Characteristics of isoniazid-induced psychosis: a systematic review of case reports and case series.

PURPOSE: Isoniazid, a first-line antitubercular drug, is associated with nervous system adverse drug reactions such as seizures, peripheral neuropathy, and psychosis. This systematic review of case reports and case series aimed to characterize the demographic, social, and clinical factors associated with isoniazid-induced psychosis in patients with active tuberculosis (TB) and those who received isoniazid for latent TB infection (LTBI). METHODS: We comprehensively searched the Embase, PubMed, and Scopus databases to identify relevant studies published between the date of inception of the database and June 2024. RESULTS: A total of 28 studies, including 21 case reports and 7 case series involved 37 patients who developed isoniazid-induced psychosis. A higher frequency of isoniazid-induced psychosis was observed during the first 2 months of treatment, with a relatively early onset observed among patients aged 18 years or less. Delusions and/or hallucinations are the common symptoms of isoniazid-induced psychosis. Psychomotor disturbances, disorganized speech or formal thought disorder, disorganized or abnormal behaviour, and neuropsychiatric symptoms (sleep disturbances, hostility or aggression, confusion, affective symptoms, anxiety symptoms, and cognitive difficulties) were the other symptoms observed in the included studies. More than 80% of cases rechallenged with isoniazid resulted in the recurrence of psychotic symptoms. CONCLUSION: Patients with TB and LTBI should be assessed for psychotic and neuropsychiatric symptoms during isoniazid therapy, mainly in the first 2 months. Further research is required to understand the impact of underlying risk factors, such as genetic predisposition and isoniazid pharmacokinetics, as well as the clinical utility and dosage recommendations of pyridoxine for managing isoniazid-induced psychosis.

Precision Medicine Strategies to Improve Isoniazid Therapy in Patients with Tuberculosis.

Due to interindividual variability in drug metabolism and pharmacokinetics, traditional isoniazid fixed-dose regimens may lead to suboptimal or toxic isoniazid concentrations in the plasma of patients with tuberculosis, contributing to adverse drug reactions, therapeutic failure, or the development of drug resistance. Achieving precision therapy for isoniazid requires a multifaceted approach that could integrate various clinical and genomic factors to tailor the isoniazid dose to individual patient characteristics. This includes leveraging molecular diagnostics to perform the comprehensive profiling of host pharmacogenomics to determine how it affects isoniazid metabolism, such as its metabolism by N-acetyltransferase 2 (NAT2), and studying drug-resistant mutations in the Mycobacterium tuberculosis genome for enabling targeted therapy selection. Several other molecular signatures identified from the host pharmacogenomics as well as other omics-based approaches such as gut microbiome, epigenomic, proteomic, metabolomic, and lipidomic approaches have provided mechanistic explanations for isoniazid pharmacokinetic variability and/or adverse drug reactions and thereby may facilitate precision therapy of isoniazid, though further validations in larger and diverse populations with tuberculosis are required for clinical applications. Therapeutic drug monitoring and population pharmacokinetic approaches allow for the adjustment of isoniazid dosages based on patient-specific pharmacokinetic profiles, optimizing drug exposure while minimizing toxicity and the risk of resistance. Current evidence has shown that with the integration of the host pharmacogenomics-particularly NAT2 and Mycobacterium tuberculosis genomics data along with isoniazid pharmacokinetic concentrations in the blood and patient factors such as anthropometric measurements, comorbidities, and type and timing of food administered-precision therapy approaches in isoniazid therapy can be tailored to the specific characteristics of both the host and the pathogen for improving tuberculosis treatment outcomes.

Isoniazid-induced pancreatitis: A systematic review.

BACKGROUND: Isoniazid-induced pancreatitis is a potentially serious adverse drug reaction, however, the frequency of its occurrence is unknown. We conducted a systematic review to explore this adverse drug reaction comprehensively. METHODS: We performed an advanced search in PubMed, Web of Science, Scopus, Ovid, and Embase for studies that reported isoniazid-induced pancreatitis. From the extracted data of eligible cases, we performed a descriptive analysis and a methodological risk of bias assessment using a standardized tool. RESULTS: We included 16 case reports from eight countries comprising 16 patients in our systematic review. Most of the isoniazid-induced pancreatitis cases were extrapulmonary tuberculosis cases. We found the mean age across all case reports was 36.7 years. In all the cases, discontinuation of isoniazid resulted in the resolution of pancreatitis. CONCLUSIONS: We found the latency period for isoniazid-induced pancreatitis to be ranged from 12 to 45 days after initiation of isoniazid therapy. A low threshold for screening of pancreatitis by measuring pancreatic enzymes in patients on isoniazid presenting with acute abdominal pain is recommended. This would facilitate an early diagnosis and discontinuation of isoniazid, thus reducing the severity of pancreatitis and preventing the complications of pancreatitis.

Case report: Death caused by multi-organ metastatic calcifications as a result of intramuscular injections with paraffin oil.

In this forensic case report, we present autopsy findings from a young male in his thirties who had been self-injecting paraffin oil into his upper extremities 8 years prior to death. The injections induced an inflammatory response, leading to granuloma formation. This, in turn, resulted in severe hypercalcemia. The external autopsy examination revealed gross macroscopic ulcerations and enlargement of upper extremities, while calcifications of ligaments, heart, kidneys and dura mater was revealed on postmortem CT-scans. Histopathological examination showed extensive multiorgan metastatic calcifications in several tissues including the lungs, heart and kidney. Cause of death was estimated to be the extensive calcific deposits in the heart likely resulting in cardiac arrest. To our knowledge this is the first case reporting findings from an autopsy in which the cause of death was linked to cosmetic oil injections.

Influence of N-acetyltransferase 2 polymorphisms and clinical variables on liver function profile of tuberculosis patients.

BACKGROUND: Single nucleotide polymorphisms (SNPs) in the N-acetyltransferase 2 (NAT2) gene as well as several other clinical factors can contribute to the elevation of liver function test values in tuberculosis (TB) patients receiving antitubercular therapy (ATT). RESEARCH DESIGN AND METHODS: A prospective study involving dynamic monitoring of the liver function tests among 130 TB patients from baseline to 98 days post ATT initiation was undertaken to assess the influence of pharmacogenomic and clinical variables on the elevation of liver function test values. Genomic DNA was extracted from serum samples for the assessment of NAT2 SNPs. Further, within this study population, we conducted a case control study to identify the odds of developing ATT-induced drug-induced liver injury (DILI) based on NAT2 SNPs, genotype and phenotype, and clinical variables. RESULTS: NAT2 slow acetylators had higher mean [90%CI] liver function test values for 8-28 days post ATT and higher odds of developing DILI (OR: 2.73, 90%CI: 1.05-7.09) than intermediate acetylators/rapid acetylators. CONCLUSION: The current study findings provide evidence for closer monitoring among TB patients with specific NAT2 SNPs, genotype and phenotype, and clinical variables, particularly between the period of more than a week to one-month post ATT initiation for better treatment outcomes.

Novel Developments in the Treatment of Multiple Myeloma-Associated Bone Disease.

Osteolytic bone disease is present in about 80% of patients with multiple myeloma at the time of diagnosis. Managing bone disease in patients with multiple myeloma is a challenge and requires a multi-faceted treatment approach with medication, surgery, and radiation. The established treatments with intravenous or subcutaneous antiresorptives can cause debilitating adverse events for patients, mainly osteonecrosis of the jaw, which, traditionally, has been difficult to manage. Now, oral surgery is recommended and proven successful in 60-85% of patients. Patients with spinal involvement may benefit from surgery in the form of vertebroplasty and kyphoplasty for pain relief, improved mobility, and reestablished sagittal balance, as well as the restoration of vertebral height. These procedures are considered safe, but the full therapeutic impact needs to be investigated further. Ixazomib, the first oral proteasome inhibitor, increases osteoblast differentiation, and recently published preliminary results in patients treated with Ixazomib maintenance have promisingly shown increased trabecular volume caused by prolonged bone formation activity. Other novel potential treatment strategies are discussed as well.

Transitory Activation and Improved Transition from Erosion to Formation within Intracortical Bone Remodeling in Hypoparathyroid Patients Treated with rhPTH(1-84).

In hypoparathyroidism, lack of parathyroid hormone (PTH) leads to low calcium levels and decreased bone remodeling. Treatment with recombinant human PTH (rhPTH) may normalize bone turnover. This study aimed to investigate whether rhPTH(1-84) continued to activate intracortical bone remodeling after 30 months and promoted the transition from erosion to formation and whether this effect was transitory when rhPTH(1-84) was discontinued. Cortical histomorphometry was performed on 60 bone biopsies from patients (aged 31 to 78 years) with chronic hypoparathyroidism randomized to either 100 µg rhPTH(1-84) a day (n = 21) (PTH) or similar placebo (n = 21) (PLB) for 6 months as add-on to conventional therapy. This was followed by an open-label extension, where patients extended their rhPTH(1-84) (PTH) (n = 5), continued conventional treatment (CON) (n = 5), or withdrew from rhPTH(1-84) and resumed conventional therapy (PTHw) for an additional 24 months (n = 8). Bone biopsies were collected at months 6 (n = 42) and 30 (n = 18). After 6 and 30 months, the overall cortical microarchitecture (cortical porosity, thickness, pore density, and mean pore diameter) in the PTH group did not differ from that of the PLB/CON and PTHw groups. Still, the PTH group had a significantly and persistently higher percentage of pores undergoing remodeling than the PLB/CON groups. A significantly higher percentage of these pores was undergoing bone formation in the PTH compared with the PLB/CON groups, whereas the percentage of pores with erosion only was not different. This resulted in a shift in the ratio between formative and eroded pores, reflecting a faster transition from erosion to formation in the PTH-treated patients. In the rhPTH(1-84) withdrawal group PTHw, the latter effects of PTH were completely reversed in comparison to those of the PLB/CON groups. In conclusion, rhPTH(1-84) replacement therapy in hypoparathyroidism patients promotes intracortical remodeling and its transition from erosion to formation without affecting the overall cortical microstructure. The effect persists for at least 30 months and is reversible when treatment is withdrawn. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Microfibrillar-associated protein 4 as a potential marker of acute relapse in inflammatory demyelinating diseases of the central nervous system: Pathological and clinical aspects.

BACKGROUND: Microfibrillar-associated protein 4 (MFAP4) is an extracellular matrix protein not previously described in the human central nervous system (CNS). OBJECTIVES: We determined MFAP4 CNS expression and measured cerebrospinal fluid (CSF) and serum levels. METHODS: Tissue was sampled at autopsy from patients with acute multiple sclerosis (MS) (n = 3), progressive MS (n = 3), neuromyelitis optica spectrum disorder (NMOSD) (n = 2), and controls (n = 9), including 6 healthy controls (HC). MFAP4 levels were measured in 152 patients: 49 MS, 62 NMOSD, 22 myelin oligodendrocyte glycoprotein-associated disease (MOGAD), and 19 isolated optic neuritis (ION). RESULTS: MFAP4 localized to meninges and vascular/perivascular spaces, intense in the optic nerve. At sites of active inflammation, MFAP4 reactivity was reduced in NMOSD and acute MS and less in progressive MS. CSF MFAP4 levels were reduced during relapse and at the onset of diseases (mean U/mL: MS 14.3, MOGAD 9.7, and ION 14.6 relative to HC 17.9. (p = 0.013, p = 0.000, and p = 0.019, respectively). Patients with acute ON (n = 68) had reduced CSF MFAP4 (mean U/mL: 14.5, p = 0.006). CSF MFAP4 levels correlated negatively with relapse severity (rho = -0.41, p = 0.017). CONCLUSION: MFAP4 immunoreactivity was reduced at sites of active inflammation. CSF levels of MFAP4 were reduced following relapse and may reflect disease activity.

Lineage classification and antitubercular drug resistance surveillance of Mycobacterium tuberculosis by whole-genome sequencing in Southern India.

Whole-genome sequencing has created a revolution in tuberculosis management by providing a comprehensive picture of the various genetic polymorphisms with unprecedented accuracy. Studies mapping genomic heterogeneity in clinical isolates of Mycobacterium tuberculosis using a whole-genome sequencing approach from high tuberculosis burden countries are underrepresented. We report whole-genome sequencing results of 242 clinical isolates of culture-confirmed M. tuberculosis isolates from tuberculosis patients referred to a tertiary care hospital in Southern India. Phylogenetic analysis revealed that the isolates in our study belonged to five different lineages, with Indo-Oceanic (lineage 1, n = 122) and East-African Indian (lineage 3, n = 80) being the most prevalent. We report several mutations in genes conferring resistance to first and second line antitubercular drugs including the genes rpoB, katG, ahpC, inhA, fabG1, embB, pncA, rpsL, rrs, and gyrA. The majority of these mutations were identified in relatively high proportions in lineage 1. Our study highlights the utility of whole-genome sequencing as a potential supplemental tool to the existing genotypic and phenotypic methods, in providing expedited comprehensive surveillance of mutations that may be associated with antitubercular drug resistance as well as lineage characterization of M. tuberculosis isolates. Further larger-scale whole-genome datasets with linked minimum inhibition concentration testing are imperative for resolving the discrepancies between whole-genome sequencing and phenotypic drug sensitivity testing results and quantifying the level of the resistance associated with the mutations for optimization of antitubercular drug and precise dose selection in clinics. IMPORTANCE Studies mapping genetic heterogeneity of clinical isolates of M. tuberculosis for determining their strain lineage and drug resistance by whole-genome sequencing are limited in high tuberculosis burden settings. We carried out whole-genome sequencing of 242 M. tuberculosis isolates from drug-sensitive and drug-resistant tuberculosis patients, identified and collected as part of the TB Portals Program, to have a comprehensive insight into the genetic diversity of M. tuberculosis in Southern India. We report several genetic variations in M. tuberculosis that may confer resistance to antitubercular drugs. Further wide-scale efforts are required to fully characterize M. tuberculosis genetic diversity at a population level in high tuberculosis burden settings for providing precise tuberculosis treatment.

Osteoprogenitor recruitment and differentiation during intracortical bone remodeling of adolescent humans.

BACKGROUND: Recruitment and proliferation of osteoprogenitors during the reversal-resorption phase, and their differentiation into mature bone-forming osteoblasts is crucial for initiation of bone formation during bone remodeling. This study investigates the osteoprogenitors' gradual recruitment, proliferation, and differentiation into bone-forming osteoblasts within intracortical remodeling events of healthy adolescent humans. METHODS: The study was conducted on cortical bone specimens from 11 adolescent human controls - patients undergoing surgery due to coxa valga. The osteoprogenitor recruitment route and differentiation into osteoblasts were backtracked using immunostainings and in situ hybridizations with osteoblastic markers (CD271/NGFR, osterix/SP7, COL3A1 and COL1A1). The osteoblastic cell populations were defined based on the pore surfaces, and their proliferation index (Ki67), density and number/circumference were estimated in multiplex-immunofluorescence (Ki67, TRAcP, CD34) stained sections. RESULTS: During the reversal-resorption phase, osteoclasts are intermixed with (COL3A1+NFGR+) osteoblastic reversal cells, which are considered to be osteoprogenitors of (COL1A1+SP7+) bone-forming osteoblasts. Initiation of bone formation requires a critical density of these osteoprogenitors (43 ± 9 cells/mm), which is reached though proliferation (4.4 ± 0.5 % proliferative) and even more so through recruitment of osteoprogenitors, but challenged by the ongoing expansion of the canal circumference. These osteoprogenitors most likely originate from osteoblastic bone lining cells and mainly lumen osteoprogenitors, which expand their population though proliferation (4.6 ± 0.3 %) and vascular recruitment. These lumen osteoprogenitors resemble canopy cells above trabecular remodeling sites, and like canopy cells they extend above bone-forming osteoblasts where they may rejuvenate the osteoblast population during bone formation. CONCLUSION: Initiation of bone formation during intracortical remodeling requires a critical density of osteoprogenitors on eroded surfaces, which is reached though proliferation and recruitment of local osteoprogenitors: bone lining cells and lumen osteoprogenitors.

Trabecular bone deterioration in a postmenopausal female suffering multiple spontaneous vertebral fractures due to a delayed denosumab injection - A post-treatment re-initiation bone biopsy-based case study.

Background: Denosumab, is a potent anti-resorptive that, increases bone mineral density, and reduces fracture risk in osteoporotic patients. However, several case studies have reported multiple vertebral fractures in patients discontinuing denosumab. Case presentation: This case report describes a 64-year-old female with postmenopausal osteoporosis treated with denosumab, who had her 11th injection delayed by 4 months. The patient suffered eight spontaneous vertebral fractures. After consent, an iliac crest bone biopsy was obtained following re-initiation of the denosumab treatment and analyzed by micro-computed tomography and histomorphometry. Results: micro-computed tomography analysis revealed a low trabecular bone volume of 10 %, a low trabecular thickness of 97 µm, a low trabecular spacing of 546 µm, a high trabecular number of 1.8/mm, and a high structure model index of 2.2, suggesting trabecular thinning and loss of trabecular plates. Histomorphometric trabecular bone analysis revealed an eroded perimeter per bone perimeter of 33 % and an osteoid perimeter per bone perimeter of 62 %. Importantly, 88 % of the osteoid perimeter was immediately above an eroded-scalloped cement line with no sign of mineralization, and often with no clear bone-forming osteoblasts on the surface. Moreover, only 5 % of the bone perimeter was mineralizing, reflecting that only 8 % of the osteoid perimeter underwent mineralization, resulting in a mineralization lag time of 545 days. Taken together, this indicates limited bone formation and delayed mineralization. Conclusion: We present a case report of multiple vertebral fractures after denosumab discontinuation with histomorphometric evidence that denosumab discontinuation leads to extensive trabecular bone resorption followed by a limited bone formation and delayed mineralization if the denosumab treatment is reinitiated. This highlights the importance of developing optimal discontinuation strategies for patients that are to discontinue treatment.

Local coordination between intracortical bone remodeling and vascular development in human juvenile bone.

Although failure to establish a vascular network has been associated with many skeletal disorders, little is known about what drives development of vasculature in the intracortical bone compartments. Here, we show that intracortical bone resorption events are coordinated with development of the vasculature. We investigated the prevalence of vascular structures at different remodeling stages as well as their 3D organization using proximal femoral cortical bone from 5 girls and 6 boys (aged 6-15 years). A 2D analysis revealed that non-quiescent intracortical pores contained more vascular structures than quiescent pores (p < 0.0001). Type 2 pores, i.e., remodeling of existing pores, had a higher density of vascular structures than type 1 pores, i.e., de novo created pores (p < 0.05). Furthermore, pores at the eroded-formative remodeling stage, had more vascular structures than pores at any other remodeling stage (p < 0.05). A 3D reconstruction of an intracortical remodeling event showed that osteoclasts in the advancing tip of the cutting cone as well as preosteoclasts in the lumen expressed vascular endothelial growth factor-A (VEGFA), while VEGFA-receptors 1 and 2 mainly were expressed in endothelial cells in the adjacent vasculature. Consequently, we propose that the progression of the vascular network in intracortical remodeling events is driven by osteoclasts expressing VEGFA. Moreover, the vasculature is continuously reconfigured according to the demands of the remodeling events at the surrounding bone surfaces.

KIAA1199 deficiency enhances skeletal stem cell differentiation to osteoblasts and promotes bone regeneration.

Upon transplantation, skeletal stem cells (also known as bone marrow stromal or mesenchymal stem cells) can regulate bone regeneration by producing secreted factors. Here, we identify KIAA1199 as a bone marrow stromal cell-secreted factor in vitro and in vivo. KIAA1199 plasma levels of patients positively correlate with osteoporotic fracture risk and expression levels of KIAA1199 in patient bone marrow stromal cells negatively correlates with their osteogenic differentiation potential. KIAA1199-deficient bone marrow stromal cells exhibit enhanced osteoblast differentiation in vitro and ectopic bone formation in vivo. Consistently, KIAA1199 knockout mice display increased bone mass and biomechanical strength, as well as an increased bone formation rate. They also exhibit accelerated healing of surgically generated bone defects and are protected from ovariectomy-induced bone loss. Mechanistically, KIAA1199 regulates osteogenesis by inhibiting the production of osteopontin by osteoblasts, via integrin-mediated AKT and ERK-MAPK intracellular signaling. Thus, KIAA1199 is a regulator of osteoblast differentiation and bone regeneration and could be targeted for the treatment or management of low bone mass conditions.

A Critical Role of the Bone Marrow Envelope in Human Bone Remodeling.

Proper bone remodeling depends not only on a team of bone-resorbing osteoclasts and bone-forming osteoblasts. It also depends on the site-specific delivery of a large amount of osteoblast lineage cells to the bone remodeling site. How this delivery occurs is poorly known. Here, we gained insight into this mechanism by analyzing the distribution of markers of osteoblastogenesis on bone surfaces and in their bone marrow neighborhood in human cancellous bone. We found a CD271-positive/PDGFß-R-positive cell layer surrounding the bone marrow that provides osteoblastogenic potential along all bone surfaces, whether quiescent or remodeling. This bone marrow envelope cell layer takes the appearance of a canopy above remodeling sites, where it then also shows an upregulation of the proliferation marker Ki67, smooth muscle actin (SMA), tenascin C, fibronectin, and MMP13. This indicates that the canopy is a region of the bone marrow envelope where early markers of osteoblastogenesis are activated concurrently with initiation of bone remodeling. Importantly, the high proliferation index in the canopy is not associated with increasing cell densities at the canopy level, but it is at the bone surface level, thereby supporting delivery of cells from the canopy to the bone surface. This delivery route explains why lack of canopies was previously found to coincide with lack of bone formation, and fits current knowledge on the canopies as a target for regulators of bone remodeling. We conclude that the coordination of bone marrow envelope activities and bone surface activities allows integrating osteoblastogenesis and bone remodeling into the same functional unit, and propose that the bone marrow envelope is critical for preserving bone health. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Potential Drug-Drug Interactions Between Anti-Cancer Drugs and Other Medications in Lung Cancer Patients: A Retrospective Study.

BACKGROUND: Cancer patients are more vulnerable to developing drug-drug interactions as multiple medications are administered concomitantly with cytotoxic agents to treat the underlying comorbidities. These drug-drug interactions often receive less medical attention and consequently are associated with adverse clinical outcomes. OBJECTIVE: We intended to comprehensively characterize the drug-drug interactions among anticancer drugs and other concomitantly prescribed drugs in hospitalized lung cancer patients. METHODS: A retrospective, observational, single-centre study was conducted on lung cancer inpatients from the medical records department of Kasturba Hospital, Manipal, India. Drug-drug interactions were identified using the drug interaction checkers of two drug information databases, Micromedex and Epocrates. These drug-drug interactions were categorized based on the source from which they were identified, mechanism, severity/significance, adverse consequences, and management strategies required. RESULTS: Among 196 patients, 555 drug-drug interactions were identified in 185 patients using Micromedex and Epocrates. Based on the mechanism of action, 74% and 22% of the drug-drug interactions were classified as pharmacodynamic and pharmacokinetic respectively. 112 drug-drug interactions were recorded from Micromedex alone, while 549 interactions were found using Epocrates. The oral chemotherapeutic drug gefitinib was found to be associated with the highest number of drug-drug interactions. CONCLUSION: Drug-drug interactions were highly prevalent among hospitalized lung cancer patients. Structured screening and monitoring for these potentially clinically relevant drug-drug interactions by oncologists in collaboration with clinical pharmacists should be carried out prior to initiation and during anticancer treatment to prevent adverse clinical outcomes.

Impact of tuberculosis disease on human gut microbiota: a systematic review.

INTRODUCTION: This systematic review evaluates the gut microbiota (GM) status in tuberculosis (TB) patients compared to healthy volunteers due to the disease or its treatment. AREAS COVERED: We conducted a systematic review of all articles published in PubMed, Web of Science, and Embase that assessed the impact of TB disease and anti-tubercular therapy (ATT) on GM from inception till January 2022 (Protocol registration number in PROSPERO: CRD42021261884). Regarding the microbial diversity indices and taxonomy, we found a significant difference in GM status between the TB and healthy control (HC) groups. We found an overabundance of Phylum Proteobacteria and depletion of some short-chain fatty acid-producing bacteria genera like Bifidobacteria, Roseburia, and Ruminococcus in the TB group. We found that ATT exacerbates the degree of dysbiosis caused by Mycobacteria tuberculosis disease. EXPERT OPINION: The modulation of GM in TB patients in clinical practice may serve as a promising target to reverse the dysbiosis caused. Moreover, this can optimistically change the TB treatment outcome. We expect that appropriate probiotic supplementation with antimycobacterial treatment during tuberculosis disease will help stabilize the GM throughout the treatment phase and protect the GM from dysbiosis.

FIBCD1 is an endocytic GAG receptor associated with a novel neurodevelopmental disorder.

Whole-exome sequencing of two patients with idiopathic complex neurodevelopmental disorder (NDD) identified biallelic variants of unknown significance within FIBCD1, encoding an endocytic acetyl group-binding transmembrane receptor with no known function in the central nervous system. We found that FIBCD1 preferentially binds and endocytoses glycosaminoglycan (GAG) chondroitin sulphate-4S (CS-4S) and regulates GAG content of the brain extracellular matrix (ECM). In silico molecular simulation studies and GAG binding analyses of patient variants determined that such variants are loss-of-function by disrupting FIBCD1-CS-4S association. Gene knockdown in flies resulted in morphological disruption of the neuromuscular junction and motor-related behavioural deficits. In humans and mice, FIBCD1 is expressed in discrete brain regions, including the hippocampus. Fibcd1 KO mice exhibited normal hippocampal neuronal morphology but impaired hippocampal-dependent learning. Further, hippocampal synaptic remodelling in acute slices from Fibcd1 KO mice was deficient but restored upon enzymatically modulating the ECM. Together, we identified FIBCD1 as an endocytic receptor for GAGs in the brain ECM and a novel gene associated with an NDD, revealing a critical role in nervous system structure, function and plasticity.

Influence of N-acetyltransferase 2 (NAT2) genotype/single nucleotide polymorphisms on clearance of isoniazid in tuberculosis patients: a systematic review of population pharmacokinetic models.

PURPOSE: Significant pharmacokinetic variabilities have been reported for isoniazid across various populations. We aimed to summarize population pharmacokinetic studies of isoniazid in tuberculosis (TB) patients with a specific focus on the influence of N-acetyltransferase 2 (NAT2) genotype/single-nucleotide polymorphism (SNP) on clearance of isoniazid. METHODS: A systematic search was conducted in PubMed and Embase for articles published in the English language from inception till February 2022 to identify population pharmacokinetic (PopPK) studies of isoniazid. Studies were included if patient population had TB and received isoniazid therapy, non-linear mixed effects modelling, and parametric approach was used for building isoniazid PopPK model and NAT2 genotype/SNP was tested as a covariate for model development. RESULTS: A total of 12 articles were identified from PubMed, Embase, and hand searching of articles. Isoniazid disposition was described using a two-compartment model with first-order absorption and linear elimination in most of the studies. Significant covariates influencing the pharmacokinetics of isoniazid were NAT2 genotype, body weight, lean body weight, body mass index, fat-free mass, efavirenz, formulation, CD4 cell count, and gender. Majority of studies conducted in adult TB population have reported a twofold or threefold increase in isoniazid clearance for NAT2 rapid acetylators compared to slow acetylators. CONCLUSION: The variability in disposition of isoniazid can be majorly attributed to NAT2 genotype. This results in a trimodal clearance pattern with a multi-fold increase in clearance of NAT2 rapid acetylators compared to slow acetylators. Further studies exploring the generalizability/adaptability of developed PopPK models in different clinical settings are required.

Vitamin D receptor gene polymorphism and vitamin D supplementation on clinical/ treatment outcome in tuberculosis: current and future perspectives.

INTRODUCTION: Tuberculosis (TB) is a transnational public health concern, which requires more precise treatment strategies than the existing approaches. Vitamin D modulates the inflammatory and immune response to the disease. Robust evidence shows that vitamin D deficiency and its receptor gene polymorphism influence the susceptibility to TB and the outcome of the anti-tubercular treatment (ATT). However, in the different populations, these findings were inconsistent and even contradictory. AREAS COVERED: The current review focuses on the association between vitamin D receptor (VDR) gene polymorphism with the risk of development of TB disease and response to the ATT. Additionally, it reviews various systematic reviews and meta-analyses on the impact of vitamin D supplements on both clinical and treatment outcomes in TB patients. EXPERT OPINION: Although the majority of the findings rule out the benefits of the supplementation, sufficient evidence is available to warrant larger epidemiological research that should be aimed to generate possible interaction among the VDR polymorphism, vitamin D status, and the outcome in TB. We conclude that establishing such an association in different ethnic populations will help design nutrigenomics- or pharmacogenomics-based vitamin D supplementation to develop a personalized medicine approach to flatten the curve of TB disease.

2D size of trabecular bone structure units (BSU) correlate more strongly with 3D architectural parameters than age in human vertebrae.

Bone tissue is continuously remodeled. In trabecular bone, each remodeling transaction forms a microscopic bone structural unit (BSU), also known as a hemiosteon or a trabecular packet, which is bonded to existing tissue by osteopontin-rich cement lines. The size and shape of the BSUs are determined by the size and shape of the resorption cavity, and whether the cavity is potentially over- or under-filled by the subsequent bone formation. The present study focuses on the recently formed trabecular BSUs, and how their 2D size and shape changes with age and trabecular microstructure. The study was performed using osteopontin-immunostained frontal sections of L2 vertebrae from 8 young (aged 18.5-37.6 years) and 8 old (aged 69.1-96.4 years) control females, which underwent microcomputed tomography (µCT) imaging prior to sectioning. The contour of 4230 BSU profiles (181-385 per vertebra) within 1024 trabecular profiles were outlined, and their 2D width, length, area, and shape were assessed. Of these BSUs, 22 (0.5%) were generated by modeling-based bone formation (i.e. without prior resorption), while 99.5% were generated by remodeling-based bone formation (i.e. with prior resorption). The distributions of BSU profile width, length, and area were significantly smaller in the old versus young females (p < 0.005), and the median profile width, length, and area were negative correlated with age (p < 0.018). Importantly, these BSU profile size parameters were more strongly correlated with trabecular bone volume (BV/TV, p < 0.002) and structure model index (SMI, p < 0.008) assessed by µCT, than age. Moreover, the 2D BSU size parameters were positively correlated to the area of the individual trabecular profiles (p < 0.0001), which were significantly smaller in the old versus young females (p < 0.024). The BSU shape parameters (aspect ratio, circularity, and solidity) were not correlated with age, BV/TV, or SMI. Collectively, the study supports the notion that not only the BSU profile width, but also its length and area, are more influenced by the age-related bone loss and shift from plates to rods (SMI), than age itself. This implies that BSU profile size is mainly driven by changes in the trabecular microstructure, which affect the size of the resorption cavity that the BSU refills.