Association of Hepatitis B Surface Antigen Levels With Long-Term Complications in Chronic Hepatitis B Virus Infection: A Systematic Literature Review.

Chronic hepatitis B virus (HBV) infection is a global issue and can lead to cirrhosis and hepatocellular carcinoma (HCC). Hepatitis B surface antigen (HBsAg) is an important marker of HBV infection and HBsAg quantification could be a useful tool in clinical practice. This systematic literature review aimed to explore the association between HBsAg titres and long-term disease outcomes and evaluate the relationship between HBsAg titres, or changes in HBsAg titres, and clinical and treatment characteristics in patients with chronic HBV infection. Structured searches were performed in MEDLINE and Embase (January 2000 to 31 March 2023). Eighty-two studies were included, comprising 51% retrospective cohort studies, mostly conducted in Asia (85%). HBsAg levels were shown to predict the long-term development of cirrhosis and HCC in patients who were untreated prior to and during follow-up; however, these data were inconclusive in mixed and treated populations. HBsAg titres were significantly associated with various virological markers including serum HBV DNA, HBcrAg, HBeAg, HBV RNA levels, intrahepatic covalently closed circular DNA (cccDNA) and intrahepatic HBsAg expression. HBsAg titres generally declined over time; this decline was more pronounced in early (HBeAg-positive) than later disease phases (HBeAg-negative). Higher decline in HBsAg levels was consistently associated with subsequent HBsAg seroclearance and a greater decline in total intrahepatic HBV DNA and cccDNA levels. In conclusion, this review showed that HBsAg levels and rates of decline could inform assessment, management and prediction of outcomes in chronic HBV infection. Further studies in broader, more diverse populations and treated patients are needed.

Challenges With the Use of Digital Sham: Systematic Review and Recommendations.

BACKGROUND: Digital therapeutics (DTx) are software-based products that prevent, manage, or treat a medical condition and are delivered through a smartphone app, web application, or wearable device. Clinical trials assessing DTx pose challenges, foremost among which is designing appropriate digital shams (or digital placebos), which should ideally mimic DTx (in terms of design, components, and duration of treatment) while omitting the active principle or component. OBJECTIVE: The objective of our review was to understand how digital shams are being used in clinical research on DTx in neuroscience, which is the most common therapy area for DTx. METHODS: We conducted a systematic literature review of DTx in neuroscience (including neurodevelopmental, neurodegenerative, and psychiatric disorders) with a focus on controlled clinical trials involving digital shams. Studies were identified from trial registries (ClinicalTrials.gov, the European Union Clinical Trials Register, and Trial Trove) and through structured searches in MEDLINE and Embase (both via the Embase website) and were limited to articles in English published from 2010 onward. These were supplemented by keyword-based searches in PubMed, Google, and Google Scholar and bibliographic searches. Studies assessing DTx in neuroscience (including neurodevelopmental, neurodegenerative, and psychiatric disorders) were included. Details related to the publication, DTx, comparator, patient population, and outcomes were extracted and analyzed. RESULTS: Our search criteria identified 461 neuroscience studies involving 213 unique DTx. Most DTx were extended reality based (86/213, 40.4%) or mobile device based (56/213, 26.3%); 313 were comparative, of which 68 (21.7%) used shams. The most common therapeutic areas assessed in these studies were stroke (42/213, 19.7%), depression (32/213, 15%), and anxiety (24/213, 11.3%). The most common treatments were cognitive behavioral therapy or behavioral therapy (67/213, 32.4%), physical rehabilitation (60/213, 28.2%), and cognitive training (41/213, 19.2%). We identified the following important issues related to the use of digital shams in neuroscience: shams were not validated before use in studies, they varied widely in design (from being nearly identical to the DTx to using different software programs altogether), and the level of patient engagement or satisfaction with the sham and the impact of the sham on study outcomes were infrequently reported. CONCLUSIONS: Digital shams are critical for the clinical development of DTx in neuroscience. Given the importance of sham controls in evaluating DTx efficacy, we provide recommendations on the key information that should be reported in a well-designed DTx trial and propose an algorithm to allow the correct interpretation of DTx study results. Sham-controlled studies should be routinely used in DTx trials-in early-phase studies-to help identify DTx active components and-in late-phase studies-to confirm the efficacy of DTx. The use of shams early in development will ensure that the appropriate sham control is used in later confirmatory trials.

Health-related quality of life, fatigue and health utilities in lupus nephritis: A systematic literature review.

BACKGROUND: Systemic lupus erythematosus (SLE) is a chronic, autoimmune disease characterized by abnormal B-cell activation and the presence of autoantibodies, which can result in organ damage. Lupus nephritis (LN) is the most common severe organ manifestation of SLE and may result in impaired kidney function. However, there is limited research on the health-related quality of life (HRQoL) burden amongst patients with LN. The objective of this systematic literature review was to assess the HRQoL, fatigue and health utilities associated with LN. METHODS: A structured literature search (GSK Study 212980) of the MEDLINE and Embase databases was conducted in July 2019 and updated September 2021. Relevant international congress abstracts from 2016 to 2021 were searched, and gray literature searches and keyword-based searches in PubMed, Google, and Google Scholar were also conducted. Results were screened according to predefined criteria and data on the outcomes of interest were extracted. A quantitative analysis was conducted to supplement the narrative review, to provide 36-item Short Form survey (SF-36) estimates, and to determine variation by prognostic factors. RESULTS: Of 1155 articles identified, 26 studies for a total of 3440 patients were included. Patients with LN showed poorer HRQoL and more fatigue than healthy controls/the general population, although these were similar between patients with SLE with and without LN. HRQoL was worse in patients with LN Class III/IV or with active disease. Fatigue was generally reported as the most burdensome symptom and was associated with lower HRQoL and increased treatment dissatisfaction. During induction treatment, HRQoL and fatigue were improved with mycophenolate mofetil versus cyclophosphamide. HRQoL improved over time with treatment amongst patients with active LN. Very limited data were identified assigning utilities to health states for cost-effectiveness analysis. Nine studies were considered for quantitative analysis of baseline SF-36 scores. The analysis suggested that LN has a significant impact across all SF-36 domains, with the lowest scores in the general health perceptions and role-physical domains and physical component summary. CONCLUSIONS: There is a large HRQoL burden in patients with LN, in particular regarding symptoms of fatigue. Future research should focus on investigating fatigue severity and health utilities in LN.

The relationship between cognition and functioning in schizophrenia: A semi-systematic review.

In schizophrenia, impairments in neurocognition (NC) and social cognition (SC) are associated with reduced functional capacity (FC) and poor real-world functioning (RWF). In this semi-systematic review, we examined this association across a range of research questions. We conducted a systematic search in Embase and MEDLINE from 2005 to 2019, and conducted additional pragmatic searches. After screening of titles, abstracts and full-texts, we included 564 citations, of which 44 (26 primary studies, 15 systematic reviews and 3 narrative reviews) were prioritized for reporting. Both NC and SC were significantly associated with functioning, with slightly stronger association for SC. Effect sizes were generally larger for FC than for RWF. NC showed stronger associations with occupational functioning and independent living, and SC with social functioning. Baseline cognition predicted long-term RWF up to 20 years of follow-up, though long-term data were limited for SC. Cognitive remediation improved RWF functioning, especially when it was combined with psychosocial rehabilitation. SC mediated the relationship of NC with functioning. Negative symptoms appeared to mediate and moderate the association of cognition with functioning. Other factors involved included severity of cognitive dysfunction, metacognition, depression and choice of RWF instrument. We discuss potential implications for studies of pharmacological cognitive interventions in schizophrenia - the relevance of both NC and SC, the advantage of adjunctive psychosocial rehabilitation, the role of relevant moderating and mediating variables, and the challenges with RWF instrument selection. Successful cognitive interventions could allow patients with schizophrenia to improve their potential for community functioning.

A systematic review of seizure clusters: Prevalence, risk factors, burden of disease and treatment patterns.

Seizure clusters (SCs) are episodes of consecutive seizures that occur within a short period. The treatment patterns of rescue medications (RMs), as well as the burden of SCs, have not been assessed. A systematic literature search on Embase.com (in PubMed and Embase), supplemented with keyword-based and bibliographic searches, identified 44 articles for disease burden, three treatment guidelines, and three articles for treatment patterns. Common SC definitions were ≥3 seizures/24 h, ≥2/24 h and ≥2/6 h. The rate of SCs in prospective studies ranged from 21.7 %-42.5 %. The frequency of status epilepticus (SE) was higher in SC patients. SCs were associated with higher seizure frequency, higher risk of treatment resistance, and lower likelihood of seizure remission. Quality of life (QoL) was lower in children with SCs than in those with isolated seizures. Seizure-related hospitalization was more common in SC than non-SC patients. SCs adversely affected the productivity of patients and their caregivers. In outpatients with SCs, RMs were prescribed to 24.6 %-89.6 % and utilized by 15.6 %-44.5 %, with rates being higher in children. Key reasons for RM under-utilization were lack of seizure action plans, poor physician-patient communication, and concerns with administration route. In conclusion, SCs are associated with a higher risk of SE, treatment resistance, and low rate of seizure remission. They adversely affect patient and caregiver QoL and work productivity. However, RMs are under-prescribed, and there is an urgent need to improve recognition of SCs, improve use of seizure action plans, and remove barriers to RM use.

The clinical, humanistic, and economic burden of palmoplantar pustulosis: a structured review.

Introduction: Palmoplantar pustulosis (PPP) is a chronic, relapsing and refractory disease characterized by sterile pustules appearing on the palms and/or soles, accompanied by erythema, blistering, scales and/or keratinization. The overall burden of PPP in terms of its clinical impact, effect on patients and families, and economic consequences has not previously been investigated in a structured manner.Areas covered: A structured search focused on identification of studies in PPP using specific search terms in PubMed and EMBASE® from 2005 onwards, with additional back-referencing and pragmatic searches. Outcomes of interest included clinical burden, humanistic burden, and economic burden.Expert opinion: In cross-sectional studies, approximately 75% of all PPP patients suffer from active disease, with risk of relapse remaining constant over time. Patients' health-related quality of life is significantly impaired, as expected for a disease affecting hands and feet. Tools have been described that assess the clinical as well as patient-reported burden of PPP; their performance in larger cohorts and/or clinical trials remains to be investigated. The key data limitations identified include inconsistent definitions for characterizing remission/relapse, and limited humanistic and economic burden data; future studies are required to address these evidence gaps.

The clinical, humanistic, and economic burden of generalized pustular psoriasis: a structured review.

Introduction: Generalized pustular psoriasis (GPP) is characterized by widespread erythema and edema, superficial sterile coalescing pustules, and lakes of pus. Although the impact of GPP is thought to be substantial, emerging literature on its clinical, humanistic, and economic burden has not previously been described in a structured way.Areas covered: A structured search focused on the identification of studies in GPP using specific search terms in PubMed and EMBASE® from 2005 onwards, with additional back-referencing and pragmatic searches. Outcomes of interest included clinical, humanistic, and economic burden.Expert opinion: Despite its significant clinical, humanistic, and economic burden, GPP is poorly classified and inadequately studied. A recent European (ERASPEN) consensus classifies GPP into relapsing and persistent disease and classifies patients on the presence or absence of psoriasis vulgaris. Classification of GPP lesions involving >30% body surface area or use of hospitalization as a surrogate may be a way to identify significant flares. Given the frequency of flares, the impaired quality of life during the post-flare period, and safety/tolerability issues, it is clear that current treatment options are not sufficient. Long-term studies utilizing the European consensus statement with subclassifiers are required to supplement our current understanding of the burden of GPP.

Connected drug delivery devices to complement drug treatments: potential to facilitate disease management in home setting.

Connected drug delivery devices are increasingly being developed to support patient supervision and counseling in home setting. Features may include dosing reminders, adherence trackers, tools for patient education, and patient diaries to collect patient-reported outcomes, as well as monitoring tools with interfaces between patients and health care professionals (HCPs). Five connected devices have been selected as the basis for a review of the clinical evidence concerning the impact of electronic tools on treatment adherence and efficacy outcomes. Disease areas covered include multiple sclerosis, diabetes, hypertension, liver and renal transplant recipients, tuberculosis, hepatitis C, clinically isolated syndrome, asthma, and COPD. From studies comparing the use of electronic feedback tools to standard of care, there is an initial evidence for a higher adherence to treatment and better outcomes among patients who use the electronic tools. To substantiate the assumption that connected devices can improve adherence in an outpatient setting over a prolonged period of time, further data from controlled randomized studies are required. Key barriers to the broader adoption of connected devices include data privacy laws that may prevent data sharing with HCPs in some countries, as well as the need to demonstrate that the tools are consistently used and generate a high-quality and reproducible database. If these challenges can be addressed in a way that is agreeable to all stakeholders, it is expected that the future value of connected devices will be to 1) facilitate and improve patient involvement in disease management in a flexible care setting, 2) enable early treatment decisions, and 3) complement value-based reimbursement models.

Informed consent in psychiatry clinical research: A conceptual review of issues, challenges, and recommendations.

Obtaining informed consent in psychiatry clinical research involving subjects with diminished mental abilities and impaired consent capacity has been a challenge for researchers, posing many ethical concerns and procedural hurdles due to participants' cognitive deficits and impaired ability to judge reality. Regulations seem inadequate and provide limited guidance, not sufficient to address all the ethical issues inherent in different situations related to obtaining consent from decisionally impaired persons. Researchers are struggling to find a balance between risk-benefit ratio, research advancement, and autonomy of study subjects. Inspired to improve the consent process in psychiatry clinical research, many studies have been conducted focusing on various informed consent-related ethical concerns, with the aim of developing appropriate strategies and optimizing the informed consent procedure in psychiatry clinical research, overcoming the ethical concerns. This article critically reviews the various ethical issues and consent challenges, their underlying reasons, and investigates the appropriate strategies and practices needed to be adopted while obtaining informed consent from subjects with impaired consent capacity, participating in psychiatry clinical research.

Challenges in conducting psychiatry studies in India.

A large number of psychiatry studies are conducted in India. Psychiatry studies are complex and present unique challenges in the Indian setting. Ethical issues pertaining to the risk of worsening of illness, use of placebo and validity of informed consents are commonly faced. Site selection can be difficult due to the relative paucity of ICH-GCP (International Conference on Harmonisation - Good Clinical Practice) trained psychiatry investigators in India. Recruitment can be challenging due to issues such as strict eligibility criteria, (lack of) availability of caregiver, illness-related considerations, etc. Assessment of the consent capacity of patients is not simple, while structured assessments are not commonly employed. As the illness fluctuates, the consent capacity may change, thus requiring continued assessment of consent capacity. Study patients run the risk of worsening of illness and suicide due to exposure to inactive treatments; this risk is counterbalanced by use of appropriate study designs, as well as the indirect psychotherapeutic support received. Psychiatry studies are associated with a high placebo response. This necessitates conduct of placebo-controlled studies despite the attendant difficulties. Also, the high placebo response is often the cause of failed trials. Rating scales are essential for assessment of drug response. Some rating instruments as well as some rater training procedures may not be suitable for the Indian setting. Technological advancements may increase the procedural complexity but improve the quality of ratings. Psychiatry studies present monitors and auditors with unique scenarios too. Utilization of psychiatry specific training and expertise is recommended to ensure successful conduct of these studies in India.