In an era of cost pressure, substituting generic drugs represents one of the main cost-containment strategies of healthcare systems. Despite the obvious financial benefits, in a minority of cases, substitution may require caution or even be contraindicated. In most jurisdictions, to obtain approval, the bioequivalence of generic products with the brand-name equivalent needs to be shown via bioavailability studies in healthy subjects. Rare diseases, defined as medical conditions with a low prevalence, are a group of heterogenous diseases that are typically severe, disabling, progressive, degenerative, and life-threatening or chronically debilitating, and disproportionally affect the very young and elderly. Despite these unique features of rare diseases, generic bioequivalence studies are typically carried out with single doses and exclude children or the elderly. Furthermore, the excipients and manufacturing processes for generic/biosimilar products can differ from the brand products which may affect the shelf-life of the product, its appearance, smell, taste, bioavailability, safety and potency. This may result in approval of generics/biosimilars which are not bioequivalent/comparable in their target population or that meet bioequivalence but not therapeutic equivalence criteria. Another concern relates to the interchangeability of generics and biosimilars which cannot be guaranteed due to the phenomenon of biocreep. This review summarizes potential concerns with generic substitution of orphan drugs and discusses potentially problematic cases including narrow therapeutic index drugs or critical conditions where therapeutic failure could lead to serious complications or even death. Finally, we put forward the need for refining regulatory frameworks, with emphasis on Saudi Arabia, for generic substitution and recent efforts toward this direction.

This study aimed to a) compute the prevalence of violence exposure types, polyvictimization, and self-reported depression, anxiety, and using substances to cope among youth ages 12 to 18 years living on the streets or in the slums of Kampala, Uganda, (b) examine the independent associations among orphan status, violence exposure types, and self-reported mental health concerns, and c) explore the association between polyvictimization and mental health concerns. Data are from a 2014 cross-sectional survey of service-seeking youth ages 12 to 18 years (N = 1134) in Kampala, Uganda. Violence exposure types explored in this study were: witnessing family physical violence, direct physical abuse by a parent, any rape history, and physical dating violence. We used descriptive statistics and multivariable logistic regression to test study objectives. Over half of the sample (60.5%) reported experiencing at least one type of violence exposure; many youth endorsed self-reported depression (57.8%), anxiety (76.8%), and substance use to cope (37.0%). Exposure to violence was associated with higher odds for self-reported depression, anxiety, and using substances to cope. These findings underscore the urgent need to implement evidence-based interventions among this young, underserved population and their families to prevent violence, improve mental health outcomes, and promote resilience.

BACKGROUND: Adoption is frequently viewed as a way to complete the family because of the infertility that some families experience and the desire for kids and teenagers, especially orphans, to have a loving family.
OBJECTIVE: This work intends to identify and propose adaptation solutions to address the psychological problems faced by adoptive families. By doing so, it is hoped that the mental health and overall well-being of individuals and society as a whole will be enhanced.
METHODS: In the first stage of this study, the grounded theory approach based on Strauss and Corbin\'s methodology was used to interview representatives of adoptive families in Iran in 2022 and identify the problems they experience. In the second stage, the same approach and methodology were used to interview representatives of experts. In the second stage, the results of the first stage were presented to a sample of purposefully selected experts, who subsequently proposed solutions for the families to adapt to their problems. Data analysis was conducted using MAXQDA 2020 software (VERBI Software, Berlin, Germany). Ethical requirements were followed at every stage of the study.
RESULTS: Four problem categories were identified in the first step of the study: legal-psychological problems, problems related to the growth of the child in an environment of social harm, attitude and worldview, and the resilience of the adoptive couple. In the second step of the study, four groups of solutions for psychological adjustment were extracted: explaining the issue of what, how, and why of adoption (correct identification of the problems faced by adoptive families, clarification of concepts and demystification, the need for research to address other gaps in the knowledge infrastructure, and the importance of critical thinking education), operational solutions (supervising the adoption database to become more efficient, unitization of adoption national institutes in each province, selection of officials based on both factors of professional and complete mental health, alignment of the provisions and other related legal matters between the involved institutions, and utilization of media influence are recommended, interactional solutions for family resilience (cognitive-therapeutic interactions for mental health based on flexibility, raising the family\'s social capacity through active counseling, improving problem-solving skills, fostering family self-efficacy, creating purposefulness, and appropriate beliefs to predict a bright future), attitude-changing solutions (redefining social norms and facilitating the adoption of desired attitudes by employing social psychology principles, exploiting the power of media and influential figures, employing techniques derived from the psychology of learning, establishing conducive conditions within the framework of individuals\' cognitive dissonance to modify their attitudes, and employing persuasion strategies).
CONCLUSIONS: Legislators and law enforcers, adoptive families, psychologists and consultants working in this field, and physicians specializing in infertility treatment can benefit from the findings of this study.

OBJECTIVE: To determine the long-term outcomes, including mortality and recurrent seizures, among children living with HIV (CLWH) who present with new onset seizure.
METHODS: Zambian CLWH and new onset seizure were enrolled prospectively to determine the risk of and risk factors for recurrent seizures. Demographic data, clinical profiles, index seizure etiology, and 30-day mortality outcomes were previously reported. After discharge, children were followed quarterly to identify recurrent seizures and death. Given the high risk of early death, risk factors for recurrent seizure were evaluated using a model that adjusted for mortality.
RESULTS: Among 73 children enrolled, 28 died (38%), 22 within 30-days of the index seizure. Median follow-up was 533 days (IQR 18-957) with 5% (4/73) lost to follow-up. Seizure recurrence was 19% among the entire cohort. Among children surviving at least 30-days after the index seizure, 27% had a recurrent seizure. Median time from index seizure to recurrent seizure was 161 days (IQR 86-269). Central nervous system opportunistic infection (CNS OI), as the cause for the index seizure was protective against recurrent seizures and higher functional status was a risk factor for seizure recurrence.
CONCLUSIONS: Among CLWH presenting with new onset seizure, mortality risks remain elevated beyond the acute illness period. Recurrent seizures are common and are more likely in children with higher level of functioning even after adjusting for the outcome of death. Newer antiseizure medications appropriate for co-usage with antiretroviral therapies are needed for the care of these children. CNS OI may represent a potentially reversible provocation for the index seizure, while seizures in high functioning CLWH without a CNS OI may be the result of a prior brain injury or susceptibility to seizures unrelated to HIV and thus represent an ongoing predisposition to seizures.
CONCLUSIONS: This study followed CLWH who experienced a new onset seizure to find out how many go on to have more seizures and identify any patient characteristics associated with having more seizures. The study found that mortality rates continue to be high beyond the acute clinical presentation with new onset seizure. Children with a CNS OI causing the new onset seizure had a lower risk of later seizures, possibly because the trigger for the seizure can be treated. In contrast, high functioning children without a CNS OI were at higher risk of future seizures.

Neuropeptides and G protein-coupled receptors (GPCRs) have long been, and continue to be, one of the most popular target classes for drug discovery in CNS disorders, including alcohol use disorder (AUD). Yet, orphaned neuropeptide systems and receptors (oGPCR), which have no known cognate receptor or ligand, remain understudied in drug discovery and development. Orphan neuropeptides and oGPCRs are abundantly expressed within the brain and represent an unprecedented opportunity to address brain function and may hold potential as novel treatments for disease. Here, we describe the current literature regarding orphaned neuropeptides and oGPCRs implicated in AUD. Specifically, in this review, we focus on the orphaned neuropeptide cocaine- and amphetamine-regulated transcript (CART), and several oGPCRs that have been directly implicated in AUD (GPR6, GPR26, GPR88, GPR139, GPR158) and discuss their potential and pitfalls as novel treatments, and progress in identifying their cognate receptors or ligands.

Orphans, especially those who experience maternal loss at a young age, face significant long-term negative impacts on their lives and psychological well-being, extending beyond the age of 18. As of July 2023, the global death toll of COVID-19 has reached 6.9 million, leaving behind an unknown number of orphans who require immediate attention and support from policymakers. In Thailand, from April 2020 to July 2022, the total number of COVID-19-related deaths reached 42,194, resulting in 4,139 parental orphans. Among them, 452 (10.9%) were children under the age of five, who are particularly vulnerable and necessitate special policy attention and ongoing support. While the provision of 12 years of free education for all and Universal Health Coverage helps alleviate the education and health expenses borne by households supporting these orphans, the monthly government support of 2,000 Baht until the age of 18 is insufficient to cover their living costs and other education-related expenditures. We advocate for adequate financial and social support for COVID-19 orphans, emphasizing the importance of placing them with relatives rather than institutional homes. In the context of post-pandemic recovery, this perspective calls upon governments and global communities to estimate the number of orphans and implement policies to safeguard and support them in the aftermath of COVID-19.

Tens of millions of children lack adequate care, many having been separated from or lost one or both parents. Despite the problem\'s severity and its impact on a child\'s lifelong health and wellbeing, the care of vulnerable children-which includes strengthening the care of children within families, preventing unnecessary family separation, and ensuring quality care alternatives when reunification with the biological parents is not possible or appropriate-is a low global priority. This analysis investigates factors shaping the inadequate global prioritization of the care of vulnerable children. Specifically, the analysis focuses on factors internal to the global policy community addressing children\'s care, including how they understand, govern, and communicate the problem.
Drawing on agenda setting scholarship, we triangulated among several sources of data, including 32 interviews with experts, as well as documents including peer-reviewed literature and organizational reports. We undertook a thematic analysis of the data, using these to create a historical narrative on efforts to address children\'s care, and specifically childcare reform.
Divisive disagreements on the definition and legitimacy of deinstitutionalization-a care reform strategy that replaces institution-based care with family-based care-may be hindering priority for children\'s care. Multiple factors have shaped these disagreements: a contradictory evidence base on the scope of the problem and solutions, divergent experiences between former Soviet bloc and other countries, socio-cultural and legal challenges in introducing formal alternative care arrangements, commercial interests that perpetuate support for residential facilities, as well as the sometimes conflicting views of impacted children, families, and the disability community. These disagreements have led to considerable governance and positioning difficulties, which have complicated efforts to coordinate initiatives, precluded the emergence of leadership that proponents universally trust, hampered the engagement of potential allies, and challenged efforts to secure funding and convince policymakers to act.
In order to potentially become a more potent force for advancing global priority, children\'s care proponents within international organizations, donor agencies, and non-governmental agencies working across countries will need to better manage their disagreements around deinstitutionalization as a care reform strategy.

Bacterial virulence, persistence and defence are affected by epigenetic modifications, including DNA methylation. Solitary DNA methyltransferases modulate a variety of cellular processes and influence bacterial virulence; as part of a restriction-modification (RM) system, they act as a primitive immune system in methylating the own DNA, while unmethylated foreign DNA is restricted. We identified a large family of type II DNA methyltransferases in Metamycoplasma hominis, comprising six solitary methyltransferases and four RM systems. Motif-specific 5mC and 6mA methylations were identified with a tailored Tombo analysis on Nanopore reads. Selected motifs with methylation scores >0.5 fit with the gene presence of DAM1 and DAM2, DCM2, DCM3, and DCM6, but not for DCM1, whose activity was strain-dependent. The activity of DCM1 for CmCWGG and of both DAM1 and DAM2 for GmATC was proven in methylation-sensitive restriction and finally for recombinant rDCM1 and rDAM2 against a dam-, dcm-negative background. A hitherto unknown dcm8/dam3 gene fusion containing a (TA) repeat region of varying length was characterized within a single strain, suggesting the expression of DCM8/DAM3 phase variants. The combination of genetic, bioinformatics, and enzymatic approaches enabled the detection of a huge family of type II DNA MTases in M. hominis, whose involvement in virulence and defence can now be characterized in future work.

UNASSIGNED: Children who have lost their parents are especially susceptible because they lack the mental and physical maturity to handle the emotional distress that comes with parental loss. This study aimed to assess the psychological effects of orphanhood in southwest Ethiopia.
UNASSIGNED: We conducted a cross-sectional survey in southwest Ethiopia from January 1, 2019, to March 30, 2019. Orphan students who attended primary school at regular programs and those who live at orphanage centers were included. The study ecluded those orphans, who were adopted, not attending education, live in the street, and attending education, but absent at the time of data collection. A simple random sampling technique was employed to select participants. The SPSS version 21 used to entered and analyzed the collected data. Statistical tests such as independent sample t-test and one-way ANOVA were used to compare the mean of depression, anxiety, and stress level of orphan students regarding age, sex, and grade levels.
UNASSIGNED: Of the 322 participants, 176 (54.7%) of the respondents were males. One hundred ninety-two (59.6%) of the participants were aged 14-17 years. Male and female orphans differed significantly in terms of depression, and stress levels (P < 0.05), but not in terms of anxiety levels (p > 0.05). Across age groups and grade levels, there was a significant difference in the aspects of stress, anxiety, and depression (P 0.05).
UNASSIGNED: Generally, we can conclude that psychological problems (depression, anxiety, and stress) are common problems among orphans in the study area. Orphans who were grade 5thstudents are less psychologically challenged compared to others. Orphans aged 10-13 years were relatively less psychologically challenged than other age groups. As a result, strengthening connections between the care of orphans and other support groups, including charitable organizations or direct healthcare providers should be taken into consideration.

This retrospective study investigated growth outcomes of Kenyan children born to women living with HIV, comparing children who were orphaned maternally, paternally, and totally (both parents deceased) to those who were non-orphaned. We reviewed HIV clinic visits performed in Kenya from January 2011 to August 2016 in children 0 to 4 years of age. Malnutrition was assessed using stunting, underweight status, and wasting (z-scores of ≤-2). Descriptive statistics, Chi-square, t-tests, multivariable logistic regression, and ANCOVA models were performed. Of 15 027 total children in the study population, 3.5% (n = 520) were orphaned maternally, 8.1% (n = 1222) were orphaned paternally, and 2.2% (n = 336) were orphaned totally. Children who were orphans had higher rates of malnutrition compared to non-orphans (P < .001). Children who were orphaned maternally and totally had lower anthropometric mean scores, presented to clinic later, and were more likely to be living with HIV. Children who are orphaned maternally or totally should be targeted in interventional strategies.