Evaluating the Effect of Maternal Opioid Maintenance Dose on the NOWS-COS Outcome Criteria: A Pilot Study.

This retrospective cohort study included 77 mother-infant dyads that delivered term pregnancies at a single tertiary care institution. The primary objective was to investigate whether maternal dose of opioid maintenance therapy during pregnancy affects infant outcomes. All infants had prenatal exposure to opioid maintenance therapies. Maternal dose was converted into morphine milligram equivalents (MMEs) and stratified into high- (MME >1000 mg) and low-dose groups (MME ≤1000 mg). Associations between infant outcomes and MME dosage were examined using Wilcoxon rank-sum and Fisher's Exact tests. Days to symptom control were significantly higher in the high MME group (5 days vs 2.8 days, P = .016). Rates of developmental delay at 24 months were higher in the high MME group (21.2% vs 4.5%, P = .0335). Maternal MME did not predict need for NOWS treatment. Higher MME-exposed infants should have optimized nonpharmacologic interventions for consolation and be increasingly observed for signs of developmental delay.

Smoking, Lung Cancer Stage, and Prognostic Factors-Findings from the National Lung Screening Trial.

BACKGROUND: Low-dose computed tomography (LDCT) increases the early detection of lung cancer. Identifying modifiable behaviors that may affect tumor progression in LDCT-detected patients increases the likelihood of long-term survival and a good quality of life. METHODS: We examined cigarette smoking behaviors on lung cancer stage, progression, and survival in 299 ever-smoking patients with low-dose CT-detected tumors from the National Lung Screening Trial. Univariate and multivariate Cox models were used to estimate the hazard ratio (HR) for smoking variables on survival time. RESULTS: Current vs. former smokers and early morning smokers (≤5 min after waking, i.e., time to first cigarette (TTFC) ≤ 5 min) had more advanced-stage lung cancer. The adjusted HR for current vs. former smokers was 1.3 (95% confidence interval [CI] 0.911-1.98, p = 0.136) for overall survival (OS) and 1.3 (0.893-1.87, p = 0.1736) for progression-free survival (PFS). The univariate hazard ratios for TTFC ≤ 5 min vs. >5 min were 1.56 (1.1-2.2, p = 0.013) for OS and 1.53 (1.1-2.12, p = 0.01) for PFS. Among current smokers, the corresponding HRs for early TTFC were 1.78 (1.16-2.74, p = 0.0088) and 1.95 (1.29-2.95, p = 0.0016) for OS and PFS, respectively. In causal mediation analysis, the TTFC effect on survival time was mediated entirely through lung cancer stage. CONCLUSION: The current findings indicate smoking behaviors at diagnosis may affect lung cancer stage and prognosis.

D-CRSE: Diminishing chemotherapy-related side effects through patient education, a mixed-methods pilot study.

OBJECTIVES: Patient education materials regarding self-management of chemotherapy-related side effects are limited, which may result in patients using disreputable sources. We created a brochure that educates patients on common side effects, tools to address problems themselves, and guidance on when to contact their oncologist or seek emergency care. This mixed-methods study conducted at Penn State Cancer Institute evaluates the feasibility of using an educational brochure to improve patient outcomes through education. METHODS: Chemotherapy naïve patients with breast or gastrointestinal (GI) cancer were enrolled in a single-arm clinical trial from December 2021 to 2022. Participants received the educational brochure and were asked to provide their initial impressions. They completed The Emotional Thermometer Scale (ETS) and the Memorial Symptom Assessment Scale (MSAS) to measure changes in patient symptoms and mental health throughout their chemotherapy course at 0, 6, and 12-week intervals. The drop-out rate was recorded as a measure of study feasibility. RESULTS: The study participants were split between the following cancer types: 77.8% breast and 22.2% GI cancer. A significant decrease in overall mean ETS score was observed between baseline and week 6 (p = 0.001) and 12 (p = 0.0004), respectively. Moreover, the mean MSAS psychological symptoms decreased significantly at week 12 compared to baseline (p = 0.005), while no change was observed in physical symptoms (p = 0.101). Of the 40 participants who completed baseline surveys, 37 had at least one additional visit for a drop-out rate of 7.5%. CONCLUSION: This mixed-methods pilot study was successful in demonstrating the feasibility of distributing a standardized educational brochure as an intervention for chemotherapy patients. While participants' emotional scores and psychological symptoms decreased over time, physical symptoms did not, which aligns with side effect progression from cumulative chemotherapy burden.

Empowering Psychiatric Inpatients to Vote: Perceptions of Voting and the Barriers Encountered.

Individuals with psychiatric illness believe that voting is important. However, these individuals have lower rates of voting when compared to the general population. A survey of psychiatrically hospitalized adult patients was conducted to assess perceptions of and barriers to voting in patients with psychiatric illness. Data from 113 surveys was analyzed. A majority of survey participants agreed that they cared about voting, that their vote made a difference, and that their vote was important. 74% of individuals reported previously experiencing at least one barrier when exercising their right to vote. The most commonly experienced barriers reported were not having enough information to make an informed choice, not knowing where to vote, not having transportation, and not being registered to vote. Individuals who encountered a higher number of barriers in the past had a higher chance of encountering barriers more often. In conclusion, a high percentage of individuals with mental illness severe enough to warrant hospitalization have experienced barriers to voting, with many experiencing multiple barriers. Reduction of these barriers is important, as voting and the resultant public policies can directly affect this population's mental health and access to both mental and physical healthcare services.

Pediatric Traumatic Injuries Due to Agrarian Hay-Hole Falls.

Hay-holes are a design feature in many traditionally built barns that serve as a portal through which stored hay is passed to the lower level where animals are fed. Unfortunately, children sometimes fall through the hay-hole to the concrete or packed earth below. Available data on the frequency and types of hay-hole injuries is limited. The purpose of this study was to better characterize the resultant injuries and identify prognostic factors that predict outcomes from them. We performed a retrospective review of 53 children admitted to the Penn State Hershey Children's Hospital at the Penn State Hershey Medical Center with injuries due to a fall through a hay-hole over 15 years. Compared to urban trauma, hay-hole falls more frequently involve younger children and craniofacial injuries. Although they may result in significant injuries, they are rarely fatal. Greater fall height is associated with longer length of stay (LOS) but not with a greater frequency of intubation, intracranial hemorrhage, or skull fracture. A re-examination of barn design may help to reduce the frequency of this injury type.

Proton Pump Inhibitor Use and Iron Deficiency Anemia in Celiac Patients.

INTRODUCTION: We sought to evaluate the effect of proton pump inhibitor (PPI) use on the development and severity of iron deficiency anemia (IDA) in celiac disease (CD). METHODS: We conducted a retrospective chart review of patients older than 18 years of age at Milton S. Hershey Medical Center who were diagnosed with CD. We analyzed four cohorts of celiac patients: (1) IDA diagnosis with PPI usage, (2) no IDA diagnosis with PPI usage, (3) IDA diagnosis with no PPI usage, and (4) no IDA diagnosis with no PPI usage. We also stratified celiac patients with IDA by anemia severity. RESULTS: Of 366 celiac patients, 92 (25.1%) were diagnosed with IDA, of which 60 (65.2%) were on a PPI. The mean Hgb of celiac patients with IDA on a PPI was 11.1 g/dL and 12.1 g/dL for those without PPI (p = 0.04). For all celiac patients on a PPI without IDA, the mean was 13.3 g/dL and 13.7 g/dL for those without PPI (p = 0.02). PPI use occurred in 12 (70.6%) of the 17 patients with low severity anemia, 11 (64.7%) of the 17 patients with medium severity and 6 (85.7%) of the 7 patients with severe (p = 0.55). CONCLUSIONS: There is significant association between PPI use and IDA in celiac patients (p < 0.0001). Of those with IDA on PPIs, the distribution of the severity of anemia is not statistically different compared to those not on PPI. Discontinuation of PPIs or usage of alternative acid suppressive treatments may be indicated in patients with CD and iron deficiency anemia.

Safety and efficacy of endovascular versus microsurgical treatment of unruptured wide-necked middle cerebral artery aneurysms: a propensity score-matched analysis of the NeuroVascular Quality Initiative Quality Outcomes Database Cerebral Aneurysm Registry.

OBJECTIVE: Unruptured, wide-necked middle cerebral artery (WN-MCA) aneurysms have traditionally been considered ideal candidates for microsurgery (MS), although endovascular treatment (EVT) has dramatically increased in popularity with the advent of novel devices such as intrasaccular flow disruptors. The purpose of this study was to evaluate the safety and efficacy of MS versus EVT for unruptured WN-MCA aneurysms. METHODS: The NeuroVascular Quality Initiative Quality Outcomes Database (NVQI-QOD) Cerebral Aneurysm Registry, a multiinstitutional, prospectively collected procedural database, was queried for cases of unruptured WN-MCA aneurysms treated with MS or EVT between 2015 and 2022. A wide neck was defined as an aneurysm neck ≥ 4 mm or a dome/neck ratio ≤ 2. Demographics and aneurysm characteristics were queried. Propensity score matching (PSM) was utilized to match aneurysm size, number of aneurysms treated, patient age, and aneurysm status. Safety outcomes were evaluated including intraoperative and postoperative complication rates. Aneurysm occlusion status and clinical outcomes using the modified Rankin Scale (mRS) score at discharge and the last follow-up were also assessed. RESULTS: Of 671 unruptured MCA aneurysms, 319 were wide necked. Thirty cases were excluded, as the aneurysm had been previously treated. Two hundred eighty-nine operations (203 EVT, 86 MS) in 282 patients satisfied inclusion criteria. After PSM, there were 86 operations in each group for analysis. The mean aneurysm width was 5.0 (EVT) versus 4.9 mm (MS; p = 0.285). Safety data showed similar intraoperative (7.0% EVT vs 3.5% MS, p = 0.496) and postoperative (4.7% vs 7%, p = 0.746) complication rates. The MS patients were more likely to have complete aneurysm occlusion at discharge (90.4% vs 58.8%, p < 0.001). In a limited subset of patients (52.9%) for whom outcome data were available, the EVT patients were more likely to have an mRS score 0 at discharge (50/59 [84.7%] vs 29/54 [53.7%], p < 0.0003] and at the last follow-up (36/55 [65.5%] vs 13/36 [36.1%], p = 0.006). CONCLUSIONS: This study describes a large, modern cohort of propensity score-matched patients who underwent treatment of unruptured WN-MCA aneurysms. Safety data on intraoperative and postoperative complication rates were similar in both treatment groups. MS was more likely to result in complete aneurysm occlusion at discharge. In a subset of patients with available outcome data, EVT was associated with better functional outcomes at discharge and the last follow-up. Given the lack of complete follow-up data and rates of retreatment, these results should be interpreted cautiously.

HeartWare Left Ventricular Assist Device Exercise Hemodynamics With Speed Adjustment Based on Left Ventricular Filling Pressures.

Functional capacity remains limited in heart failure patients with left ventricular assist devices (LVADs) due to fixed pump speed and inability to offload the left ventricle adequately. We hypothesized that manually adjusting LVAD speed during exercise based on pulmonary capillary wedge pressures would increase total cardiac output and maximal oxygen consumption. Two participants with a HeartWare LVAD underwent an invasive ramp study at rest followed by an invasive cardiopulmonary stress test exercising in two randomized phases: fixed speed and adjusted speed. In the latter phase, speed was adjusted every 1 minute during exercise at ±20 rpm/1 mm Hg change from baseline pulmonary capillary wedge pressure. There was no difference in maximal oxygen consumption between the two phases, with a modest increase in total cardiac output during speed adjustment. Filling pressures were initially controlled during speed adjustment until speed was capped at 4,000 rpm, at which point filling pressures increased. Blood pressure was variable. The pressure across the head of the pump (ΔP) was higher with speed adjustment. Contrary to our hypothesis, LVAD speed adjustment during exercise did not improve total cardiac output and functional capacity. This variable response may be attributed to the native cardiac reserve and baroreceptor response; however, additional studies are needed.

Complementarity between Microbiome and Immunity May Account for the Potentiating Effect of Quercetin on the Antitumor Action of Cyclophosphamide in a Triple-Negative Breast Cancer Model.

Immunotherapy targeting program cell death protein 1 (PD-1) in addition to chemotherapy has improved the survival of triple-negative breast cancer (TNBC) patients. However, the development of resistance and toxicity remain significant problems. Using the translationally relevant 4T1 mouse model of TNBC, we report here that dietary administration of the phytochemical quercetin enhanced the antitumor action of Cyclophosphamide, a cytotoxic drug with significant immunogenic effects that is part of the combination chemotherapy used in TNBC. We observed that quercetin favorably modified the host fecal microbiome by enriching species such as Akkermansia muciniphilia, which has been shown to improve response to anti-PD-1 therapy. We also show that quercetin and, to a greater extent, Cyclophosphamide increased the systemic frequency of T cells and NK cells. In addition, Cyclophosphamide alone and in combination with quercetin reduced the frequency of Treg, which is consistent with an antitumor immune response. On the other hand, Cyclophosphamide did not significantly alter the host microbiome, suggesting complementarity between microbiome- and immune-mediated mechanisms in potentiating the antitumor action of Cyclophosphamide by quercetin. Overall, these results support the potential for microbiota-centered dietary intervention to overcome resistance to chemoimmunotherapy in TNBC.

Selective Impact of Selenium Compounds on Two Cytokine Storm Players.

COVID-19 patients suffer from the detrimental effects of cytokine storm and not much success has been achieved to overcome this issue. We sought to test the ability of selenium to reduce the impact of two important cytokine storm players: IL-6 and TNF-α. The effects of four selenium compounds on the secretion of these cytokines from THP-1 macrophages were evaluated in vitro following an LPS challenge. Also, the potential impact of methylseleninic acid (MSeA) on Nrf2 and IκBα was determined after a short treatment of THP-1 macrophages. MSeA was found to be the most potent selenium form among the four selenium compounds tested that reduced the levels of IL-6 and TNF-α secreted by THP-1 macrophages. In addition, an increase in Nrf2 and decrease in pIκBα in human macrophages was observed following MSeA treatment. Our data indicate that COVID-19 patients might benefit from the addition of MSeA to the standard therapy due to its ability to suppress the key players in the cytokine storm.

Characteristics and Outcomes of Intrahospital Transfers from Neonatal Intensive Care to Pediatric Intensive Care Units.

OBJECTIVE: Critically ill children may be transferred from the neonatal intensive care unit (NICU) to the pediatric intensive care unit (PICU) for further critical care, but the frequency and outcomes of this patient population are unknown. The aims of this study are to describe the characteristics and outcomes in patients transferred from NICU to PICUs. We hypothesized that a higher-than-expected mortality would be present for patients with respiratory or cardiovascular diagnoses that underwent a NICU to PICU transition and that specific factors (timing of transfer, illness severity, and critical care interventions) are associated with a higher risk of mortality in the cardiovascular group. STUDY DESIGN: Retrospective analysis of Virtual Pediatric Systems, LLC (2011-2019) deidentified cardiovascular and respiratory NICU to PICU subject data. We evaluated demographics, PICU length of stay, procedures, disposition, and mortality scores. Pediatric Index of Mortality 2 (PIM2) score was utilized to determine the standardized mortality ratio (SMR). RESULTS: SMR of 4,547 included subjects (3,607 [79.3%] cardiovascular and 940 [20.7%] respiratory) was 1.795 (95% confidence interval: 1.62-1.97, p < 0.0001). Multivariable logistic regression analysis demonstrated transfer age (cardiovascular: odds ratio, 1.246 [1.10-1.41], p = 0.0005; respiratory: 1.254 [1.07-1.47], p = 0.0046) and PIM2 scores (cardiovascular: 1.404 [1.25-1.58], p < 0.0001; respiratory: 1.353 [1.08-1.70], p = 0.0095) were significantly associated with increased odds of mortality. CONCLUSION: In this present study, we found that NICU to PICU observed deaths were high and various factors, particularly transfer age, were associated with increased odds of mortality. While the type of patients evaluated in this study likely influenced mortality, further investigation is warranted to determine if transfer timing is also a factor. KEY POINTS: · NICU patients may be transitioned to the PICU.. · NICU to PICU observed deaths were high.. · Transfer timing may be a factor..

Comparing Patients Diagnosed With Ineffective Esophageal Motility by the Chicago Classification Version 3.0 and Version 4.0 Criteria.

Background: The Chicago Classification version 4.0 (CCv4.0) of ineffective esophageal motility (IEM) is more stringent than the Chicago Classification version 3.0 (CCv3.0) definition. We aimed to compare the clinical and manometric features of patients meeting CCv4.0 IEM criteria (group 1) versus patients meeting CCv3.0 IEM but not CCv4.0 criteria (group 2). Methods: We collected retrospective clinical, manometric, endoscopic, and radiographic data on 174 adults diagnosed with IEM from 2011 to 2019. Complete bolus clearance was defined as evidence of exit of the bolus by impedance measurement at all distal recording sites. Barium studies included barium swallow, modified barium swallow, and barium upper gastrointestinal series studies, and collected data from these reports include abnormal motility and delay in the passage of liquid barium or barium tablet. These data along with other clinical and manometric data were analyzed using comparison and correlation tests. All records were reviewed for repeated studies and the stability of the manometric diagnoses. Results: Most demographic and clinical variables were not different between the groups. A lower mean lower esophageal sphincter pressure was correlated with greater percent of ineffective swallows in group 1 (n = 128) (r = -0.2495, P = 0.0050) and not in group 2. In group 1, increased percent of failed contractions on manometry was associated with increased incomplete bolus clearance (r = 0.3689, P = 0.0001). No such association was observed in group 2. A lower median integrated relaxation pressure was correlated with greater percent of ineffective contractions in group 1 (r = -0.1825, P = 0.0407) and not group 2. Symptom of dysphagia was more prevalent (51.6% versus 69.6%, P = 0.0347) in group 2. Dysphagia was not associated with intrabolus pressure, bolus clearance, barium delay, or weak or failed contractions in either group. In the small number of subjects with repeated studies, a CCv4.0 diagnosis appeared more stable over time. Conclusions: CCv4.0 IEM was associated with worse esophageal function indicated by reduced bolus clearance. Most other features studied did not differ. Symptom presentation cannot predict if patients are likely to have IEM by CCv4.0. Dysphagia was not associated with worse motility, suggesting it may not be primarily dependent on bolus transit.

Effect of Negative Pressure Wound Therapy on Surgical Site Infections following Stoma Reversal in Colorectal Surgery: A Meta-Analysis.

BACKGROUND: Surgical site infections (SSI) are common complications after surgery, which cause other complications and increase medical costs. However, the effect of negative-pressure wound therapy (NPWT) for the prevention of SSI at stoma reversal remains inconclusive, with controversial results. This meta-analysis aimed to evaluate the safety and efficacy of NPWT following stoma reversal in colorectal surgery to prevent SSI and other wound complications. METHODS: We conducted a systematic search of the PubMed, EMBASE, and Cochrane Library databases for articles published up to July 2022 and identified relevant studies reporting the NPWT administration following stoma reversal in colorectal surgery compared with non-pressure dressing. The primary outcome was the incidence of SSI, and the secondary outcomes were hematoma, seroma, and length of hospital stay (LOS). RESULTS: Nine studies were included in the meta-analysis, with 825 patients with (n = 310) or without (n = 515) NPWT. Pooled SSI rate was lower in the NPWT group than in the non-pressure dressing group (OR = 0.50; 95% CI: 0.29, 0.84; P = 0.01). There was no significant effect on hematoma (OR = 0.21; 95% CI: 0.03, 1.27; P = 0.09), seroma (OR = 0.26; 95% CI: 0.05, 1.28; P = 0.1) and LOS (MD = -0.16, 95% CI: -0.83, 0.51; P = 0.64). CONCLUSION: The use of NPWT following stoma reversal in colorectal surgery reduced the incidence of SSI. However, this conclusion needs to be interpreted with caution, and further studies should be conducted to confirm in higher-quality RCTs.

Concurrent durvalumab and radiation therapy (DUART) followed by adjuvant durvalumab in patients with localized urothelial cancer of bladder: results from phase II study, BTCRC-GU15-023.

BACKGROUND: Patients with bladder cancer (BC) who are cisplatin ineligible or have unresectable disease have limited treatment options. Previously, we showed targeting programmed death-ligand 1 (PD-L1) with durvalumab (durva) and radiation therapy (RT) combination was safe in BC. We now report results from a phase II study evaluating the toxicity and efficacy of durva and RT in localized BC. METHODS: This is a single-arm, multi-institutional phase II study; N=26. Enrolled patients had pure or mixed urothelial BC (T2-4 N0-2 M0) with unresectable tumors and were unfit for surgery or cisplatin ineligible. Patients received durva concurrently with RT ×7 weeks, followed by adjuvant durva × 1 year. PRIMARY ENDPOINTS: (A) progression-free survival (PFS) at 1 year and (B) disease control rate (DCR) post adjuvant durva. Key secondary endpoints: (A) complete response (CR) post durvaRT (8 weeks), (B) overall survival (OS), (C) PFS and (D) toxicity. Correlative studies included evaluation of baseline tumor and blood (baseline, post durvaRT) for biomarkers. RESULTS: Median follow-up was 27 months. Evaluable patients: 24/26 post durvaRT, 22/26 for DCR post adjuvant durva, all patients for PFS and OS. Post adjuvant durva, DCR was seen in 72.7%, CR of 54.5%. 1-year PFS was 71.5%, median PFS was 21.8 months. 1-year OS was 83.8%, median OS was 30.8 months. CR at 8 weeks post durvaRT was 62.5%. Node positive (N+) patients had similar median PFS and OS. DurvaRT was well tolerated. Grade ≥3 treatment-related adverse events: anemia, high lipase/amylase, immune-nephritis, transaminitis, dyspnea (grade 4-COPD/immune), fatigue, rash, diarrhea and scleritis. No difference in outcome was observed with PD-L1 status of baseline tumor. Patients with CR/PR or SD had an increase in naïve CD4 T cells, a decrease in PD-1+CD4 T cells at baseline and an increase in cytokine-producing CD8 T cells, including interferon gamma (IFNγ) producing cells, in the peripheral blood. CONCLUSION: Durva with RT followed by adjuvant durva was safe with promising efficacy in localized BC patients with comorbidities, including N+ patients. Larger randomized studies, like S1806 and EA8185, are needed to evaluate the efficacy of combining immunotherapy and RT in BC. TRIAL REGISTRATION NUMBER: NCT02891161.

Promoting Health Equity Through Voter Support Activities for the Inpatient Psychiatric Population.

Individuals with mental illness often face barriers to voting. One of the primary barriers is not being registered to vote. This paper describes voter support activities (VSAs) provided to hospitalized adults on the acute inpatient psychiatric units at Pennsylvania Psychiatric Institute. During the six weeks preceding the 2020 general election, adult inpatients were offered six VSAs and an optional survey examining previous voting behaviors and barriers encountered to voting. VSAs included checking voter registration status and polling location, completing a paper or electronic voter registration application, and requesting a mail-in ballot. Of 189 patients approached, 119 individuals participated in the survey and 60 individuals utilized at least one VSA. This project demonstrates that VSAs are a welcome and feasible resource for psychiatrically hospitalized adults. Psychiatric providers can serve an important role in promoting access to voting-related activities for their patients.

The effects of reduced nicotine content cigarettes on biomarkers of nicotine and toxicant exposure, smoking behavior and psychiatric symptoms in smokers with mood or anxiety disorders: A double-blind randomized trial.

BACKGROUND: The U.S. Food and Drug Administration and the government of New Zealand have proposed a reduction of the nicotine content in cigarettes to very low levels. This study examined the potential effects of this regulation in smokers with affective disorders. METHODS: In a randomized controlled parallel group trial conducted at two sites in the USA (Penn State University, Hershey, PA and Massachusetts General Hospital, Boston, MA) 188 adult smokers with a current (n = 118) or lifetime (n = 70) anxiety or unipolar mood disorder, not planning to quit in the next 6 months, were randomly assigned (1:1) to smoke either Usual Nicotine Content (UNC) (11.6 mg nicotine/cigarette) research cigarettes, or Reduced Nicotine Content (RNC) research cigarettes where the nicotine content per cigarette was progressively reduced to 0.2 mg in five steps over 18 weeks. Participants were then offered the choice to either receive assistance to quit smoking, receive free research cigarettes, or resume using their own cigarette brand during a 12-week follow-up period. Main outcomes were biomarkers of nicotine and toxicant exposure, smoking behavior and dependence and severity of psychiatric symptoms. The pre-registered primary outcome was plasma cotinine. RESULTS: A total of 143 (76.1%) randomized participants completed the randomized phase of the trial, 69 (73.4%) in the RNC group and 74 (78.8%) in the UNC group. After switching to the lowest nicotine content cigarettes, compared to smokers in the UNC group, at the last randomized visit the RNC group had significantly lower plasma cotinine (metabolite of nicotine): difference between groups, -175.7, 95% CI [-218.3, -133.1] ng/ml. Urine NNAL (metabolite of NNK, a lung carcinogen), exhaled carbon-monoxide, cigarette consumption, and cigarette dependence were also significantly lower in the RNC group than the UNC group. No between-group differences were found on a range of other biomarkers (e.g. 8-isoprostanes) or health indicators (e.g. blood pressure), or on 5 different psychiatric questionnaires, including the Kessler K6 measure of psychological distress. At the end of the subsequent 12-week treatment choice phase, those randomized to the RNC group were more likely to have quit smoking, based on initial intent-to-treat sample, n = 188 (18.1% RNC v 4.3% UNC, p = 0.004). CONCLUSION: Reducing nicotine content in cigarettes to very low levels reduces some toxicant exposures and cigarette addiction and increases smoking cessation in smokers with mood and/or anxiety disorders, without worsening mental health. TRIAL REGISTRATION: TRN: NCT01928758, registered August 21, 2013.

Overexpression of LncRNA MNX1-AS1/PPFIA4 Activates AKT/HIF-1α Signal Pathway to Promote Stemness of Colorectal Adenocarcinoma Cells.

Purpose: The purpose of this study was to explore the role of the lncRNA MNX1-AS1 and its related downstream signaling pathways in colorectal adenocarcinoma (COAD). Methods: COAD tissues and cells were prepared and treated with sh-MNX1-AS1, pcDNA-MNX1-AS1, sh-PPFIA4, LY29004, and their controls. CCK8 and colony formation assays were undertaken for evaluating cell proliferation. Tumor cell migratory ability was detected by transwell assay. Apoptosis detection was processed by YO-PRO-1/PI Staining. The regulated relationship between lncRNA MNX1-AS1 and PPFIA4 was confirmed by RIP-ChIP assay. Q-PCR was applied to detect genes related to tumor cell stemness, proliferation, migration, and apoptosis in each group. Finally, a xenograft tumor model was constructed to verify the result in vivo. Results: COAD patients with high expression of the lncRNA MNX1-AS1 have poor prognosis. LncRNA MNX1-AS1 promotes the stemness of COAD cells. PPFIA4 mediates lncRNA MNX1-AS1 expression and affects COAD cell stemness. LncRNA MNX1-AS1 accelerates proliferation and migration, while it suppresses apoptosis. LncRNA MNX1-AS1/PPFIA4 accelerates tumor growth in COAD model. LncRNA MNX1-AS1/PPFIA4 activates the downstream AKT/HIF-1α signaling pathway to promote COAD development. LY29004 significantly inhibits the tumorigenic ability of lncRNA MNX1-AS1 and PPFIA4. Conclusion: LncRNA MNX1-AS1/PPFIA4 activates AKT/HIF-1α signal pathway to promote the stemness of COAD cells, which could be a new target for COAD treatment.

Effect of menthol on nicotine reduction: Pooled results from two double-blind randomized controlled trials.

BACKGROUND: Menthol upregulates nicotinic acetylcholine receptors and is associated with tobacco dependence. The effects of menthol when smoking cigarettes with varying low nicotine content up to 98 % (e.g., non-addicting) less than commercial cigarettes is not well understood. The U.S. Food and Drug Administration is considering two tobacco product standards in cigarettes including banning menthol and reducing nicotine content. These new standards have the potential to significantly reduce smoking initiation and maintenance by limiting the mechanistic effects of nicotine and menthol on the brain. METHODS: We conducted two parallel randomized clinical trials of gradually reduced nicotine in cigarettes from 11.6 mg down to 0.2 mg nicotine/cigarette (very low nicotine content; VLNC) vs. usual nicotine content (11.6 mg; UNC) over an 18-week period in people who smoke cigarettes with low socioeconomic status (SES) and mental health conditions. RESULTS: Compared to UNC, VLNC was associated with significant reductions in cotinine, cigarettes per day, expired carbon monoxide levels, nicotine dependence and symptomology. These associations did not differ between menthol and non-menthol cigarettes, except people who smoke menthol cigarettes had less of a cotinine reduction in the SES trial. The pooled odds ratio of being adherent with using only VLNC study cigarettes in the gradual nicotine reduction arm for people who smoke non-menthol vs. menthol cigarettes was 2.6 (95 % CI:1.0, 6.4; p-value: 0.04). CONCLUSIONS: When nicotine is lowered to non-addicting levels, the results indicate an independent effect of menthol on the need to sustain nicotine intake in addicted people who smoke cigarettes.

Pilot randomized controlled trial evaluating the effect of random nicotine delivery on cigarettes per day and smoke exposure.

BACKGROUND: Many smokers report attempting to quit each year, yet most relapse, in part due to exposure to smoking-related cues. It is hypothesized that extinction of the cue-drug association could be facilitated through random nicotine delivery (RND), thus making it easier for smokers to quit. The current study aimed to evaluate the effects of RND on smoking cessation-related outcomes including cigarettes per day (CPD) and exhaled carbon monoxide (CO). METHODS: Participants were current smokers (>9 CPD) interested in quitting. Novel trans-mucosal, orally dissolving nicotine films, developed by Bionex Pharmaceuticals, were used in the study. The pharmacokinetic profile of these films was assessed in single (Experiment 1) and multiple-dose (Experiment 2) administrations prior to the smoking cessation study (Experiment 3). In Experiment 3, participants were randomized 1:1:1 to recieve 4 nicotine films per day of either: placebo delivery (0 mg), steady-state delivery (2 mg), or random nicotine delivery (RND) (0 mg or 4 mg). After two weeks, participants were advised to quit (target quit date, TQD) and were followed up 4 weeks later to collect CPD and CO and to measure dependence (Penn State Cigarette Dependence Index; PSCDI) and craving (Questionnaire of Smoking Urges; QSU-Brief). Means and frequencies were used to describe the data and repeated measures ANOVA was used to determine differences between groups. RESULTS: The pharmacokinetic studies (Experiment 1 and 2) demonstrated that the films designed for this study delivered nicotine as expected, with the 4 mg film delivering a nicotine boost of approximately 12.4 ng/mL across both the single and the multiple dose administration studies. The films reduced craving for a cigarette and were well-tolerated, overall, and caused no changes in blood pressure or heart rate. Using these films in the cessation study (Experiment 3) (n = 45), there was a significant overall reduction in cigarettes smoked per day (CPD) and in exhaled CO, with no significant differences across groups (placebo, steady-state, RND). In addition, there were no group differences in dependence or craving. Adverse events included heartburn, hiccups, nausea, and to a lesser extent, vomiting and anxiety and there were no differences across groups. CONCLUSION: Overall, this pilot study found that RND via orally dissolving films was feasible and well tolerated by participants. However, RND participants did not experience a greater reduction in self-reported CPD and exhaled CO, compared with participants in the steady-state and placebo delivery groups. Future studies to evaluate optimal RND parameters with larger sample sizes are needed to fully understand the effect of RND on smoking cessation-related outcomes.