Subthreshold depression in children and adolescents – a systematic review

Background

Depressive disorders are disabling conditions striking at all ages. In adults, subthreshold depression (SD) is viewed as being on a continuum with major depressive disorder (MDD). Whether this holds for children and adolescents, is still unclear. We performed the first systematic review of SD in subjects below 18 years, in order to explore if childhood SD and MDD share causal pathways, phenomenology and outcomes, supporting a dimensional view.

Methods

A critical systematic review in accordance with preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement. A review protocol was developed a priori, and all reports were assessed by two reviewers.

Results

The literature search generated 941 eligible references and 24 studies were included. Although diagnostic criteria for SD showed great variability, similarities for SD and MDD were striking. Both were common conditions with similar risk factor patterns. Clinical characteristics in both groups were depressed mood, suicidal ideation and high comorbidity. Outcomes were almost equally poor, with increased psychiatric morbidity and health service use. SD intervention studies showed promising results.

Limitations

Reports with data on SD not reported in keywords or abstract may have been missed by the search strategy.

Conclusion

A dimensional view of depressive disorders is also supported in children and adolescents, suggesting SD to be a precursor to MDD. Although SD is a somewhat milder condition than MDD, it has severe outcomes with psychopathology and impairment. There is a need of identifying cost-efficient and longlasting interventions in order to prevent development of early SD into MDD     

Genetic basis of myasthenia gravis – A comprehensive review

Myasthenia gravis (MG) is a rare autoimmune disease characterized by the production of autoantibodies against proteins of the postsynaptic membrane in the neuromuscular junction. The estimated number of MG patients is steadily increasing, and it had more than doubled in the last 20 years. Monozygotic MG twin concordance is estimated to be about 35% supporting the central role of environmental factors in MG etiology. Epigenetics, presume to be the mechanistic link between environmental and genetic risk factors in disease development, provides support for specific microRNAs associated with MG. Genetic studies have mainly pointed at specific HLA alleles implicated in MG susceptibility, however recently both TNFAIP3-interacting protein 1 (TNIP1) and tyrosine phosphatase non-receptor 22 (PTPN22) were indicated to be associated with MG in a GWAS study. A gender bias was observed for SNPs in the HLA-locus, suggesting female-specific alleles have an increase risk for MG. Moreover, sex hormones play a pivotal role in the gender bias in autoimmunity in general and in MG in particular. Hence the genetic basis of gender bias might be highly pertinent to MG and deserves further characterization. Pathway-based analyses that combine information across multiple genes into a limited number of molecular networks have been found to be a powerful approach. Both regulatory T-cell (Treg) differentiation and NF-κB signaling pathway have been shown to have relevance to MG pathophysiology. Hence studies centered around two pathways might be a fruitful approach to identify additional polymorphisms associated with myasthenia gravis.     

‘De novo’ and ‘recurrent’ autoimmune hepatitis after liver transplantation: A comprehensive review

Autoimmune Hepatitis (AIH) is a chronic progressive inflammatory disease of the liver that responds to immunosuppressive therapy. In patients with AIH who have an acute liver failure presentation or those who develop end stage liver disease despite medical therapy, liver transplantation (LT) may become necessary. Despite good outcomes after LT, AIH can develop/recur in the allograft with an estimated incidence of recurrence between 8 and 12% at 1 year and 36–68% at 5 years. The presence of non-organ specific autoantibodies, elevated serum aminotransferases and immunoglobulin G as well as the characteristic histologic features of interface hepatitis (peri-portal plasma cell infiltration) characterize recurrence of disease. De novo AIH is the development of features of classical AIH in the allograft of patients who have not been transplanted for AIH. There are several reports in the pediatric transplant population, where administering immunosuppressive therapy in the regimen used to treat AIH has stabilized graft function in de novo AIH. In adults, hepatitis C (HCV) is the most common indication for LT and HCV often recurs after LT, requiring treatment with Interferon and Ribavirin. Labeling the graft dysfunction ‘de novo AIH’ can be problematic in this context, particularly if HCV RNA is positive at that time. Some have chosen to give other names like ‘graft dysfunction mimicking AIH’ and ‘plasma cell hepatitis’. Regardless of the nomenclature, autoimmune liver graft dysfunction, if managed appropriately with the treatment regimen used to treat AIH, can save grafts and patients. The mechanism causing recurrent or de novo AIH after LT remains unknown. Several mechanisms have been implicated in this loss of self-tolerance including impaired thymic regulation, impaired activity of T regulatory cells, molecular mimicry, calcineurin inhibitors, glutathione-s transferase and genetic polymorphisms. While the phenotype of de novo AIH in pediatrics has been uniform, it has been more variable in adults, highlighting the need for uniform diagnostic criteria or scoring system post LT. Better understanding of the development of autoimmunity and its difference from classical rejection after LT will allow better therapeutic strategies and improved outcome.     

Life and death of β cells in Type 1 diabetes: A comprehensive review

Type 1 diabetes (T1D) is an autoimmune disorder characterized by the destruction of insulin-producing pancreatic β cells. Immune modulators have achieved some success in modifying the course of disease progression in T1D. However, there are parallel declines in C-peptide levels in treated and control groups after initial responses. In this review, we discuss mechanisms of β cell death in T1D that involve necrosis and apoptosis. New technologies are being developed to enable visualization of insulitis and β cell mass involving positron emission transmission that identifies β cell ligands and magnetic resonance imaging that can identify vascular leakage. Molecular signatures that identify β cell derived insulin DNA that is released from dying cells have been described and applied to clinical settings. We also consider changes in β cells that occur during disease progression including the induction of DNA methyltransferases that may affect the function and differentiation of β cells. Our findings from newer data suggest that the model of chronic long standing β cell killing should be reconsidered. These studies indicate that the pathophysiology is accelerated in the peridiagnosis period and manifest by increased rates of β cell killing and insulin secretory impairments over a shorter period than previously thought. Finally, we consider cellular explanations to account for the ongoing loss of insulin production despite continued immune therapy that may identify potential targets for treatment. The progressive decline in β cell function raises the question as to whether β cell failure that is independent of immune attack may be involved.     

Older adults with chronic illness – Caregiver burden in the Asian context: A systematic review

IntroductionUpsurge in life expectancy, filial responsibility of caring, and healthcare advances have increased the older adult population in Asia. The last decade has witnessed nuclear families' proliferation in Asia, leaving family caregivers with more accountability and responsibility. This review explores the pattern of caregiver burden among caregivers of older adults with chronic illness in Asia.MethodsPRISMA guidelines serves as the framework for this systematic review. Studies from selected databases assessed caregivers' physical state, psychological dysfunction, and or burden as an outcome measure. The Newcastle - Ottawa Quality Assessment Scale appraised the quality of the selected studies.ResultsThe review included 12 research articles. Caregivers consistently report mild to a moderate burden. Care recipient with functional dependency, comorbidities, memory, and sleep impairments, escalate caregiver burden. Caregiver variables intensifying burden were advancing age, male gender, spouse as a care recipient, longer care provision duration, and no assistance.ConclusionOptimal levels of emotional well-being, significant family/social support, and self-preparedness among caregivers are grounds for their empowerment.Practical ImplicationsA paradigm shift from 'caregiver burden' to 'caregiver resilience' is advocated. Routine screening, preventive measures (skill-building and psychosocial empowerment), and restorative services (respite care and problem-based home visiting) for caregivers are forecasted.     

Intraductal papillary neoplasm of the bile duct – A comprehensive review

BackgroundIntraductal papillary neoplasm of the bile ducts is a rare tumor type. Management decisions are currently based upon a small case series. The authors have large own experience with IPNB.ObjectiveThe review aims at reporting on clinicopathological features of IPNB in order to provide guidance for management.MethodsWe searched PubMed, Medline, Microsoft Academic and Embase databases to identify studies of relevance. The analysis of own experience was also included.ResultsWe analyzed 59 retrospective series and 25 cases from authors’ clinical experience. The main sign was jaundice and cholangitis, 33% and 48%, respectively. CT’s were performed in 63–76% and MR in 40–56%. Intraductal mass was found in 31–32% and duct dilatation in 27–30%. Endoscopic Retrograde Cholangio-Pancreatography (ERCP) was performed in 48–62%. IPNB with invasive carcinoma was found in 35.7–60% and IPNB with intraepithelial neoplasia in 36–60%. Histopathological confirmation before surgery was rare. The main treatment of IPNB is resection, in our material, both, hepatectomy and hepatectomy plus bile duct resections were performed in 40% of patients. The percentage of postoperative complications was 20%. The 5-year survival rate of all IPNB’s patients was 53.6%; in patients with associated invasive carcinoma - 22.2% and without invasive carcinoma - 100% (p ​= ​0.001).ConclusionsEarly surgery is advisable for radiologically suspected IPNB. The results of treatment depend on histopathology. They are worse at intraductal invasive carcinoma than at neoplasm with neoplasia.     

Sjögren's syndrome and the epithelial target: A comprehensive review

The most difficult component in our understanding of human autoimmunity remains a rigorous dissection of etiological events. Indeed, the vast literature on autoimmune diseases focuses on the inflammatory response, with the hope of developing drugs that reduce inflammation. However, there is increasing recognition that understanding the immunobiology of target tissues will also have direct relevance to disease natural history, including breach of tolerance. Sjögren's syndrome is essentially an epitheliitis and there are major changes to normal architectural salivary organization. We propose that loss of homeostasis is the initial event that precipitates inflammation and that such inflammatory response includes not only the adaptive response, but also an intense innate immune/bystander response. To understand these events this review focuses on the architecture, phenotype, function and epithelial cell organization. We further submit that there are several critical issues that must be defined to fully understand epithelial cell immunobiology in Sjögren's syndrome, including defining epithelial cell polarity, cell–cell and cell to extracellular matrix interactions and a variety of chemical and mechanical signals. We also argue that disruption of tight junctions induces disorganization of the apical pole of salivary acinar cells in Sjögren's syndrome. In addition, there will be a critical role of inflammatory cytokines in the apico-basal relocation of tight junction proteins. Further, the altered disorganization and relocation of proteins that participate in secretory granule formation are also dysregulated in Sjögren's syndrome and will contribute to abnormalities of mucins within the extracellular matrix. Our ability to understand Sjögren's syndrome and develop viable therapeutic options will depend on defining these events of epithelial cell biology.     

Saccade–vergence dynamics and interaction in children and in adults

Peak velocity, duration and accuracy of eye movements (saccade, vergence and combined saccade–vergence eye movements) were investigated in fourteen normal children (4.5 to 12 years of age) and ten normal adults (22 to 44 years of age). Horizontal movements from both eyes were recorded simultaneously by the oculometer, a photoelectric device. Peak velocity of all eye movements, saccades, and vergence (convergence and divergence), attains adult levels by the age of 4.5 years and there is no significant change over the age range studied (4.5 to 44 years). Vergence duration is longer only in young children (below 8 years of age). The reciprocal interaction between saccade and vergence during combined movements known in adults, i.e. acceleration of the vergence by the saccade (increase of velocity and decrease of duration) and deceleration of the saccade by the vergence (decrease of velocity and increase of duration) was found to be similar in children. The accuracy of eye movements is good on average for both saccades and vergence by the age of 4.5 years, and does not change with age; an exception is the variability of saccade amplitude, which is higher in children less than 8 years old. Taken together, the results indicate early maturation of brainstem structures controlling spatio-temporal aspects of saccades, vergence and their interaction.     

Muscle�Ctendon structure and dimensions in adults and children

Muscle performance is closely related to the architecture and dimensions of the muscle–tendon unit and the effect of maturation on these architectural characteristics in humans is currently unknown. This study determined whether there are differences in musculo‐tendinous architecture between adults and children of both sexes. Fascicle length and pennation angle were measured from ultrasound images at three sites along the length of the vastus intermedius, vastus lateralis, vastis medialis and rectus femoris muscles. Muscle volume and muscle–tendon length were measured from magnetic resonance images. Muscle physiological cross‐sectional area (PCSA) was calculated as the ratio of muscle volume to optimum fascicle length. Fascicle length was greater in the adult groups than in children (P < 0.05) but pennation angle did not differ between groups (P > 0.05). The ratios between fascicle and muscle length and between fascicle and tendon length were not different (P > 0.05) between adults and children for any quadriceps muscle. Quadriceps volume and PCSA of each muscle were greater in adults than children (P < 0.01) but the relative proportion of each head to the total quadriceps volume was similar in all groups. However, the difference in PCSA between adults and children (men ～ 104% greater than boys, women ～ 57% greater than girls) was greater (P < 0.05) than the difference in fascicle length (men ～ 37% greater than boys, women ～ 10% greater than girls). It is concluded that the fascicle, muscle and tendon lengthen proportionally during maturation, thus the muscle–tendon stiffness and excursion range are likely to be similar in children and adults but the relatively greater increase in PCSA than fascicle length indicates that adult muscles are better designed for force production than children’s muscles.     

Past,present and future influences of diet among older adults – A scoping review

A tacit understanding of the influence of healthy eating on chronic disease risk and quality of life among older adults is essential for successful design and roll-out of healthy ageing policies. Existing research on dietary determinants among older adults is largely outdated owing to the changing geopolitical scenarios including advancements in health and technology and global migration. Studies published between 2000 and 2020 that explored determinants of diet in older adults were identified using five databases, following Preferred Reporting of Systematic review and Meta-Analyses extended for Scoping Review (PRISMA ScR) guidelines. The final 51 studies (25 quantitative, 22 qualitative and 4 mixed methods) were analysed and interpreted to corroborate existing evidence and identify research gaps. The review identified past influences including childhood affluence and future apprehensions regarding loss of independence and fear of disability to be major drivers of food choices. Current socio-economic status, health conditions and cultural contexts were congruent with past and future influences, implying the role of behavioural change programmes in early life to achieve long term health goals for older adults.     

Novel autoantibodies in Sjögren's syndrome: A comprehensive review

Sjögren's syndrome is a systemic autoimmune disease characterized by immune- mediated injury of exocrine glands, as well as a diverse array of extraglandular manifestations. B cell over-activation is a key feature of the disease, attested by the wide spectrum of autoantibodies detected in these patients. Up to date, anti- Ro/SSA and anti-La/SSB antibodies are traditional biomarkers for disease classification and diagnosis. On the other hand, the detection of novel autoantibodies in SS has increased in the last years, opening a window of opportunity to denote particular stages of the disease, to establish clinical phenotypes, and to predict long-term complications such as lymphoma. For instance, anti-SP-1, anti-CA6 and anti-PSP antibodies occur in an earlier stage than anti-Ro/La antibodies, and may identify a subset of primary Sjögren's syndrome patients with mild or incomplete disease, whereas anti-cofilin-1, anti- alpha-enolase and anti-RGI2 antibodies are potential biomarkers of MALT lymphoma. Antibody detection is also important to elucidate new aspects of SS pathophysiology, and in the future to permit a phenotype-specific patient approach. Herein we review the literature regarding new autoantibodies in SS and attempt to dissect their usefulness as diagnostic tools, pathogenic role, identification of clinical phenotypes and as predictors of an overlap syndrome.     

Comparison between frail and non-frail older adults’ gut microbiota: A systematic review and meta-analysis

BackgroundEmerging evidence suggests that the intestinal microbiota (IM) undergoes remodelling as we age, and this impacts the ageing trajectory and mortality in older adults. The aim was to investigate IM diversity differences between frail and non-frail older adults by meta-analysing previous studies.MethodsThe protocol of this systematic review with meta-analysis was registered on PROSPERO (CRD42021276733). We searched for studies comparing IM diversity of frail and non-frail older adults indexed on PubMed, Embase, Cochrane, and Web of Science in November 2021.ResultsWe included 11 studies with 1239 participants, of which 340 were meta-analysed. Frailty was defined by a variety of criteria (i.e. Fried Scale, European Consensus on Sarcopenia). There were no differences in the meta-analyses between the frail and non-frail groups for species richness index (SMD = −0.147; 95% CI = −0.394, 0.100; p = 0.243) and species diversity index (SMD = −0.033; 95% CI = −0.315, 0.250; p = 0.820). However, we identified almost 50 differences between frail and non-frail within the relative abundance of bacteria phyla, families, genera, and species in the primary studies.ConclusionsThe evidence to prove that there are differences between frail and non-frail IM diversity by meta-analysis is still lacking. The present results suggest that further investigation into the role of specific bacteria, their function, and their influence on the physiopathology of frailty is needed.     

Epidemiologic characteristics and sequelae of closed head‐injured children and adolescents: A review

This article reviews the epidemiology of head‐injured (HI) children and adolescents, including age and sex variables, etiology, and risk factors. Within this context, the psychophysiology (i.e., primary and secondary damage) and outcome and mortality as it exists in these children are described. In addition, motor and speech/language sequelae as well as cognitive and behavioral sequelae in closed head‐injured (CHI) children are reviewed along with findings based on neuropsychological assessment of this population. We concluded that although a pattern of cognitive sequelae, including visuospatial, vi‐suomotor, and memory deficits, are seen in children and adolescents, no apparent pattern of behavioral sequelae exists. More data comparing pre‐injury personality, behavior, and environment, and family influences is warranted before specific posttraumatic behavior can be evidenced.     

Autoimmune regulator and self-tolerance – molecular and clinical aspects

The establishment of central tolerance in the thymus is critical for avoiding deleterious autoimmune diseases. Autoimmune regulator (AIRE), the causative gene in autoimmune polyendocrine syndrome type-1 (APS-1), is crucial for the establishment of self-tolerance in the thymus by promoting promiscuous expression of a wide array of tissue-restricted self-antigens. This step is critical for elimination of high-affinity self-reactive T cells from the immunological repertoire, and for the induction of a specific subset of Foxp3⁺ T-regulatory (T_reg) cells. In this review, we discuss the most recent advances in our understanding of how AIRE operates on molecular and cellular levels, as well as of how its loss of function results in breakdown of self-tolerance mechanisms characterized by a broad and heterogeneous repertoire of autoimmune phenotypes.     

Hyperhidrosis in sleep disorders – A narrative review of mechanisms and clinical significance

Hyperhidrosis is characterized by excessive sweating beyond thermoregulatory needs that affects patients' quality of life. It results from an excessive stimulation of eccrine sweat glands in the skin by the sympathetic nervous system. Hyperhidrosis may be primary or secondary to an underlying cause. Nocturnal hyperhidrosis is associated with different sleep disorders, such as obstructive sleep apnea, insomnia, restless legs syndrome/periodic limb movement during sleep and narcolepsy. The major cause of the hyperhidrosis is sympathetic overactivity and, in the case of narcolepsy type 1, orexin deficiency may also contribute. In this narrative review, we will provide an outline of the possible mechanisms underlying sudomotor dysfunction and the resulting nocturnal hyperhidrosis in these different sleep disorders and explore its clinical relevance.     

Life course socioeconomic conditions and multimorbidity in old age – A scoping review

Multimorbidity disproportionally affects individuals exposed to socioeconomic disadvantage. It is, however, unclear how adverse socioeconomic conditions (SEC) at different periods of the life course predict the occurrence of multimorbidity in later life. In this scoping review, we investigate the association between life course SEC and later-life multimorbidity, and assess to which extent it supports different life course causal models (critical period, sensitive period, accumulation, pathway, or social mobility). We identified four studies (25,209 participants) with the first measure of SEC in childhood (before age 18). In these four studies, childhood SEC was associated with multimorbidity in old age, and the associations were partially or fully attenuated upon adjustment for later-life SEC. These results are consistent with the sensitive period and the pathway models. We identified five studies (91,236 participants) with the first measure of SEC in young adulthood (after age 18), and the associations with multimorbidity in old age as well as the effects of adjustment for later-life SEC differed from one study to the other. Among the nine included studies, none tested the social mobility or the accumulation models. In conclusion, SEC in early life could have an effect on multimorbidity, attenuated at least partly by SEC in adulthood.