Clinical Trials and Future Outlooks of the Port Delivery System with Ranibizumab: A Narrative Review.

The port delivery system (PDS) of anti-VEGF therapy provides continuous delivery of ranibizumab (RBZ). In October of 2021, the American Food and Drug Administration (FDA) approved the PDS with RBZ as a treatment option for neovascular age-related macular degeneration (nAMD). As the field of PDS with RBZ is progressing rapidly, this narrative review provides a much-needed overview of existing clinical trials as well as ongoing and upcoming trials investigating PDS with RBZ. The phase 2 LADDER trial reported that the mean time to first refill with RBZ PDS 100 mg/ml was 15.8 months (80% CI 12.1-20.6), and pharmacokinetic profiling revealed a sustained concentration of RBZ in serum and aqueous humor. Later, the phase 3 ARCHWAY trial reported that PDS with RBZ (100 mg/ml) refilled every 24 weeks was non-inferior to monthly intravitreal injection (IVI) with RBZ (0.5 mg) in patients with nAMD over 9 months and 2 years. However, patients with PDS had a higher rate of adverse events including vitreous hemorrhage and endophthalmitis. Patients indicate high treatment satisfaction with both PDS and IVI, but the lower number of treatments with PDS was reported as a preferred choice. Several ongoing and future clinical trials, of which details are discussed in this paper, are further exploring the potentials of PDS with RBZ. We conclude that the PDS provides continuous deliverance of RBZ and that clinical efficacy levels are non-inferior to IVI therapy for nAMD. Yet, a higher rate of adverse events remains a concerning detail for widespread implementation. Future studies are warranted to better understand which patients may benefit best from this treatment approach, if long-term efficacy can be sustained, and if safety of PDS can be further improved.

Study protocol for measuring the impact of (quasi-)monochromatic light on post-awakening cortisol secretion under controlled laboratory conditions.

Cortisol secretion has a fundamental role in human circadian regulation. The cortisol awakening response (CAR) can be observed as a daily recurring sharp increase in cortisol concentration within the first hour after awakening and is influenced by environmental light conditions. The current work provides the study protocol for an ongoing research project that is intended to explore the spectral dependencies and to discuss measures of emotional state and cognitive functioning potentially related to the CAR. Based on a controlled within-subjects sleep laboratory study, the impact of a two-hour, (quasi-)monochromatic, post-awakening light exposure of different peak wavelength (applied from 6:00 to 8:00 am) on resulting CAR levels should be investigated in a systematic manner to eventually derive a corresponding spectral sensitivity model. As a secondary outcome, it should be explored whether a potentially light-enhanced cortisol secretion might also impact different measures of sleepiness, mood, and vigilance for certain wavelengths. The study protocol described in the present work discusses the various protocol steps using pilot data collected for two different wavelength settings (i.e., short-wavelength blue-light at λmax = 476 nm and long-wavelength red-light at λmax = 649 nm) experienced by a group of four healthy male adults at an average ± SD age of 25.25 ± 3.59 years.

Heart Transplantation in Mustard Patients Bridged With Continuous Flow Systemic Ventricular Assist Device - A Case Report and Review of Literature.

Thirty four-year-old male with history of D-transposition of the great arteries (D-TGA) who underwent Mustard operation at 14 months of age presented in cardiogenic shock secondary to severe systemic right ventricular failure. Catheterization revealed significantly increased pulmonary pressures. Due to the patient's inotrope dependence and prohibitive pulmonary hypertension, he underwent implantation of a Heart Ware HVAD® for systemic RV support. Within 4 months of continuous flow ventricular assist device (VAD) implantation complete normalization of pulmonary vascular resistance (PVR) was achieved. He ultimately underwent orthotopic heart transplantation with favorable outcomes. This is the second report of complete normalization of PVR following VAD implantation into a systemic RV in <4 months. We conducted a thorough literature review to identify Mustard patients that received systemic RV VAD as a bridge to a successful heart transplantation. In this article, we summarize the outcomes and focus on pulmonary hypertension reversibility following VAD implant.

Permanent His Bundle Pacing in Patients With Congenital Complete Heart Block: A Multicenter Experience.

OBJECTIVES: This study retrospectively assessed the safety and efficacy of permanent His bundle pacing (HBP) in patients with congenital complete heart block (CCHB). BACKGROUND: HBP has become an accepted form of pacing in adults. Its role in CCHB is not known. METHODS: Seventeen patients with CCHB who underwent successful HBP were analyzed at 6 academic centers between 2016 and 2019. Nine patients had de novo implants, and 8 patients had previous right ventricular (RV) leads. Three RV paced patients had reduced left ventricular ejection fractions at the time of HBP. Implant/follow-up device parameters, New York Heart Association functional class, QRS duration, and left ventricular ejection fraction data were analyzed. RESULTS: Patients' mean age was 27.4 ± 11.3 years, 59% were women, and mean follow-up was 385 ± 279 days. The following parameters were found to be statistically significant between implant and follow-up, respectively: impedance, 602 ± 173 Ω versus 460 ± 80 Ω (p < 0.001); and New York Heart Association functional class, 1.7 ± 0.9 versus 1.1 ± 0.3 (p = 0.014). In patients with previous RV pacing, HBP resulted in a significant decrease in QRS duration: 167.1 ± 14.3 ms versus 118.3 ± 13.9 ms (p < 0.0001). In de novo implants, HBP resulted in increases in QRS duration compared with baseline: 111.1 ± 19.4 ms versus 91.0 ± 4.8 ms (p = 0.016). Other parameters exhibited no statistically significant differences. During follow-up, 2 patients required lead revision due to elevated pacing thresholds. CONCLUSIONS: HBP seems to be safe and effective, with improvement in clinical outcomes in patients with CCHB. Larger studies with longer follow-up periods are required to confirm our findings.

His-bundle pacing: A novel treatment for left bundle branch block-mediated cardiomyopathy.

BACKGROUND: Chronic left bundle branch block (LBBB) can lead to LBBB-mediated cardiomyopathy from left ventricular dysynchrony. His-bundle pacing (HBP) results in direct electrical synchrony using the native His-Purkinje system, providing a novel treatment for this cardiomyopathy. OBJECTIVE: To assess the feasibility of HBP for cardiac resynchronization therapy (CRT) in LBBB-mediated cardiomyopathy patients. METHODS: Retrospective database review was conducted on patients who underwent CRT by the HBP capable provider at Indiana University Health and Eskenazi Hospital from August 2015 to August 2017. A subset of patients who met the predefined syndrome criteria of LBBB-mediated cardiomyopathy who underwent HBP were identified. Clinical, echocardiographic, and electrocardiographic variables were extracted at baseline and follow-up. RESULTS: Nine patients had cardiomyopathy and LBBB. Among those two were lost to follow-up. Seven patients were included in the analysis. The average time from device implantation to the last follow-up was 14.5 months. Left ventricular ejection fraction improved on average from 25% to 50% (p = .0001). The left ventricular end-systolic dimension decreased from 47 to 37 mm (p = .003) and the left ventricular end-diastolic dimension decreased from 55 to 48 mm (p = .03). QRS duration with HBP-CRT decreased from 152 to 115 ms. New York Heart Association classification improved from an average of 2.7-2. CONCLUSION: HBP is a viable technique for pursuing CRT in patients with LBBB-mediated cardiomyopathy.

Left Bundle Branch Block-Induced Cardiomyopathy in a Transplanted Heart Treated With His Bundle Pacing.

A 70-year-old male with prior orthotopic heart transplant developed left bundle branch block followed by new-onset left ventricular systolic dysfunction. He underwent His bundle pacing for cardiac resynchronization therapy with complete normalization of his ejection fraction. This is the first reported case of left bundle branch block-induced cardiomyopathy in a transplanted heart. (Level of Difficulty: Advanced.).

Sequencing the peripheral blood B and T cell repertoire - Quantifying robustness and limitations.

The adaptive immune response generates a large repertoire of T cells with T-cell receptors (TCRalpha and TCRbeta) and B cells with immunoglobulins (Ig). The repertoire changes in response to antigen stimulation both through amplification of specific cells (clonal expansion) as well as somatic hypermutation of immunoglobulins. Alterations of the immune repertoire have been observed in response to acute disease, such as external pathogens, or chronic diseases, such as autoimmunity and cancer. Here we establish experimental and analytical protocols for quantifying the peripheral blood of healthy human individuals by profiling the immune repertoire for the Complementarity determining region 3 (CDR3) of the variable regions of TCRbeta (CDRß3) and the IgG heavy chain (CDRH1, CDRH2, CDRH3). The results demonstrate that 40 ml of blood are sufficient to reliably capture the 10,000 most common TCRbeta and 1000 most common IgG and determine their relative frequency in the circulation. We conclude that by using an accessible sample size of human PBMC one is able to robustly monitor alterations in the immune repertoire.

Wearable Cardioverter-Defibrillator after Myocardial Infarction.

BACKGROUND: Despite the high rate of sudden death after myocardial infarction among patients with a low ejection fraction, implantable cardioverter-defibrillators are contraindicated until 40 to 90 days after myocardial infarction. Whether a wearable cardioverter-defibrillator would reduce the incidence of sudden death during this high-risk period is unclear. METHODS: We randomly assigned (in a 2:1 ratio) patients with acute myocardial infarction and an ejection fraction of 35% or less to receive a wearable cardioverter-defibrillator plus guideline-directed therapy (the device group) or to receive only guideline-directed therapy (the control group). The primary outcome was the composite of sudden death or death from ventricular tachyarrhythmia at 90 days (arrhythmic death). Secondary outcomes included death from any cause and nonarrhythmic death. RESULTS: Of 2302 participants, 1524 were randomly assigned to the device group and 778 to the control group. Participants in the device group wore the device for a median of 18.0 hours per day (interquartile range, 3.8 to 22.7). Arrhythmic death occurred in 1.6% of the participants in the device group and in 2.4% of those in the control group (relative risk, 0.67; 95% confidence interval [CI], 0.37 to 1.21; P=0.18). Death from any cause occurred in 3.1% of the participants in the device group and in 4.9% of those in the control group (relative risk, 0.64; 95% CI, 0.43 to 0.98; uncorrected P=0.04), and nonarrhythmic death in 1.4% and 2.2%, respectively (relative risk, 0.63; 95% CI, 0.33 to 1.19; uncorrected P=0.15). Of the 48 participants in the device group who died, 12 were wearing the device at the time of death. A total of 20 participants in the device group (1.3%) received an appropriate shock, and 9 (0.6%) received an inappropriate shock. CONCLUSIONS: Among patients with a recent myocardial infarction and an ejection fraction of 35% or less, the wearable cardioverter-defibrillator did not lead to a significantly lower rate of the primary outcome of arrhythmic death than control. (Funded by the National Institutes of Health and Zoll Medical; VEST ClinicalTrials.gov number, NCT01446965 .).

Hypnosis for Smoking Relapse Prevention: A Randomized Trial.

The purpose of this study was to determine whether hypnosis would be more effective than standard behavioral counseling in helping smokers to remain abstinent. A total of 140 current smokers were enrolled in a randomized controlled smoking cessation trial at an urban Veterans Affairs medical center. Participants (n = 102) who were able to quit for at least 3 days received either a hypnosis or behavioral relapse prevention intervention. Both relapse prevention interventions consisted of two 60 min face-to-face sessions and four 20 min follow-up phone calls (two phone calls per week). At 26 weeks, the validate\d point-prevalence quit rate was 35% for the hypnosis group and 42% for the behavioral counseling group (relative risk = 0.85; 95% confidence interval: 0.52-1.40). At 52 weeks, the validated quit rate was 29% for the hypnosis group and 28% for the behavioral group (relative risk  = 1.03; 95% confidence interval: 0.56-1.91). It was concluded that hypnosis warrants further investigation as an intervention for facilitating maintenance of quitting.

Endogenous antibodies for tumor detection.

The study of cancer immunology has provided diagnostic and therapeutic instruments through serum autoantibody biomarkers and exogenous monoclonal antibodies. While some endogenous antibodies are found within or surrounding transformed tissue, the extent to which this exists has not been entirely characterized. We find that in transgenic and xenograft mouse models of cancer, endogenous gamma immunoglobulin (IgG) is present at higher concentration in malignantly transformed organs compared to non-transformed organs in the same mouse or organs of cognate wild-type mice. The enrichment of endogenous antibodies within the malignant tissue provides a potential means of identifying and tracking malignant cells in vivo as they mutate and diversify. Exploiting these antibodies for diagnostic and therapeutic purposes is possible through the use of agents that bind endogenous antibodies.

The effectiveness of extracorporeal shock wave therapy on chronic achilles tendinopathy: a systematic review.

BACKGROUND: Achilles tendinopathy is a pathological state resulting from repetitive loading or stress on the tendon. Extracorporeal shock wave therapy (ESWT) is hypothesized to be an effective alternative intervention to surgery when other conservative therapies fail. This systematic review investigated the effectiveness of ESWT in the treatment of insertional and noninsertional Achilles tendinopathies. METHODS: Articles were electronically searched from the Cochrane Controlled Trials Register, MEDLINE, CINAHL, EMBASE, and SPORTDiscus using a comprehensive search strategy. Studies were included if they were prospective clinical trials examining the effectiveness of ESWT for insertional or noninsertional Achilles tendinopathies. Methodological quality of included studies was assessed using PEDro scale and Modified McMaster tool. The strength of the evidence was reported using the National Health and Medical Research Council body of evidence framework. A narrative summary of the findings was presented. RESULTS: Four of the included studies were randomized controlled trials, and 2 were pre-post study designs. Common methodological deficiencies included not blinding the clinician and participants. There was consistent evidence from 4 reviewed studies on the effectiveness of ESWT in the management of patients with chronic Achilles tendinopathies at a minimum 3 months' follow-up. CONCLUSION: Overall, our review showed satisfactory evidence for the effectiveness of low-energy ESWT in the treatment of chronic insertional and noninsertional Achilles tendinopathies at a minimum 3 months' follow-up before considering surgery if other conservative management fails. However, combining ESWT with eccentric loading appears to show superior results. LEVEL OF EVIDENCE: Level 1, systematic meta-analysis.

Telephone-delivered cognitive-behavioral therapy for pain management among older military veterans: a randomized trial.

This study investigated the effectiveness of telephone-delivered cognitive-behavioral therapy (T-CBT) in the management of chronic pain with older military veterans enrolled in VA primary-care clinics. We conducted a randomized clinical trial comparing T-CBT with telephone-delivered pain education (T-EDU). A total of 98 military veterans with chronic pain were enrolled in the study and randomized into one of two treatment conditions. Study participants were recruited from primary-care clinics at an urban VA medical center and affiliated VA community-based outpatient clinics (CBOCs). Pain management outcomes were measured at midtreatment (10 weeks), posttreatment (20 weeks), 3-month follow-up (32 weeks), and 6-month follow-up (46 weeks). No significant differences were found between the two treatment groups on any of the outcome measures. Both treatment groups reported small but significant increases in level of physical and mental health, and reductions in pain and depressive symptoms. Improvements in all primary outcome measures were mediated by reductions in catastrophizing. Telephone-delivered CBT and EDU warrant further study as easily accessible interventions for rural-living older individuals with chronic pain.

Expectancies regarding the interaction between smoking and substance use in alcohol-dependent smokers in early recovery.

The purpose of this study was to investigate expectancies regarding the interaction between cigarette smoking and use of alcohol among alcohol-dependent smokers in early recovery, using the Nicotine and Other Substances Interaction Expectancies Questionnaire (NOSIE). Participants were 162 veterans, 97% male, with a mean age of 50 years, enrolled in a clinical trial aimed at determining the efficacy of an intensive smoking cessation intervention versus usual care. At baseline, participants were assessed on measures of smoking behavior, abstinence thoughts about alcohol and tobacco use, symptoms of depression, and smoking-substance use interaction expectancies. In addition, biologically verified abstinence from tobacco and alcohol was assessed at 26 weeks. Participants reported that they expected smoking to have less of an impact on substance use than substance use has on smoking (p < .001). Severity of depressive symptoms was significantly associated with the expectancy that smoking provides a way of coping with the urge to use other substances (p < .01). The expectation that smoking increases substance urges/use was predictive of prospectively measured and biologically verified abstinence from smoking at 26 weeks (p < .03). The results add to our knowledge of smoking-substance use interaction expectancies among alcohol-dependent smokers in early recovery and will inform the development of more effective counseling interventions for concurrent alcohol and tobacco use disorders.

Reduction of autofluorescence at the microelectrode-cortical tissue interface improves antibody detection.

Immunohistochemistry (IHC) remains among the most utilized methods for detection of inflammatory events occurring at the microelectrode-cortical tissue interface. It has further become a standard protocol to quantify the intensity of this resulting fluorescent signal, normalized to "background", as a measurement of the extent of inflammatory events. Unfortunately, several sources of autofluorescence could result in variations in this user-defined "background". Notably, we found that the presence of hemosiderin-laden macrophages (HLMs) at the interface resulted in a variable source of background in both green and red fluorescent channels. The HLM-derived autofluorescence prevented the reproducible detection of presumably low-level antigens at the interface. Here we show that treatment of the native cortical tissue for no less than 10 min, with a minimum of 0.5mM copper sulfate, resulted in at least a 70% reduction in native HLM autofluorescence in both green and red fluorescent channels. In the case of highly expressed antigens, such as glial fibrillar acidic protein (GFAP), treatment of immuno-labeled tissue with copper sulfate reduced tissue background, compared to standard IHC methodology, but did not result in significant differences in the quantification of normalized signal intensity. However, treatment with copper sulfate substantially enhanced the detection efficiency of weakly expressed antigens at the device-tissue interface. This study demonstrates that the inclusion of copper sulfate incubation during IHC tissue preparation significantly reduced HLM-derived autofluorescence, and allowed for more accurate detection and quantification of faintly expressed inflammatory markers at the device-tissue interface.

Intensive intervention for alcohol-dependent smokers in early recovery: a randomized trial.

INTRODUCTION: The purpose of this study was to investigate the efficacy of an intensive tobacco cessation intervention for alcohol-dependent smokers in early recovery. METHODS: A total of 162 alcohol-dependent smokers were randomized to either intensive intervention for smoking cessation or usual care. The intensive intervention consisted of 16 sessions of individual cognitive behavior therapy (CBT) and combination nicotine replacement therapy that lasted 26 weeks. Usual care involved referral to a free-standing smoking cessation program that provided smoking cessation counseling of varying duration and guideline-concordant medications. The primary cessation outcome was verified 7-day point prevalence abstinence (PPA) at 12, 26, 38, and 52 weeks. RESULTS: At 12 and 26 weeks, the verified 7-day point-prevalence quit rate was significantly higher for the intensive intervention group than for the usual care group (both p=0.03). However, the quit rates for the two treatment groups were not significantly different at 38 or 52 weeks. Verified 30-day alcohol abstinence rates were not significantly different for the two treatment groups at any of the follow-up assessments. CONCLUSIONS: The intensive smoking cessation intervention yielded a higher short-term smoking quit rate without jeopardizing sobriety. A chronic care model might facilitate maintenance of smoking cessation during the first year of alcohol treatment and perhaps for longer periods of time. It is hoped that studies such as this will inform the development of more effective interventions for concurrent alcohol and tobacco use disorders.

Sustained-release bupropion for hospital-based smoking cessation: a randomized trial.

INTRODUCTION: Bupropion is a first-line pharmacological aid for smoking cessation; however, no clinical trials have been conducted in a general population of hospitalized smokers. METHODS: We enrolled 85 smokers in a hospital-based randomized smoking cessation trial conducted at the San Francisco Veterans Affairs Medical Center. A total of 42 participants received a 7-week course of sustained-release bupropion and 43 participants received placebo. All participants received cognitive-behavioral counseling. We screened 14,997 patients, of whom 25% were current smokers. Of the 536 smokers who met the entry criteria, 451 opted not to enroll. We determined on-medication, end-of-medication, 3-month, and 6-month smoking cessation rates. RESULTS: At the end of 7 weeks of drug treatment, self-reported quit rates were equivalent in the bupropion and placebo arms, 37% versus 33%, respectively (p = .82). The validated quit rates for the bupropion and placebo groups were 27% versus 29%, respectively (p = 1.00). At 6 months, the self-reported quit rates were 29% in the bupropion group and 41% in the placebo group (p = .36). In a comparison of 6-month quit rates, validated either by salivary cotinine or by spousal proxy, we found nonsignificantly higher quit rates in the placebo group than in the bupropion group, 31% versus 15% (p = .12). DISCUSSION: The addition of sustained-release bupropion to counseling did not increase quit rates, but the study was underpowered. Because of the secular trend toward shorter hospital stays, recruitment was very difficult, raising questions regarding the feasibility of future hospital-based smoking cessation trials and interventions.

The relation of alpha-linolenic acid to the risk of prostate cancer: a systematic review and meta-analysis.

BACKGROUND: alpha-Linolenic acid (ALA; 18:3n-3) has been associated inconsistently with an increased risk of prostate cancer. Additional studies have become available since the publication of 2 previous meta-analyses. OBJECTIVE: The objective was to review the published data on the relation between ALA and prostate cancer. DESIGN: We conducted a systematic review to identify studies that included data on ALA and risk of prostate cancer. Data were pooled from studies that compared the highest ALA quantile with the lowest ALA quantile, and risk estimates were combined by using a random-effects model. RESULTS: The relation between ALA and prostate cancer is inconsistent across studies. We pooled data from 8 case-control and 8 prospective studies. The summary estimate revealed that high ALA dietary intakes or tissue concentrations are weakly associated with prostate cancer risk (relative risk [RR]: 1.20; 95% CI: 1.01, 1.43). When examined by study type (ie, retrospective compared with prospective or dietary ALA compared with tissue concentration) or by decade of publication, only the 6 studies examining blood or tissue ALA concentrations revealed a statistically significant association. With the exception of these studies, there was significant heterogeneity and evidence of publication bias. After adjustment for publication bias, there was no association between ALA and prostate cancer (RR: 0.96; 95% CI: 0.79, 1.17). CONCLUSIONS: Studies examining the relation between ALA and prostate cancer have produced inconsistent findings. High ALA intakes or high blood and adipose tissue concentrations of ALA may be associated with a small increased risk of prostate cancer. However, these conclusions are qualified because of the heterogeneity across studies and the likelihood of publication bias.

Hypnosis for smoking cessation: a randomized trial.

The purpose of this study was to determine whether hypnosis would be more effective in helping smokers quit than standard behavioral counseling when both interventions are combined with nicotine patches (NP). A total of 286 current smokers were enrolled in a randomized controlled smoking cessation trial at the San Francisco Veterans Affairs Medical Center. Participants in both treatment conditions were seen for two 60-min sessions, and received three follow-up phone calls and 2 months of NP. At 6 months, 29% of the hypnosis group reported 7-day point-prevalence abstinence compared with 23% of the behavioral counseling group (relative risk [RR] = 1.27; 95% confidence interval, CI 0.84-1.92). Based on biochemical or proxy confirmation, 26% of the participants in the hypnosis group were abstinent at 6 months compared with 18% of the behavioral group (RR = 1.44; 95% CI 0.91-2.30). At 12 months, the self-reported 7-day point-prevalence quit rate was 24% for the hypnosis group and 16% for the behavioral group (RR = 1.47; 95% CI 0.90-2.40). Based on biochemical or proxy confirmation, 20% of the participants in the hypnosis group were abstinent at 12 months compared with 14% of the behavioral group (RR = 1.40; 95% CI 0.81-2.42). Among participants with a history of depression, hypnosis yielded significantly higher validated point-prevalence quit rates at 6 and 12 months than standard treatment. It was concluded that hypnosis combined with NP compares favorably with standard behavioral counseling in generating long-term quit rates.