Protein kinase C δ (PKCδ) deficiency is a rare genetic disorder identified as a monogenic cause of systemic lupus erythematosus in 2013. Since the first cases were described, the phenotype has expanded to include children presenting with autoimmune lymphoproliferative syndrome-related syndromes and infection susceptibility similar to chronic granulomatous disease or combined immunodeficiency. We review the current published data regarding the pathophysiology, clinical presentation, investigation and management of PKCδ deficiency.
Literature review was performed using MEDLINE.
Twenty cases have been described in the literature with significant heterogeneity.
The variation in clinical presentation delineates the broad and critical role of PKCδ in immune tolerance and effector functions against pathogens.

The diagnosis and monitoring of bleeding and thrombotic disorders depend on correct haemostatic measurements. The availability of high-quality biological variation (BV) data is important in this context. Many studies have reported BV data for these measurands, but results are varied. The present study aims to deliver global within-subject (CVI) and between-subject (CVG) BV estimates for haemostasis measurands by meta-analyses of eligible studies, by assessment with the Biological Variation Data Critical Appraisal Checklist (BIVAC).
Relevant BV studies were graded by the BIVAC. Weighted estimates for CVI and CVG were obtained via meta-analysis of the BV data derived from BIVAC-compliant studies (graded A-C; whereby A represents optimal study design) performed in healthy adults.
In 26 studies BV data were reported for 35 haemostasis measurands. For 9 measurands, only one eligible publication was identified and meta-analysis could not be performed. 74% of the publications were graded as BIVAC C. The CVI and CVG varied extensively between the haemostasis measurands. The highest estimates were observed for PAI-1 antigen (CVI 48.6%; CVG 59.8%) and activity (CVI 34.9%; CVG 90.2%), while the lowest were observed for activated protein C resistance ratio (CVI 1.5%; CVG 4.5%).
This study provides updated BV estimates of CVI and CVG with 95% confidence intervals for a wide range of haemostasis measurands. These estimates can be used to form the basis for analytical performance specifications for haemostasis tests used in the diagnostic work-up required in bleeding- and thrombosis events and for risk assessment.

Background: Wilson’s disease (WD) is an autosomal-recessive disorder of copper deposition caused by pathogenic variants in the copper-transporting ATP7B gene. There is not a clear correlation between genotype and phenotype in WD regarding symptom manifestations. This is supported by the presentation of genetically identical WD twins with phenotypic discordance and different response behavior to WD-specific therapy. Case Presentation: One of the female homozygous twins (age: 26 yrs) developed writing, speaking, swallowing and walking deficits which led to in-patient examination without conclusive results but recommended genetic testing. Both sisters were tested and were heterozygous for the C.2304dupC;p(Met769Hisf*26) and the C.3207C>A;p(His1069Gln) mutation. Self-medication of the affected sibling with 450 mg D-penicillamine (DPA) did not prevent further deterioration. She developed a juvenile parkinsonian syndrome and became wheelchair-bound and anarthric. A percutaneous endoscopic gastrostomy was applied. Her asymptomatic sister helped her with her daily life. Despite the immediate increase of the DPA dose (up to 1800 mg within 3 weeks) in the severely affected patient and the initiation of DPA therapy (up to 600 mg within 2 weeks) in the asymptomatic patient after the first visit in our institution, liver function tests further deteriorated in both patients. After 2 months, the parkinsonian patient started to improve and walk again, but experienced several falls, broke her right shoulder and underwent two necessary surgical interventions. With further consequent copper elimination therapy, liver dysfunction improved in both patients, without need for orthotopic liver transplantation (LTX) in the severely affected patient. Her excellent recovery of liver and brain dysfunction was only transiently interrupted by the development of a nephrotic syndrome which disappeared after switching to Cuprior®. Unfortunately, she died from fulminant pneumonia. Conclusion: Despite identical genetic disposition, WD symptom presentations may develop differently in monozygotic twins, and they may need to be placed on a very different therapeutical regimen. The underlying gene-environment interaction is unclear so far.

Dent disease is a rare X-linked renal tubulopathy due to CLCN5 and OCRL (DD2) mutations. OCRL mutations also cause Lowe syndrome (LS) involving the eyes, brain and kidney. DD2 is frequently described as a mild form of LS because some patients may present with extra-renal symptoms (ESs). Since DD2 is a rare disease and there are a low number of reported cases, it is still unclear whether it has a clinical picture distinct from LS. We retrospectively analyzed the phenotype and genotype of our cohort of 35 DD2 males and reviewed all published DD2 cases. We analyzed the distribution of mutations along the OCRL gene and evaluated the type and frequency of ES according to the type of mutation and localization in OCRL protein domains. The frequency of patients with at least one ES was 39%. Muscle findings are the most common ES (52%), while ocular findings are less common (11%). Analysis of the distribution of mutations revealed (1) truncating mutations map in the PH and linker domain, while missense mutations map in the 5-phosphatase domain, and only occasionally in the ASH-RhoGAP module; (2) five OCRL mutations cause both DD2 and LS phenotypes; (3) codon 318 is a DD2 mutational hot spot; (4) a correlation was found between the presence of ES and the position of the mutations along OCRL domains. DD2 is distinct from LS. The mutation site and the mutation type largely determine the DD2 phenotype.

H syndrome is a rare autosomal recessive disorder with clinical features comprising: hyperpigmentation, hypertrichosis, hearing loss, heart anomalies, low height, hypogonadism and hepatosplenomegaly. H syndrome results from loss-of-function mutations in SLC29A3 which leads to abnormal proliferation and function of histiocytes. Herein, we discuss the considerable phenotypic heterogeneity detected in a consanguineous Egyptian family comprising of four affected siblings, two of which are monozygotic twin and the possible therapeutics. The phenotypic variability may be attributed to the role of histiocytes in the tissue response to injury. Such variable expressivity of H syndrome renders the diagnosis challenging and delays the management. The different treatment approaches used for this rare entity are reviewed.

In recent years, a number of tyrosine kinase inhibitors (TKIs) have been approved for the treatment of non‑small cell lung cancer. These novel treatments exhibit improved efficacy and toxicity when compared to conventional chemotherapy agents. TKIs are administered orally, which has the advantages of improved flexibility and convenience for the patients. However, challenges have arisen in the use of these novel agents. Prescribing drugs for patients with hepatic or renal function impairment poses a challenge for clinicians due to the large pharmacokinetic variability in each individual patient. Moreover, several TKIs have been shown to cause laboratory test abnormalities normally associated with hepatic or renal injury. The aim of the present review was to discuss the effects of hepatic and renal function impairment on the pharmacokinetic variability of 17 TKIs and their potential hepatotoxicity and nephrotoxicity, and to recommend dose adjustment for patients with hepatic or renal impairment.

Experiencing continued growth in demand for mental health services among students, colleges are seeking digital solutions to increase access to care as classes shift to remote virtual learning during the COVID-19 pandemic. Using smartphones to capture real-time symptoms and behaviours related to mental illnesses, digital phenotyping offers a practical tool to help colleges remotely monitor and assess mental health and provide more customised and responsive care. This narrative review of 25 digital phenotyping studies with college students explored how this method has been deployed, studied and has impacted mental health outcomes. We found the average duration of studies to be 42 days and the average enrolled to be 81 participants. The most common sensor-based streams collected included location, accelerometer and social information and these were used to inform behaviours such as sleep, exercise and social interactions. 52% of the studies included also collected smartphone survey in some form and these were used to assess mood, anxiety and stress among many other outcomes. The collective focus on data that construct features related to sleep, activity and social interactions indicate that this field is already appropriately attentive to the primary drivers of mental health problems among college students. While the heterogeneity of the methods of these studies presents no reliable target for mobile devices to offer automated help-the feasibility across studies suggests the potential to use these data today towards personalising care. As more unified digital phenotyping research evolves and scales to larger sample sizes, student mental health centres may consider integrating these data into their clinical practice for college students.

OBJECTIVE: Evidence exists regarding the beneficial effects of diets rich in plant-based foods regarding the prevention of cardiometabolic diseases. These plant-based foods are an exclusive and abundant source of a variety of biologically active phytochemicals, including polyphenols, carotenoids, glucosinolates and phytosterols, with known health-promoting effects through a wide range of biological activities, such as improvements in endothelial function, platelet function, blood pressure, blood lipid profile and insulin sensitivity. We know that an individual\'s physical/genetic makeup may influence their response to a dietary intervention, and thereby may influence the benefit/risk associated with consumption of a particular dietary constituent. This inter-individual variation in responsiveness has also been described for dietary plant bioactives but has not been explored in depth. To address this issue, the European scientific experts involved in the COST Action POSITIVe systematically analyzed data from published studies to assess the inter-individual variation in selected clinical biomarkers associated with cardiometabolic risk, in response to the consumption of plant-based bioactives (poly)phenols and phytosterols. The present review summarizes the main findings resulting from the meta-analyses already completed.
RESULTS: Meta-analyses of randomized controlled trials conducted within POSITIVe suggest that age, sex, ethnicity, pathophysiological status and medication may be responsible for the heterogeneity in the biological responsiveness to (poly)phenol and phytosterol consumption and could lead to inconclusive results in some clinical trials aiming to demonstrate the health effects of specific dietary bioactive compounds. However, the contribution of these factors is not yet demonstrated consistently across all polyphenolic groups and cardiometabolic outcomes, partly due to the heterogeneity in trial designs, low granularity of data reporting, variety of food vectors and target populations, suggesting the need to implement more stringent reporting practices in the future studies. Studies investigating the effects of genetic background or gut microbiome on variability were limited and should be considered in future studies.
CONCLUSIONS: Understanding why some bioactive plant compounds work effectively in some individuals but not, or less, in others is crucial for a full consideration of these compounds in future strategies of personalized nutrition for a better prevention of cardiometabolic disease. However, there is also still a need for the development of a substantial evidence-base to develop health strategies, food products or lifestyle solutions that embrace this variability.

Therapeutic monoclonal antibodies (mAbs) are increasingly used to treat a variety of conditions. The sources of their interindividual pharmacokinetic (PK) variability have been extensively studied, but few data on their intraindividual PK variability are available. In this article, we reviewed the published population compartmental models used to describe the time-varying PK of mAbs in clinical settings. Of 189 publications, 13 report the use of time-varying parameters and 30 describe the effects of antidrug antibody (ADA) development. Currently published time-varying models mainly describe fast decreases in clearance due to target-mediated elimination or slow decreases in clearance owing to cachexia reduction. Immunogenicity models mostly describe \'on-off\' increases of clearance due to a rapid elimination of mAbs-ADA complexes. Some more sophisticated models attempted to decipher the time course of immunogenic response, notably by accounting for the time of onset and progressive increase in ADA production. Currently available time-varying and immunogenicity models are empirical approximations of the complex mAb disposition, but they emphasize the necessity to account for the temporal variations of mAb PK in model building. The clinical implications of the time-varying PK of mAbs are not fully understood, but some publications reported a link between clearance decrease and disease improvement. The future perspectives offered by this knowledge include the possibility to adapt the regimen to the disease and the patients\' state, and also to immune status, and to monitor their evolution by monitoring PK variations.

For several decades, laboratory evolution has served as a powerful method to manipulate microorganisms and to explore long-term dynamics in microbial populations. Next to canonical Escherichia coli planktonic cultures, experimental evolution has expanded into alternative cultivation methods and species, opening the doors to new research questions. Bacillus subtilis, the spore-forming and root-colonizing bacterium, can easily develop in the laboratory as a liquid-air interface colonizing pellicle biofilm. Here, we summarize recent findings derived from this tractable experimental model. Clonal pellicle biofilms of B. subtilis can rapidly undergo morphological and genetic diversification creating new ecological interactions, for example, exploitation by biofilm non-producers. Moreover, long-term exposure to such matrix non-producers can modulate cooperation in biofilms, leading to different phenotypic heterogeneity pattern of matrix production with larger subpopulation of \"ON\" cells. Alternatively, complementary variants of biofilm non-producers, each lacking a distinct matrix component, can engage in a genetic division of labor, resulting in superior biofilm productivity compared to the \"generalist\" wild type. Nevertheless, inter-genetic cooperation appears to be evanescent and rapidly vanquished by individual biofilm formation strategies altering the amount or the properties of the remaining matrix component. Finally, fast-evolving mobile genetic elements can unpredictably shift intra-species interactions in B. subtilis biofilms. Understanding evolution in clonal biofilm populations will facilitate future studies in complex multispecies biofilms that are more representative of nature.