Identifying novel risk conferring genes involved in glycosylation processes with familial schizophrenia in an Indian cohort: Prediction of ADAMTS9 gene variant for structural stability.

Schizophrenia is a complex neuropsychiatric disorder and heritability is as high as 80 % making it the most heritable mental disorder. Although GWAS has identified numerous variants, the pathophysiology is still elusive. Here, an attempt was made to identify genetic risk factors in familial cases of schizophrenia that are associated with a common causative pathway. To achieve this objective, exome sequencing was done in 4 familial cases and identified six unique coding variants in five genes. Among these genes, PIGQ gene has two pathogenic variants, one nonsense and in-frame deletion. One missense variant in GALNT16 and one in GALNT5 have variable damaging score, however, the other variants, in ADAMTS9 and in LTBP4 have the highest damaging score. Further analysis showed that the variant of LTBP4 was not present in the functional domain. The other missense variant in the ADAMTS9 gene was found to be significant and was present in the thrombospondin repeat motif, one of the important motifs. Detailed molecular dynamics simulation study on this variant showed a damaging effect on structural stability. Since, all these genes culminated into the glycosylation process, it was evident that an aberrant glycosylation process may be one of the risk factors. Although, extracellular matrix formation through glycosylation have been shown to be associated, the involvement of ADAMTS9 and PIGQ gene mediated glycosylation has not been reported. In this paper, a novel link between ADAMTS9 and PIGQ gene with schizophrenia have been reported. Therefore, this novel observation has contributed immensely to the existing knowledge on risk factor of Schizophrenia.

Plasmodium falciparum-Induced Autoimmune Hemolytic Anemia in a Pregnant Patient with Sickle Cell Disease.

BACKGROUND Sickle cell disease (SCD) is an autosomal recessive hereditary condition characterized by chronic hemolytic anemia and painful vaso-occlusive episodes. Homozygous sickle cell patients are at increased risk of morbidity and mortality from malaria. Autoimmune hemolytic anemia (AIHA) secondary to, or in the setting of, malarial infection is rare. In our case, the concurrence of Plasmodium falciparum malarial parasitemia and AIHA led to severe hemolytic anemia with an extensive packed red blood cell transfusion requirement. The patient's underlying SCD also contributed to the severity of the anemia and persistence of the malarial infection. CASE REPORT We report the case of a 29-year-old woman in the second trimester of pregnancy, with a history of SCD, who presented with severe anemia beyond her typical baseline in the setting of P. falciparum malaria. Hemolysis markers, including lactate dehydrogenase and bilirubin, were elevated. Direct Coombs testing was positive for IgG and C3 antibodies. Treatment with antimalarial agents and steroids led to clinical improvement and eventual clearance of the parasitemia. CONCLUSIONS Our patient's clinical course was most compatible with P. falciparum malaria-induced AIHA. Although she received a short course of steroids, it was treatment and clearance of the parasitemia that led to resolution of the hemolysis and a return to baseline hemoglobin levels. While the exact mechanism of AIHA in malaria is not well characterized, several unique mechanisms have been proposed and should be considered in cases of P. falciparum malaria manifesting with particularly severe hemolytic anemia.

Granzyme K+ CD8 T cells form a core population in inflamed human tissue.

T cell-derived pro-inflammatory cytokines are a major driver of rheumatoid arthritis (RA) pathogenesis. Although these cytokines have traditionally been attributed to CD4 T cells, we have found that CD8 T cells are notably abundant in synovium and make more interferon (IFN)-γ and nearly as much tumor necrosis factor (TNF) as their CD4 T cell counterparts. Furthermore, using unbiased high-dimensional single-cell RNA-seq and flow cytometric data, we found that the vast majority of synovial tissue and synovial fluid CD8 T cells belong to an effector CD8 T cell population characterized by high expression of granzyme K (GzmK) and low expression of granzyme B (GzmB) and perforin. Functional experiments demonstrate that these GzmK+ GzmB+ CD8 T cells are major cytokine producers with low cytotoxic potential. Using T cell receptor repertoire data, we found that CD8 GzmK+ GzmB+ T cells are clonally expanded in synovial tissues and maintain their granzyme expression and overall cell state in blood, suggesting that they are enriched in tissue but also circulate. Using GzmK and GzmB signatures, we found that GzmK-expressing CD8 T cells were also the major CD8 T cell population in the gut, kidney, and coronavirus disease 2019 (COVID-19) bronchoalveolar lavage fluid, suggesting that they form a core population of tissue-associated T cells across diseases and human tissues. We term this population tissue-enriched expressing GzmK or TteK CD8 cells. Armed to produce cytokines in response to both antigen-dependent and antigen-independent stimuli, CD8 TteK cells have the potential to drive inflammation.

Direct oral anticoagulants versus warfarin in patients with single antibody-positive anti-phospholipid syndrome.

BACKGROUND: The role of direct oral anticoagulants (DOACs) among patients with antiphospholipid syndrome (APLS) remains unclear. Warfarin has been shown to be superior to DOACs among high-risk APLS patients (particularly those with triple-positive APLS). However, it remains unknown whether DOACs may be appropriate for lower-risk patients such as those with single-positive APLS. METHODS: We conducted a retrospective study comparing the risk of recurrent thrombosis among single-positive APLS patients treated with DOACs (apixaban or rivaroxaban), and those treated with warfarin. RESULTS: One-hundred-forty-three single-positive APLS patients, newly started on anticoagulation following a first thrombotic event, were included. Median follow-up was 54 months (IQR 29-73 months). Ninety-one patients (64%) received warfarin and 52 patients (36%) received a DOAC. Six patients (6.6%) who received warfarin experienced a recurrent thrombotic event compared with 3 of 52 (5.8%) patients who received a DOAC (p = .845). There was no difference in event-free survival between groups (HR DOAC:Warfarin = 0.952, 95% CI 0.232 - 3.908). Major bleeding was similar in both groups. CONCLUSIONS: These findings suggest that DOACs may be a safe and effective option for patients with single-positive APLS. Prospective studies are needed to confirm these findings.

Suicidal behaviour: What's the brain up to?

BACKGROUND: Individuals with suicidal behaviours are increasingly recognized as having impairments in brain metabolism. However, these are not well delineated. AIM: To evaluate regional cerebral glucose metabolism (rCMglu) in subjects with suicidal behaviours and assess differences in rCMglu between depressed and non-depressed suicidal subjects. METHODS: Thirty-three subjects with suicidal behaviours were assessed using Columbia Suicide Severity Rating scale (CSSRS) and Beck's Depression Inventory (BDI). Brain metabolism was assessed using [18F]Fluoro,Deoxy-Glucose Positron Emission Tomography (FDG-PET). RESULTS: Of 33 subjects, eighteen had depression. FDG-PET findings revealed that in comparison to mean asymptomatic controls, subjects had decreased rCMglu in right inferior frontal, left Broca's, left inferiolateral andsuperiolateral temporal, right inferior parietal and left posterior cingulate cortex. Increased rCMglu was seen in bilateral superior and medial frontal, right inferiolateral and posteriomedial temporal cortex, and midbrain. CSSRS total intensity inversely correlated with rCMglu in medial frontal cortex, left Broca's and superiolateral temporal cortex and directly correlated with rCMglu in right cerebellum. There was no significant difference in rCMglu between depressed and non depressed group. CONCLUSIONS: Significant differences exist in rCMglu of suicidal individuals, chiefly in frontal and temporal regions. Understanding these would help us identify individuals more at risk for suicidal behaviours.

Embryo transfer day does not affect the initial maternal serum ß-hCG levels: A retrospective cohort study.

The aim of this study is to compare the serum ß-hCG values post transfer of a cleavage stage embryo versus a blastocyst stage embryo at equal time intervals post oocyte retrieval (OR) in clinically pregnant patients, and to ascertain a ß-hCG value to predict pregnancy outcomes. This is a retrospective cohort study of 560 women with clinical pregnancy who underwent an embryo transfer performed at either the cleavage stage or the blastocyst stage of embryo development between January 2003 and June 2014 at the Center for Assisted Reproduction (CARE), Singapore General Hospital. The serum ß-hCG level was measured on day 17 post OR. The ß-hCG values were not significantly different in the cleavage stage versus the blastocyst stage embryos (mean±SD: 387±486IU/L D3 vs. 352±268IU/L D5, p=0.96, median value 297 in both groups). Our study suggests that the initial maternal serum ß-hCG values were not affected by the day of transfer of the embryos since assessing the ß-hCG at equivalent points after transfer should not lead to a significant difference assuming the progress and development of the embryos occurred as expected.

A long-term study of durability and risk factors for aneurysm recurrence after microsurgical clip ligation.

OBJECTIVE With the recent evolution of endovascular therapies, objective evaluation of the efficacy of clip ligation for cerebral aneurysms should be performed. This study was undertaken to evaluate the durability of microsurgical clip ligation, identify risk factors for recurrence, and assess the need for long-term follow-up imaging. METHODS A retrospective review of medical records identified 616 consecutive patients (156 male and 460 female patients; mean age 48.4 ± 12.4 years; range 6-90 years) who underwent microsurgical clip ligation and follow-up imaging at least 1 year after discharge between 1990 and 2010 at our institution. Of a total of 926 aneurysms in 616 patients, 758 aneurysms were microsurgically clip-ligated. At presentation, 431 of these aneurysms were ruptured and 327 aneurysms were unruptured. All patients underwent postoperative baseline imaging within the 1st month of their operation. A logistic regression analysis was performed to identify which variables are more likely to predict recurrence. RESULTS Late follow-up angiographic imaging was obtained at a mean of 7.2 ± 4.7 years postdischarge (median 5.7 years; range 1-23 years). Of the 699 clipped aneurysms without residua, late follow-up angiography revealed only 1 (0.14%) recurrent aneurysm. Of the 59 residual aneurysms that remained after initial clip ligation on early postoperative imaging, 8 (13.6%) demonstrated growth. All of these aneurysms required treatment. None of the recurrences were due to broken or delayed displacement of clips. A total of 111 patients presented with multiple aneurysms. De novo aneurysm formation occurred in 8 (0.97%) patients, all of whom initially presented with multiple aneurysms. CONCLUSIONS This study provides additional evidence to support the long-term efficacy of aneurysm clip ligation. The chance of aneurysm recurrence after complete clip ligation is very small. However, there is a regrowth risk of 1.83% per year for aneurysm remnants after incomplete clip ligation. These findings support the necessity for continued followup, late angiographic imaging, and the potential need for further intervention of incompletely ligated aneurysms. Furthermore, completely clip-ligated aneurysms may not require additional surveillance imaging unless multiple aneurysms were evident at presentation.

Clip ligation of contralateral P1 aneurysm: extending the working depth of microsurgery along the skull base.

Clip ligation of posterior circulation aneurysms can be challenging because of limited operative working space and angles. Certain proximal posterior cerebral (P1) aneurysms are especially challenging because of their locations within the lateral anterior interpeduncular fossa. We present a 52-year-old woman who had previously undergone coil embolization of a ruptured right-sided posterior communicating artery aneurysm. She also had two other small aneurysms (left posterior communicating artery and right P1 aneurysms). She underwent clip ligation of the latter two unruptured aneurysms through a left-sided pterional craniotomy. The microsurgical techniques to clip ligate a contralateral P1 aneurysm are discussed in the video. The video can be found here: http://youtu.be/YBE7FcFGlpQ .

Evaluation of effectiveness of integrated intervention in autistic children.

OBJECTIVES: To assess the effectiveness of integrated therapy over the past 3 y on the recipient autistic children and its correlation with the following variables - age at admission, duration of therapy given and initial severity of symptoms. METHODS: The index study was a retrospective study with 18 autistic children as subjects; the maximum duration of intervention was 3 y. The integrated approach consisted of special education using principles of applied behavior analysis, occupational and speech therapy. The progress records, the occupational therapy and the speech therapy progress reports were tabulated as data. The Childhood Autism Rating Scale (Schopler, Reichler and Renner, 1986) was used for evaluation of severity of symptoms at admission and in present day. The data was then compared and analyzed. RESULTS: The present study showed significant positive results. Only few domains requiring very high integrated cognitive and sensorimotor functioning showed non-significant results. Age at intervention correlated negatively and, duration of therapy given and initial severity of symptoms correlated positively with effectiveness of therapy. CONCLUSIONS: Continuous feedback and modification of the therapy is required to maintain performance and develop target interventions for problematic areas identified. Longitudinal as well as comparative studies are required to better understand the benefits of integrated approach.