potently induced the activation of mouse macrophages and hPBMCs at low-nanomolar concentrations.

Atrial fibrillation is a risk factor for major adverse cardiovascular events in COVID-19.

Background: New-onset atrial fibrillation (AF) during COVID-19 infection is associated with worse cardiovascular outcomes and mortality, with new-onset AF being associated with worse clinical outcomes than recurrent AF. However, it is not known whether a prior history of AF is an independent cardiovascular risk factor predicting worse outcomes in COVID-19 patients. The present investigation sought to determine whether AF should be considered a risk factor for worse outcomes in COVID-19 illness. Methods: From March 2020-September 2021 patients testing positive for SARS-CoV-2 with a prior AF diagnosis (n = 3623) were propensity matched to non-AF SARS-CoV-2 positive patients (n = 3610). Multivariable Cox hazard regression was used to determine subsequent MACE (all-cause death, myocardial infarction, HF and stroke) risk among patients with and without AF. Results: COVID-19 patients with a prior history of AF were more likely to be hospitalized, require ICU care, supplemental oxygen, and ventilator support compared COVID-19 patients without a history of AF. There was a 1.40 times higher rate of MACE in the COVID-19 patients with prior AF compared to patients without prior AF (p < 0.0001). The increased rate of MACE in patients with a prior AF was primarily secondary to increases in heart failure hospitalization and death. This finding was confirmed even after controlling for acute AF during COVID-19 illness (HR 1.22, p = 0.0009). Conclusion: AF history was shown to be an independent risk factor for MACE during a COVID-19 illness. Both recurrent and principally new-onset AF were associated with an increased risk of poor clinical outcomes during COVID-19 illness.

Indoloquinoline-Mediated Targeted Downregulation of KRAS through Selective Stabilization of the Mid-Promoter G-Quadruplex Structure.

KRAS is a well-validated anti-cancer therapeutic target, whose transcriptional downregulation has been demonstrated to be lethal to tumor cells with aberrant KRAS signaling. G-quadruplexes (G4s) are non-canonical nucleic acid structures that mediate central dogmatic events, such as DNA repair, telomere elongation, transcription and splicing events. G4s are attractive drug targets, as they are more globular than B-DNA, enabling more selective gene interactions. Moreover, their genomic prevalence is increased in oncogenic promoters, their formation is increased in human cancers, and they can be modulated with small molecules or targeted nucleic acids. The putative formation of multiple G4s has been described in the literature, but compounds with selectivity among these structures have not yet been able to distinguish between the biological contribution of the predominant structures. Using cell free screening techniques, synthesis of novel indoloquinoline compounds and cellular models of KRAS-dependent cancer cells, we describe compounds that choose between KRAS promoter G4near and G4mid, correlate compound cytotoxic activity with KRAS regulation, and highlight G4mid as the lead molecular non-canonical structure for further targeting efforts.

Design and Characterization of Immune-Stimulating Imidazo[4,5-c]quinoline Antibody-Drug Conjugates.

Traditional antibody-drug conjugate (ADC) technology has employed tumor-targeting antibodies to selectively deliver ultrapotent cytotoxins to tumor tissue. While this technology has been highly successful, resulting in the FDA approval of over 10 ADCs, the field continues to struggle with modest efficacy and significant off-target toxicity. Concurrent with the struggles of the ADC field, a new generation of immune-activating therapeutics has arisen, most clearly exemplified by the PD-1/PD-L1 inhibitors that are now part of standard-of-care treatment regimens for a variety of cancers. The success of these immuno-oncology therapeutic agents has prompted the investigation of a variety of new immuno-stimulant approaches, including toll-like receptor (TLR) activators. Herein, we describe the optimization of ADC technology for the selective delivery of a potent series of TLR7 agonists. A series of imidazole[4,5-c]quinoline agonists (as exemplified by compound 1) were shown to selectively agonize the human and mouse TLR7 receptor at low nanomolar concentrations, resulting in the release of IFNα from human peripheral blood mononuclear cells (hPBMCs) and the upregulation of CD86 on antigen-presenting cells. Compound 1 was attached to a deglycosylated (Fc-γ null) HER2-targeting antibody via a cleavable linker, resulting in an ADC (anti-HER2_vc-1) that potently and selectively activated the TLR7 pathway in tumor-associated macrophages via a "bystander" mechanism. We demonstrated that this ADC rapidly released the TLR7 agonist into the media when incubated with HER2+ cells. This release was not observed upon incubation with an isotype control ADC and furthermore was suppressed by co-administration of the naked antibody. In co-culture experiments with HER2+ HCC1954 cells, this ADC induced the activation of the NFκB pathway in mouse macrophages and the release of IFNα from hPBMCs, while a corresponding isotype control ADC did not. Finally, we demonstrated that IP administration of anti-HER2_vc-1 induced complete tumor regression in an HCC1954 xenograft study in SCID beige mice. Unlike related ADC technology that has been reported recently, our technology relies on the passive diffusion of the TLR7 agonist into tumor-associated macrophages rather than Fc-γ-mediated uptake. Based on these observations, we believe that this ADC technology holds significant potential for both oncology and infectious disease applications.

Medication for Gravid and Nursing Oral and Maxillofacial Surgery Patients.

The purpose of this article is to clarify clinically impactful features of the perioperative and postoperative pharmacologic management of pregnant and lactating patients in the maxillofacial or dental setting. Before prescribing any drug to a nursing mother or pregnant patient, the maxillofacial surgeon and other dental and medical providers should consider the available evidence, benefits, and risk for that particular drug. There are many complex factors to consider when prescribing in order to maintain the safety of the pregnant individual, fetus, and infant. This article aims to provide concise, memorable, and actionable information to use in your clinical practice.

Adverse device-device interaction between pacemaker and subcutaneous implantable cardiac defibrillator.

A 26-year-old patient with prior surgery for Ebstein's anomaly and a pacemaker (placed for post-surgical heart block and poor underlying rhythm) underwent SICD was placement. During defibrillation testing, device-device interaction led to undersensing of ventricular fibrillation with failure to shock. Increasing the pacemaker sensitivity resolved the problem but post shock pacing was unable to capture the heart after both shocks. The patient underwent removal of both the pacemaker and the SICD and placement of a transvenous ICD. Complex device-device interactions can occur in patients who are pacemaker dependent and undergo placement of a SICD.

Enzyme-Agnostic Lysosomal Screen Identifies New Legumain-Cleavable ADC Linkers.

Over the past two decades, antibody drug conjugates (ADCs) and small molecule drug conjugates (SMDCs) have widely employed valine-citruline and related cathepsin-cleavable linkers due to their stability in plasma and their rapid cleavage by lysosomal cathepsins. However, a number of recent studies have illustrated that these linkers are subject to cleavage by exogenous enzymes such as Ces1C and neutrophil elastase, thus resulting in off-target release of drug. As such, there is a need to diversify the portfolio of ADC linkers in order to overcome nonspecific drug release. Rather than targeting cathepsins, we began with an "enzyme agnostic" screen in which a panel of 75 peptide FRET pairs were screened for cleavage in lysosomal extracts and in plasma. Unexpectedly, a series of Asn-containing peptides emerged from this screen as being cleaved far more quickly than traditional ValCit-type linkers while retaining excellent stability in plasma. Catabolism studies demonstrated that these linkers were cleaved by legumain, an asparaginyl endopeptidase that is overexpressed in a variety of cancers and is known to be present in the lysosome. MMAE-containing ADCs that incorporated these new linkers were shown to exhibit highly potent and selective cytotoxicity, comparable to analogous ValCit ADCs. Importantly, the Asn-containing linkers were shown to be completely stable to human neutrophil elastase, an enzyme thought to be responsible for the neutropenia and thrombocytopenia associated with ValCitPABC-MMAE ADCs. The legumain-cleavable ADCs were shown to have excellent stability in both mouse and human serum, retaining >85% of the drug after 1 week of incubation. Moreover, the corresponding small molecule FRET pairs exhibited <10% cleavage after 18 h in mouse and human serum. On the basis of these results, we believe that these new linkers (AsnAsn in particular) have significant potential in both ADC and SMDC drug delivery applications.

Influence of various water quality parameters on passive sampler accumulation kinetics of different metal valencies in freshwater.

Stabilized liquid membrane devices (SLMDs) have been used for passive integrative sampling of metals in freshwater systems. Field measurements of metal accumulation on SLMDs can provide a time-weighted average mass of labile metals over the deployment period. We exposed SLMDs in the laboratory to 0.5 µM solutions of silver, zinc, or aluminum as nitrate salts at three levels of water hardness, measuring metal accumulation every 4 days for 32 days. We saw linear accumulation in all experimental treatments, except for silver in high hardness (345.9 mg/L as CaCO3). The time-accumulation relationships indicated that metal sorption rates vary across valency with the lower valency metals generally accumulating at greater rates. Water hardness also affected accumulation rates and accumulated mass with greater rates as hardness increased for zinc and aluminum. The accumulated zinc mass at 32 days in soft water was 78% of the mass in hard water for zinc, and accumulated aluminum mass was 29% of the mass in hard water. Factors such as oleate formation on the SLMD surface and solution chemistry, including pH and chemical speciation, were evaluated in explaining our results. Our work supports that SLMDs have utility for sampling metals in freshwater over extended time periods, which may be beneficial when there is limited access to sites; it also provide important interpretive guidance for the use of SLMDs.

Transvenous management of cardiac implantable electronic device late lead perforation.

INTRODUCTION: Late lead perforation (LLP), defined as perforation ≥30 days from cardiac implantable electronic device implant, is a rare diagnosis and little data exist regarding management practices and outcomes. The purpose of this study was to evaluate the occurrence, safety, and efficacy of transvenous management of clinically significant LLP. METHODS: The electronic medical records of a single-center tertiary hospital were reviewed for all patients who were referred for LLP or its sequelae. RESULTS: Eleven consecutive patients were identified from October 2011 to December 2018 with clinically significant LLP. Patients most often presented with pericardial symptoms with the exception of one asymptomatic patient. The median time from lead implant to intervention for LLP was 246 days. Nine patients were managed with an initial transvenous approach, with one requiring sternotomy (lead 6.3 years old). Two patients had a surgical approach, one performed at an outside hospital with subsequent death and another had a mini-thoracotomy, but the lead was removed percutaneously with no surgical repair. In this small cohort, there was no association between the lead extending beyond the parietal pericardium and surgical repair (P = .99). CONCLUSION: Our single-center experience suggests that LLP can be initially managed with a cautious transvenous approach in most patients, but intraprocedural ultrasound for pericardial monitoring and a rescue plan with immediate surgical back up is mandatory.

High Power Ultra Short Duration Ablation with HD Grid Improves Freedom from Atrial Fibrillation and Redo Procedures Compared to Circular Mapping Catheter.

BACKGROUND: High power ultra-short duration (HPUSD) ablation has been advocated to prevent esophageal injuries during atrial fibrillation (AF) ablation procedures. Prior research using the standard circular mapping catheter (CMC) has shown that ultra-short ablations may compromise lesion durability resulting in an increased need for redo procedures. The purpose of this study was to determine if HD mapping of concealed pulmonary vein (PV) connections could improve freedom from atrial fibrillation and redo procedures compared to CMC guided AF ablation. METHODS: A total of 472 consecutive first time AF ablation procedure patients with at least one year of follow up were included with an average follow-up of 18 months. HPUSD AF ablation consisted of 50 W for 2-3 seconds on the posterior wall and 5-15 seconds on the anterior wall of the left atrium. Acute pulmonary vein isolation (PVI) was defined as no concealed 1) PV signals, 2) activation into PVs, or 3) voltage into PVs with no intra-procedural waiting period utilizing the HD Grid catheter versus entrance/exit block with a 30-minute wait with the circular mapping catheter. Freedom from atrial fibrillation and all atrial arrhythmias following a 90-day blanking period were assessed. RESULTS: Acute pulmonary vein isolation was achieved in all 472 patients. HPUSD ablation using the HD Grid was associated with shorter procedure (70.2 vs 104.3 minutes, p<0.001) and fluoroscopy times (4.2 vs 15.0 minutes, p<0.001) when compared to CMC. The recurrence of any atrial arrhythmias at 1 year was 13% with HD Grid and 25% with CMC (p<0.001) with the need for redo procedures of 6% for HD Grid and 20% for CMC (p<0.001). No esophageal ulcerations/perforations were seen. No deaths, strokes, or TIAs were observed in either group. CONCLUSIONS: HPUSD AF Ablation, as guided by HD Grid mapping, may prevent esophageal injuries while at the same time improve freedom from any atrial arrhythmias and the need for redo procedures. Procedure and fluoroscopy times were also significantly decreased when compared to traditional CMC mapping.

The "TRAUMA LIFE" initiative: The impact of a multidisciplinary checklist process on outcomes and communication in a Trauma Intensive Care Unit.

BACKGROUND: Checklists have been advocated to improve quality outcomes/communication in the critical care setting, but results have been mixed. A new checklist process, "TRAUMA LIFE", was implemented in our Trauma Intensive Care Unit (TICU) to replace prior checklists. The purpose of this study was to evaluate the impact of the "TRAUMA LIFE" process implementation on quality metrics and on patient/family communication in the TICU. METHODS: "TRAUMA LIFE" was considered maturely implemented by 2016. Multiple quality metrics, including restraint order compliance, were compared between 2013 and 2016 (pre- and post-implementation). Compliance with the "Family Message" (FM), a part of the "TRAUMA LIFE" communication process, was analyzed in 2016. RESULTS: Improvement was seen in CAUTI, VAE, and IUCU; CLABSI rates increased. Restraint order compliance increased significantly. FM delivery compliance was inconsistent; improvement was noted in concordance between update content and FM documented in Electronic Medical Record. CONCLUSION: Implementation of "TRAUMA LIFE" was well integrated into the rounding process and was associated with some improvement in quality metrics and communication. Additional evaluation is required to assess sustainability.

Spinal Lewy body pathology in older adults without an antemortem diagnosis of Parkinson's disease.

To test the hypothesis that Lewy body pathology (LBs) is present in the spinal cord of older community-dwelling adults without a clinical diagnosis of Parkinson's disease (PD). We studied 162 prospective autopsies from older adults with PD (N = 6) and without PD (N = 156). We documented the presence of LBs in cerebrum and brainstem structures from each of the six regions used for Braak PD staging and four spinal cord levels (C5/6, T7, L4/5 and S4/5). Parkinsonism proximate to death was based on a previously validated measure present if two or more of the four signs of parkinsonism were present based on a modified version of the Unified Parkinson's Disease Rating Scale (UPDRS). Fifty-three of 156 individuals without PD (34%) had LBs in a least one site within the CNS. About half of cases with LBs in the cerebrum or brainstem, (25/53, 47%) also had spinal LBs. Almost 90% (22/25, 88%) of cases with spinal LBs had LBs in the cerebrum (Braak stages 4-6) and about 10% (3/25, 12%) had only brainstem LBs (Braak stages 1-3). Four of six cases with PD showed LBs in cerebrum, brainstem and spinal cord. Individuals with LBs in the spinal cord were more likely to have clinical parkinsonism proximate to death compared to individuals with LBs in brainstem and cerebrum alone (52% vs. 32%; Chi-Square x2 = 5.368, d.f. = 1, P = 0.0.021) and more severe nigral neuronal loss (48% vs. 11%; Chi-Square x2 = 9.049, d.f. = 1, P = 0.003). These findings were unchanged when we included cases with a history of PD. Older community-dwelling adults without a clinical diagnosis of PD have evidence of LBs throughout the CNS including the spinal cord which is associated with parkinsonism and more severe nigral neuronal loss.

An updated meta-analysis of novel oral anticoagulants versus vitamin K antagonists for uninterrupted anticoagulation in atrial fibrillation catheter ablation.

BACKGROUND: Catheter ablation is recommended as a first- or second-line rhythm control therapy for selected patients with atrial fibrillation (AF). There is a wide variability in the periprocedural management of oral anticoagulation in patients undergoing AF ablation. OBJECTIVE: We aimed to perform an updated meta-analysis of novel oral anticoagulants (NOACs) vs vitamin K antagonists (VKAs) as uninterrupted anticoagulation in patients undergoing AF ablation. METHODS: Databases and conference abstracts were searched. Studies were excluded if oral anticoagulants were held at any periprocedural period. The primary outcomes were stroke or transient ischemic attack (TIA) and major bleeding. RESULTS: Twelve studies and 4962 patients were included. Stroke or TIA was rare (NOAC, 0.08%; VKA, 0.16%) and not different between groups (odds ratio [OR] 0.66; 95% confidence interval [CI] 0.19-2.30). The incidence of silent cerebral embolic events was also not significantly different between NOACs (8%) and VKAs (9.6%) (OR 0.86; 95% CI 0.42-1.76). Major bleeding was significantly reduced in the NOAC group (0.9%) as compared with VKA-treated patients (2%) (OR 0.50; 95% CI 0.30-0.84; P < .01). This finding was confirmed in a subgroup analysis of randomized and cohort studies with matched controls (OR 0.45; 95% CI 0.24-0.83; P = .01). There was no significant difference in the outcomes of individual NOACs and VKAs, although these analyses may have been underpowered to detect minor differences in such rare outcomes. CONCLUSION: In patients undergoing AF ablation, uninterrupted periprocedural NOACs are associated with a low incidence of stroke or TIA and a significant reduction in major bleeding as compared with uninterrupted VKAs.

Helping employees sleep well: Effects of cognitive behavioral therapy for insomnia on work outcomes.

Drawing from recent research advances indicating the harmful effects of insomnia on negative affect, job satisfaction, self-control, organizational citizenship behavior, and interpersonal deviance, we hypothesized that treating insomnia with Internet based cognitive behavior therapy for insomnia would lead to improvements in these outcomes. In a field experiment with a randomized wait-list control group, we found that treatment had a beneficial direct effect on negative affect, job satisfaction, and self-control. Moreover, the effect of treatment on job satisfaction was mediated by negative affect. We were not able to detect a direct effect of treatment on organizational citizenship behavior or interpersonal deviance. However, treatment had a beneficial indirect effect on organizational citizenship behavior through the mediators of negative affect and job satisfaction, and a beneficial indirect effect on interpersonal deviance through the mediator of self-control. These results move the applied psychology literature on insomnia beyond simply pointing out problematic effects of employee insomnia to providing evidence of a partial solution to such effects. (PsycINFO Database Record

Implantable Electronic Cardiac Devices and Compatibility With Magnetic Resonance Imaging.

There is a growing population of patients with implanted electronic cardiac devices and a concomitant increase in the use of magnetic resonance (MR). There are theoretical safety risks posed to such devices by MR. However, there are now considerable laboratory data and clinical experience demonstrating safety in this setting, assuming appropriate device selection and patient monitoring. Herein, we review these data and our safety protocol and the new generation of devices that have been prospectively designed and tested to be safe for MR scanning, assuming certain conditions are met (i.e., devices that are MR-conditional). We also argue that the available data do not support a complete transition to implantation of MR-conditional devices.

Botulinum Toxin Type A: Review and Its Role in the Dental Office.

For the general dentist, the use of botulinum toxin type A (BTA) confers the ability to exert control over the soft tissues surrounding the mouth to better create a harmonious smile. The injection of BTA into the facial musculature requires a level of finesse to achieve the desired outcomes. A sound understanding of the toxin's mechanism of action and the ability to manage potential complications are also necessary, as the dentist administering BTA must be competent to the same level as other providers who have traditionally been the gatekeepers of such agents.