RNA Interference Therapeutics for Chronic Hepatitis B: Progress, Challenges, and Future Prospects.

Chronic hepatitis B (CHB) is a global health challenge that can result in significant liver-related morbidity and mortality. Despite a prophylactic vaccine being available, patients already living with CHB often must engage in lifelong therapy with nucleoside analogues. However, the potential of RNA interference (RNAi) therapeutics as a promising avenue for CHB treatment is being explored. RNAi, particularly using small interfering RNA (siRNA), targets viral RNA that can be used to inhibit hepatitis B virus (HBV) replication. Several candidates are currently being studied and have exhibited varying success in reducing hepatitis B surface antigen (HBsAg) levels, with some showing sustained HBsAg loss after cessation of therapy. The dynamic evolution of RNAi therapy presents a promising trajectory for the development of effective and sustained treatments for CHB. This review highlights recent findings on RNAi therapeutics, including modifications for stability, various delivery vectors, and specific candidates currently in development.

Primary prevention of venous thromboembolism for cancer patients in randomized controlled trials: a bibliographical analysis of funding and trial characteristics.

Background: The majority of randomized controlled trials (RCTs) investigating venous thromboembolism (VTE) prophylaxis in patients with cancer involve commercial sponsorship. Commercial sponsorship overcomes feasibility limitations inherent in RCTs, such as recruitment and funding, but has attracted scrutiny for its potential for bias. Objectives: In RCTs of VTE prophylaxis in patients with cancer, how do trial characteristics compare between commercially sponsored RCTs and noncommercially sponsored RCTs? Methods: Medline, Embase, and Cochrane Central Register of Controlled Trials were searched for RCTs that investigated at least 1 pharmacologic intervention for VTE prophylaxis in adult patients with cancer. Screening and data extraction were conducted by independent reviewers. Outcomes included trial characteristics, reporting of favorable outcomes, protocol-manuscript discrepancies, and appraisal of spin. Outcomes were compared using the independent t-test, Mann-Whitney U-test, Pearson chi-squared test, and Fisher's exact test. Logistic regression was performed to identify factors associated with possible bias. Results: Of the 54 trials analyzed, 34 (63%) reported commercial sponsorship. Commercial sponsorship was not associated with the reporting of favorable outcomes, presence of spin, retrospective registration, or protocol-manuscript discrepancy. Spin was most prevalent in the abstract conclusions (9 out of 17 [53.3%]) and manuscript conclusions (8 out of 17 [46.7%]).Commercially sponsored trials had a higher rate of intention-to-treat analysis. Noncommercially sponsored trials were more likely to report retrospective registration of trial protocol and the use of composite primary outcomes. Conclusion: There were few significant differences between trial characteristics, suggesting that the evidence from commercially sponsored trials investigating VTE prophylaxis in patients with cancer is unlikely to be subject to bias attributable to commercial sponsorship.

Estimating the risk of brain metastasis for patients newly diagnosed with cancer.

BACKGROUND: Brain metastases (BM) affect clinical management and prognosis but limited resources exist to estimate BM risk in newly diagnosed cancer patients. Additionally, guidelines for brain MRI screening are limited. We aimed to develop and validate models to predict risk of BM at diagnosis for the most common cancer types that spread to the brain. METHODS: Breast cancer, melanoma, kidney cancer, colorectal cancer (CRC), small cell lung cancer (SCLC), and non-small cell lung cancer (NSCLC) data were extracted from the National Cancer Database to evaluate for the variables associated with the presence of BM at diagnosis. Multivariable logistic regression (LR) models were developed and performance was evaluated with Area Under the Receiver Operating Characteristic Curve (AUC) and random-split training and testing datasets. Nomograms and a Webtool were created for each cancer type. RESULTS: We identify 4,828,305 patients from 2010-2018 (2,095,339 breast cancer, 472,611 melanoma, 407,627 kidney cancer, 627,090 CRC, 164,864 SCLC, and 1,060,774 NSCLC). The proportion of patients with BM at diagnosis is 0.3%, 1.5%, 1.3%, 0.3%, 16.0%, and 10.3% for breast cancer, melanoma, kidney cancer, CRC, SCLC, and NSCLC, respectively. The average AUC over 100 random splitting for the LR models is 0.9534 for breast cancer, 0.9420 for melanoma, 0.8785 for CRC, 0.9054 for kidney cancer, 0.7759 for NSCLC, and 0.6180 for SCLC. CONCLUSIONS: We develop accurate models that predict the BM risk at diagnosis for multiple cancer types. The nomograms and Webtool may aid clinicians in considering brain MRI at the time of initial cancer diagnosis.

When patients are diagnosed with cancer, it is unknown which patients have a significant risk of cancer spread to the brain. Cancer spread to the brain is important to diagnose since it changes how patients are treated and affects their prognosis. This study used a large national database of patients diagnosed with cancer and studied the characteristics that were associated with cancer spread to the brain. The results can be used by doctors to assess the risk of cancer spread to the brain and determine which patients with cancer may benefit most from brain imaging.

Causes of death among people living with metastatic cancer.

Studying survivorship and causes of death in patients with advanced or metastatic cancer remains an important task. We characterize the causes of death among patients with metastatic cancer, across 13 cancer types and 25 non-cancer causes and predict the risk of death after diagnosis from the diagnosed cancer versus other causes (e.g., stroke, heart disease, etc.). Among 1,030,937 US (1992-2019) metastatic cancer survivors, 82.6% of patients (n = 688,529) died due to the diagnosed cancer, while 17.4% (n = 145,006) died of competing causes. Patients with lung, pancreas, esophagus, and stomach tumors are the most likely to die of their metastatic cancer, while those with prostate and breast cancer have the lowest likelihood. The median survival time among patients living with metastases is 10 months; our Fine and Gray competing risk model predicts 1 year survival with area under the receiver operating characteristic curve of 0.754 (95% CI [0.754, 0.754]). Leading non-cancer deaths are heart disease (32.4%), chronic obstructive and pulmonary disease (7.9%), cerebrovascular disease (6.1%), and infection (4.1%).

Association of differential censoring with survival and suboptimal control arms among oncology clinical trials.

Differential censoring (DC), referring to censoring imbalance between treatment arms, may bias the interpretation of survival outcomes in clinical trials. In 146 phase 3 oncology trials with statistically significant time-to-event surrogate primary endpoints (PEPs), we evaluated the association between DC in the surrogate PEP, control arm adequacy, and the subsequent statistical significance of OS results. Twenty-four (16%) trials exhibited DC favoring the control arm (ConDC), while 15 (10%) exhibited experimental arm DC (ExpDC). Positive OS was more common in ConDC trials (63%) than trials without DC (37%) or with ExpDC (47%; odds ratio [OR] 2.64, 95% CI 1.10-7.20; P=.04). ConDC trials more frequently used suboptimal control arms (46%) compared to 20% without DC and 13% with ExpDC (OR 3.60, 95% CI 1.29-10.0; P=.007). The presence of ConDC in trials with surrogate PEPs, especially in those with OS conversion, may indicate an inadequate control arm and should be examined and explained.

Surgical management of Rathke cleft cysts in pediatric patients: a single institution experience.

OBJECTIVE: Rathke cleft cysts (RCCs) are benign, epithelial-lined sellar lesions that arise from remnants of the craniopharyngeal duct. Due to their rarity in the pediatric population, data are limited regarding the natural history and optimal management of growing or symptomatic RCCs. We present our institutional experience with the surgical management of RCCs. METHODS: We performed a retrospective study of consecutive RCC patients ≤ 18 years old treated surgically at our institution between 2006 and 2022. RESULTS: Overall, 567 patients with a diagnosis of pituitary mass or cyst were identified. Of these, 31 had a histopathological diagnosis of RCC, 58% female and 42% male. The mean age was 13.2 ± 4.2 years. Presenting symptoms included headache (58%), visual changes (32%), and endocrinopathies or growth delay (26%); 13% were identified incidentally and subsequently demonstrated growth on serial imaging. Six percent presented with symptomatic intralesional hemorrhage. Surgical approach was transsphenoidal for 90% of patients and orbitozygomatic for 10%. Preoperative headaches resolved in 61% of patients and preoperative visual deficits improvement in 55% after surgery. New pituitary axis deficits were seen in 9.7% of patients. Only two complications occurred from a first-time surgery: one cerebrospinal fluid leak requiring lumbar drain placement, and one case of epistaxis requiring cauterization. No patients experienced new visual or neurological deficits. Patients were followed postoperatively with serial imaging at a mean follow-up was 62.9 ± 58.4 months. Recurrence requiring reoperation occurred in 32% of patients. Five-year progression-free survival was 47.9%. Except for one patient with multiple neurological deficits from a concurrent tectal glioma, all patients had a modified Rankin Scale score of 0 or 1 (good outcome) at last follow-up. CONCLUSION: Due to their secretory epithelium, pediatric RCCs may demonstrate rapid growth and can cause symptoms due to local mass effect. Surgical management of symptomatic or growing pediatric RCCs via cyst fenestration or partial resection of the cyst wall can be performed safely, with good neurologic outcomes. There is a nontrivial risk of endocrinologic injury, and long-term follow up is needed due to high recurrence rates.

Outcomes following lung transplantation for American Indians/Alaska Natives in the United States.

Limited data is available for American Indians/Alaska Natives (AI/AN) undergoing lung transplant. The goal of our study was to assess outcomes for AI/AN lung transplant recipients (LTR). A retrospective review of data from the Organ Procurement and Transplant Network was performed comparing AI/AN (n = 88) and Caucasian (n = 22,767) LTRs between May 4, 2005 and October 31, 2019. AI/AN LTRs had worse functional parameters prior to transplantation but had similar post-transplant outcomes compared to Caucasians LTRs.

An Unexpected Cause of Lung Disease Identified After Lung Transplantation.

CASE PRESENTATION: A 54-year-old woman with systemic lupus erythematosus with associated interstitial lung disease (ILD) presented to the lung transplant clinic for assessment of candidacy for transplantation. She was initially diagnosed with ILD based on clinical and radiographic features (never underwent lung biopsy). In addition, she had associated mixed group I/III pulmonary arterial hypertension. The patient had no family history of pulmonary disease and had never used tobacco and did not have a history of illicit drug use. She was maintained on systemic immunosuppression with hydroxychloroquine, mycophenolate mofetil, and nintedanib for ILD as well as inhaled treprostinil, sildenafil, and macitentan for pulmonary arterial hypertension. Given her progressive symptoms on maximal medical therapy, she was referred for consideration to undergo lung transplantation.

General practitioners' decision-making process to prescribe pain medicines for low back pain: a qualitative study.

BACKGROUND: Pain medicines are widely prescribed by general practitioners (GPs) when managing people with low back pain (LBP), but little is known about what drives decisions to prescribe these medicines. OBJECTIVES: The aim of this study was to investigate what influences GPs' decision to prescribe pain medicines for LBP. DESIGN: Qualitative study with in-depth interviews. SETTING: Australian primary care. PARTICIPANTS: We interviewed 25 GPs practising in Australia experienced in managing LBP (mean (SD) age 53.4 (9.1) years, mean (SD) years of experience: 24.6 (9.3), 36% female). GPs were provided three vignettes describing common LBP presentations (acute exacerbation of chronic LBP, subacute sciatica and chronic LBP) and were asked to think aloud how they would manage the cases described in the vignettes. DATA ANALYSIS: We summarised GP's choices of pain medicines for each vignette using content analysis and used framework analysis to investigate factors that affected GP's decision-making. RESULTS: GPs more commonly prescribed opioid analgesics. Anticonvulsants and antidepressants were also commonly prescribed depending on the presentation described in the vignette. GP participants made decisions about what pain medicines to prescribe for LBP largely based on previous experiences, including their own personal experiences of LBP, rather than guidelines. The choice of pain medicine was influenced by a range of clinical factors, more commonly the patient's pathoanatomical diagnosis. While many adhered to principles of judicious use of pain medicines, polypharmacy scenarios were also common. Concerns about drug-seeking behaviour, adverse effects, stigma around opioid analgesics and pressure from regulators also shaped their decision-making process. CONCLUSIONS: We identified several aspects of decision-making that help explain the current profile of pain medicines prescribed for LBP by GPs. Themes identified by our study could inform future implementation strategies to improve the quality use of medicines for LBP.

Milk antibody response after 3rd COVID-19 vaccine and SARS-CoV-2 infection and implications for infant protection.

Little is known about the persistence of human milk anti-SARS-CoV-2 antibodies after 2nd and 3rd vaccine doses and infection following 3rd dose. In this study, human milk, saliva, and blood samples were collected from 33 lactating individuals before and after vaccination and infection. Antibody levels were measured using ELISA and symptoms were assessed using questionnaires. We found that after vaccination, milk anti-SARS-CoV-2 antibodies persisted for up to 8 months. In addition, distinct patterns of human milk IgA and IgG production and higher milk RBD-blocking activity was observed after infection compared to 3-dose vaccination. Infected mothers reported more symptoms than vaccinated mothers. We examined the persistence of milk antibodies in infant saliva after breastfeeding and found that IgA was more abundant compared to IgG. Our results emphasize the importance of improving the secretion of IgA antibodies to human milk after vaccination to improve the protection of breastfeeding infants.

Assessment of Adverse Reactions, Antibody Patterns, and 12-month Outcomes in the Mother-Infant Dyad After COVID-19 mRNA Vaccination in Pregnancy.

Importance: Longitudinal data on COVID-19 messenger RNA (mRNA) vaccine reactogenicity and immunogenicity in pregnancy and for the mother-infant dyad are needed. Objective: To examine COVID-19 mRNA vaccine reactogenicity and immunogenicity in pregnancy and observe longitudinal maternal and infant outcomes. Design, Setting, and Participants: This prospective cohort study of pregnant individuals enrolled in the COVID-19 Vaccination in Pregnancy and Lactation study from December 1, 2020, through December 31, 2021, with follow-up through March 31, 2022, was conducted at a large academic medical center in an urban metropolitan area in California. Pregnant individuals receiving COVID-19 mRNA vaccines (mRNA-1273 [Moderna] and BNT162b2 [Pfizer-BioNTech]) were eligible. Of 81 participants enrolled, 5 were excluded after enrollment: 1 terminated pregnancy, 1 received the third vaccine dose prior to delivery, and 3 delivered prior to completing the initial vaccine series. Exposure: COVID-19 mRNA vaccination at any time during pregnancy. Main Outcomes and Measures: The primary outcomes were vaccine response as measured by blood Immunoglobulin G (IgG) titers after each vaccine dose and self-reported postvaccination symptoms. Patients' IgG titers were measured in cord blood and in infant blood at intervals up to 1 year of life; IgG and IgA titers were measured in maternal milk. Clinical outcomes were collected from medical records. Results: Of 76 pregnant individuals included in final analyses (median [IQR] maternal age, 35 [29-41] years; 51 [67.1%] White; 28 [36.8%] primigravid; 37 [48.7%] nulliparous), 42 (55.3%) received BNT162b2 and 34 (44.7%) received mRNA-1237. There were no significant differences in maternal characteristics between the 2 vaccine groups. Systemic symptoms were more common after receipt of the second vaccine dose than after the first dose (42 of 59 [71.2%] vs 26 of 59 [44.1%]; P = .007) and after mRNA-1237 than after BNT162b2 (25 of 27 [92.6%] vs 17 of 32 53.1%; P = .001). Systemic symptoms were associated with 65.6% higher median IgG titers than no symptoms after the second vaccine dose (median [IQR], 2596 [1840-4455] vs 1568 [1114-4518] RFU; P = .007); mean cord titers in individuals with local or systemic symptoms were 6.3-fold higher than in individuals without symptoms. Vaccination in all trimesters elicited a robust maternal IgG response. The IgG transfer ratio was highest among individuals vaccinated in the second trimester. Anti-SARS-CoV-2 IgG was detectable in cord blood regardless of vaccination trimester. In milk, IgG and IgA titers remained above the positive cutoff for at least 5-6 months after birth, and infants of mothers vaccinated in the second and third trimesters had positive IgG titers for at least 5 to 6 months of life. There were no vaccine-attributable adverse perinatal outcomes. Conclusions and Relevance: The findings of this cohort study suggest that mRNA COVID-19 vaccination in pregnancy provokes a robust IgG response for the mother-infant dyad for approximately 6 months after birth. Postvaccination symptoms may indicate a more robust immune response, without adverse maternal, fetal, or neonatal outcomes.

Sleep is required to consolidate odor memory and remodel olfactory synapses.

Animals with complex nervous systems demand sleep for memory consolidation and synaptic remodeling. Here, we show that, although the Caenorhabditis elegans nervous system has a limited number of neurons, sleep is necessary for both processes. In addition, it is unclear if, in any system, sleep collaborates with experience to alter synapses between specific neurons and whether this ultimately affects behavior. C. elegans neurons have defined connections and well-described contributions to behavior. We show that spaced odor-training and post-training sleep induce long-term memory. Memory consolidation, but not acquisition, requires a pair of interneurons, the AIYs, which play a role in odor-seeking behavior. In worms that consolidate memory, both sleep and odor conditioning are required to diminish inhibitory synaptic connections between the AWC chemosensory neurons and the AIYs. Thus, we demonstrate in a living organism that sleep is required for events immediately after training that drive memory consolidation and alter synaptic structures.

Clinical practice guideline for deprescribing opioid analgesics: summary of recommendations.

INTRODUCTION: Long term opioids are commonly prescribed to manage pain. Dose reduction or discontinuation (deprescribing) can be challenging, even when the potential harms of continuation outweigh the perceived benefits. The Evidence-based clinical practice guideline for deprescribing opioid analgesics was developed using robust guideline development processes and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology, and contains deprescribing recommendations for adults prescribed opioids for pain. MAIN RECOMMENDATIONS: Eleven recommendations provide advice about when, how and for whom opioid deprescribing should be considered, while noting the need to consider each person's goals, values and preferences. The recommendations aim to achieve: implementation of a deprescribing plan at the point of opioid initiation; initiation of opioid deprescribing for persons with chronic non-cancer or chronic cancer-survivor pain if there is a lack of overall and clinically meaningful improvement in function, quality of life or pain, a lack of progress towards meeting agreed therapeutic goals, or the person is experiencing serious or intolerable opioid-related adverse effects; gradual and individualised deprescribing, with regular monitoring and review; consideration of opioid deprescribing for individuals at high risk of opioid-related harms; avoidance of opioid deprescribing for persons nearing the end of life unless clinically indicated; avoidance of opioid deprescribing for persons with a severe opioid use disorder, with the initiation of evidence-based care, such as medication-assisted treatment of opioid use disorder; and use of evidence-based co-interventions to facilitate deprescribing, including interdisciplinary, multidisciplinary or multimodal care. CHANGES IN MANAGEMENT AS A RESULT OF THESE GUIDELINES: To our knowledge, these are the first evidence-based guidelines for opioid deprescribing. The recommendations intend to facilitate safe and effective deprescribing to improve the quality of care for persons taking opioids for pain.

Considerations for Designing and Implementing a Multi-institution Undergraduate Medical Education Experience.

Cancer Care Experience (CCE) is a unique elective educational program to further explore the subspecialty of oncology beyond the scope of the traditional undergraduate medical education curriculum. During the COVID-19 pandemic, CCE moved from an in-person to a virtual learning platform. This transition allowed program leaders to offer CCE as a multi-institutional program, with students participating from both Duke University School of Medicine and Penn State College of Medicine. Our study aimed to investigate the effectiveness of virtual learning, student perspectives on multi-institutional collaboration, and the program's impact on the student's understanding of oncology care and clerkship preparedness. Overall, students indicated CCE was an impactful program for them to learn more about oncology and that virtual learning was an effective learning platform. Furthermore, our results suggest students found the multi-institutional aspect valuable and that a multi-institution, hybrid (in-person and virtual) platform was preferred. Our study highlights the success of CCE as a multi-institution program and an effective elective program to expose students to the field of oncology further.

Assessment of Median and Mean Survival Time in Cancer Clinical Trials.

This cohort study assesses the relative stability of median and mean survival time estimates reported in cancer clinical trials.

Nirmatrelvir-Ritonavir (Paxlovid) for Mild Coronavirus Disease 2019 (COVID-19) in Pregnancy and Lactation.

Nirmatrelvir-ritonavir (Paxlovid) is recommended to reduce the risk of hospitalization from coronavirus disease 2019 (COVID-19) in pregnancy. Data on use in pregnancy, including prescribing patterns and patient experience (adverse effects, incidence of rebound), are limited. We performed a cross-sectional study in which we surveyed a cohort of vaccinated pregnant or lactating individuals with breakthrough COVID-19. Of 35 pregnant respondents, 51.4% were prescribed and 34.3% took nirmatrelvir-ritonavir; of these, 91.7% experienced dysgeusia and 50.0% had rebound (50.0% positive test result, 33.3% return of symptoms). Three of five lactating respondents were prescribed and two took nirmatrelvir-ritonavir. There were no significant adverse outcomes. Unknown risk was the most common reason for declining nirmatrelvir-ritonavir. More research is needed to establish the safety of nirmatrelvir-ritonavir in pregnancy and lactation, to improve public health messaging, and to increase uptake of this treatment.

Breast and cervical cancer screening rates in student-run free clinics: A systematic review.

OBJECTIVE: To assess rates of breast and cervical cancer screening at student-run free clinics to understand challenges and strategies for advancing quality and accessibility of women's health screening. METHODS: The authors performed a systematic search of publications in Ovid MEDLINE, PubMed, Web of Science, and Google Scholar databases from database inception to 2020. English-language publications assessing rates of breast and cervical cancer screening in student-run free clinics were included. Structured data extraction was completed for each publication by two reviewers independently. Risk of bias was assessed using a modified Agency for Healthcare Research and Quality checklist. Results were synthesized qualitatively because of study heterogeneity. RESULTS: Of 3634 references identified, 12 references met study inclusion criteria. The proportion of patients up-to-date on breast cancer screening per guidelines ranged from 45% to 94%. The proportion of patients up-to-date on cervical cancer screening per guidelines ranged from 40% to 88%. CONCLUSION: Student-run free clinics can match breast and cervical cancer screening rates among uninsured populations nationally, although more work is required to bridge the gap in care that exists for the underinsured and uninsured.

Milk antibody response after 3rd dose of COVID-19 mRNA vaccine and SARS-CoV-2 breakthrough infection and implications for infant protection.

Anti-SARS-CoV-2 antibodies have been found in human-milk after COVID-19 infection and vaccination. However, little is known about their persistence in milk after booster vaccination and breakthrough infection. In this study, human-milk, saliva and blood samples were collected from 33 lactating individuals before and after mRNA-based vaccination and COVID-19 breakthrough infections. Antibody levels were measured using ELISA and symptoms were assessed using questionnaires. Evaluation of maternal and infant symptomatology revealed that infected mothers reported more symptoms than vaccinated mothers. We found that after vaccination, human-milk anti-SARS-CoV-2 antibodies persisted for up to 8 months. In addition, distinct patterns of human milk IgA and IgG production we observed after breakthrough infection compared to 3-dose vaccination series alone, indicating a differential central and mucosal immune profiles in hybrid compared with vaccine-induced immunity. To investigate passively-derived milk antibody protection in infants, we examined the persistence of these antibodies in infant saliva after breastfeeding. We found that IgA was more abundant in infant saliva compared to IgG and persist in infant saliva longer after feeding. Our results delineate the differences in milk antibody response to vaccination as compared to breakthrough infection and emphasize the importance of improving the secretion of IgA antibodies to human milk after vaccination to improve the protection of breastfeeding infants.

Current and emerging biologic and small molecule systemic treatment options for psoriasis and psoriatic arthritis.

Psoriasis and psoriatic arthritis are chronic inflammatory diseases affecting the skin and joints, respectively. Psoriasis and psoriatic arthritis are associated with a high comorbidity burden as well as negative impact on quality of life. Impact on health-related quality of life is optimized when both skin and joint manifestations are effectively treated. The identification of key cytokines involved in disease pathogenesis has led to the development of several therapeutic options for psoriatic disease. When selecting a therapy, it is important to consider disease severity, psoriasis disease subtypes or domains of psoriatic arthritis, comorbidities, patient preference for treatment, among other factors. This review summarizes current biologic and small molecule treatment options as well as emerging therapies for moderate-to-severe adult plaque psoriasis and psoriatic arthritis.