Citations

PURPOSETo determine the contribution of germline pathogenic variants (PVs) in hereditary cancer testing panel genes to invasive lobular carcinoma (ILC) of the breast.MATERIALS AND METHODSThe study included 2,999 women with ILC from a population-based cohort and 3,796 women with ILC undergoing clinical multigene panel testing (clinical cohort). Frequencies of germline PVs in breast cancer predisposition genes ( ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, PALB2, PTEN, RAD51C, RAD51D, and TP53) were compared between women with ILC and unaffected female controls and between women with ILC and infiltrating ductal carcinoma (IDC).RESULTSThe frequency of PVs in breast cancer predisposition genes among women with ILC was 6.5% in the clinical cohort and 5.2% in the population-based cohort. In case-control analysis, CDH1 and BRCA2 PVs were associated with high risks of ILC (odds ratio [OR] > 4) and CHEK2, ATM, and PALB2 PVs were associated with moderate (OR = 2-4) risks. BRCA1 PVs and CHEK2 p.Ile157Thr were not associated with clinically relevant risks (OR < 2) of ILC. Compared with IDC, CDH1 PVs were > 10-fold enriched, whereas PVs in BRCA1 were substantially reduced in ILC.CONCLUSIONThe study establishes that PVs in ATM, BRCA2, CDH1, CHEK2, and PALB2 are associated with an increased risk of ILC, whereas BRCA1 PVs are not. The similar overall PV frequencies for ILC and IDC suggest that cancer histology should not influence the decision to proceed with genetic testing. Similar to IDC, multigene panel testing may be appropriate for women with ILC, but CDH1 should be specifically discussed because of low prevalence and gastric cancer risk.

Background: PSAP encodes saposin C, the co-activator of glucocerebrosidase, encoded by GBA. GBA mutations are associated with idiopathic/isolated REM sleep behavior disorder (iRBD), a prodromal stage of synucleinopathy. Objective: To examine the role of PSAP mutations in iRBD. Methods: We fully sequenced PSAP and performed Optimized Sequence Kernel Association Test in 1,113 iRBD patients and 2,324 controls. We identified loss-of-function (LoF) mutations, which are very rare in PSAP, in three iRBD patients and none in controls (uncorrected p = 0.018). Results: Two variants were stop mutations, p.Gln260Ter and p.Glu166Ter, and one was an in-frame deletion, p.332_333del. All three mutations have a deleterious effect on saposin C, based on in silico analysis. In addition, the two carriers of p.Glu166Ter and p.332_333del mutations also carried a GBA variant, p.Arg349Ter and p.Glu326Lys, respectively. The co-occurrence of these extremely rare PSAP LoF mutations in two (0.2%) GBA variant carriers in the iRBD cohort, is unlikely to occur by chance (estimated co-occurrence in the general population based on gnomAD data is 0.00035%). Although none of the three iRBD patients with PSAP LoF mutations have phenoconverted to an overt synucleinopathy at their last follow-up, all manifested initial signs suggestive of motor dysfunction, two were diagnosed with mild cognitive impairment and all showed prodromal clinical markers other than RBD. Their probability of prodromal PD, according to the Movement Disorder Society research criteria, was 98% or more. Conclusion: These results suggest a possible role of PSAP variants in iRBD and potential genetic interaction with GBA, which requires additional studies.

Abstract Background While cardiovascular complications, including arrhythmias are now a recognized manifestation of Multisystem inflammatory syndrome in children (MIS-C), there are no reports of primary bradycardia preceding the clinical presentation. We sought to describe a case series of sinus bradycardia as an initial manifestation of MIS-C. Methods We included a series of 10 consecutive patients with confirmed COVID-19 who met WHO and CDC criteria for MIS-C, who developed sinus bradycardia with a heart rate measured in the awake state that was below the normal range for age for children, as an initial manifestation of the disease, in a prospective observational multicenter study. Patients underwent clinical, laboratory evaluation, ECG, Holter, telemetry, echocardiogram, chest X Ray, and a chest CT scan. Results Of the 10 patients included, 6 were male, with a mean age of 6.52±5.35 years, range 4 months to 14 years. All cases were Hispanic. Bradycardia was transient and did not merit treatment. Coronary abnormalities were noted in 6 cases; 4 patients had mild coronary ectasia; 9 patients had pericardial effusion with no evidence of tamponade. All patients had a mild clinical course; none had shock, heart failure, the need for mechanical ventilation, or died. All blood markers (Troponin, BNP, Platelet count, C-reactive protein, D-dimer, Ferritin) returned to normal levels by discharge/follow-up with a favorable outcome including resolution of coronary dilatation in all but 2 in which aneurysm persisted. Treatment All patients received steroids and low-weight-molecular heparin 10 patients, 8 aspirin and 8 intravenous immunoglobulins. Conclusion Sinus bradycardia may be the initial manifestation of MIS-C, usually transient and mild. Physicians should be aware of this presentation. Funding Acknowledgement Type of funding sources: None. Kid, MIS-C. Bradycardia/Atrial Rhythm

AbstractKallikrein related peptidase 6 (Klk6) is a secreted serine protease highly expressed in oligodendrocytes and implicated in demyelinating conditions. To gain insights into the significance of Klk6 to oligodendrocyte biology, we investigated the impact of global Klk6 gene knockout on CNS developmental myelination using the spinal cord of male and female mice as a model. Results demonstrate that constitutive loss of Klk6 expression accelerates oligodendrocyte differentiation developmentally, including increases in the expression of myelin proteins such as MBP, PLP and CNPase, in the number of CC‐1+ mature oligodendrocytes, and myelin thickness by the end of the first postnatal week. Co‐ordinate elevations in the pro‐myelinating signaling pathways ERK and AKT, expression of fatty acid 2‐hydroxylase, and myelin regulatory transcription factor were also observed in the spinal cord of 7d Klk6 knockouts. LC/MS/MS quantification of spinal cord lipids showed sphingosine and sphingomyelins to be elevated in Klk6 knockouts at the peak of myelination. Oligodendrocyte progenitor cells (OPCs)‐derived from Klk6 knockouts, or wild type OPCs‐treated with a Klk6 inhibitor (DFKZ‐251), also showed increased MBP and PLP. Moreover, inhibition of Klk6 in OPC cultures enhanced brain derived neurotrophic factor‐driven differentiation. Altogether, these findings suggest that oligodendrocyte‐derived Klk6 may operate as an autocrine or paracrine rheostat, or brake, on pro‐myelinating signaling serving to regulate myelin homeostasis developmentally and in the adult. These findings document for the first time that inhibition of Klk6 globally, or specifically in oligodendrocyte progenitors, is a strategy to increase early stages of oligodendrocyte differentiation and myelin production in the CNS.

ObjectiveMiddle‐aged subjects with meniscal tear treated with arthroscopic partial meniscectomy (APM) experience greater progression of damage to joint structures on imaging than subjects treated nonoperatively. It is unclear whether these changes are clinically relevant. The goal of this study was to assess whether worsening in magnetic resonance imaging (MRI)–assessed tissue damage over 18 months leads to subsequent worsening in knee pain over the subsequent 3.5 years.MethodsWe used data from the Meniscal Tear in Osteoarthritis Research (MeTeOR) trial of APM versus physical therapy for subjects ages ≥45 years with knee pain, cartilage damage, and meniscal tear. We assessed whether change in cartilage surface area damage score (and other structural measures) from baseline to 18 months, assessed on MRI with the MRI Osteoarthritis Knee Score (MOAKS) system, was associated with change in Knee Injury and Osteoarthritis Outcome Score (KOOS) pain score (range 0–100; 100 = worst) from 18 to 60 months.ResultsThe primary analysis included 168 subjects with complete MRI data at baseline and 18 months and KOOS data at 18 and 60 months. We did not observe clinically important associations between change in cartilage surface area score between baseline and 18 months and change in pain scores from 18 to 60 months. Pain scores in the worst tertile for cartilage surface area damage score progression worsened by 0.45 points more than in the best tertile (95% confidence interval –4.45, 5.35). Similarly, we did not observe clinically important associations between changes in bone marrow lesions, osteophytes, or synovitis and subsequent pain.ConclusionWe did not observe clinically important associations between early changes in cartilage damage and other structural measures and worsening in pain over the subsequent 3.5 years. Further follow‐up is required to assess this association over a longer follow‐up period.

Background and Objectives: Diabetes mellitus type 2 (T2DM) is a chronic disease associated with fluid accumulation in the interstitial tissue. Manual lymphatic drainage (MLD) plays a role in reducing lymphoedema, like intermittent pneumatic compression (IPC). By the present pilot study, we aimed to evaluate the efficacy of a synergistic treatment with MLD and IPC in reducing lower limb lymphedema in T2DM patients. Materials and Methods: Adults with a clinical diagnosis of T2DM and lower limb lymphedema (stage II–IV) were recruited from July to December 2020. Study participants were randomized into two groups: experimental group, undergoing a 1-month rehabilitative program consisting of MLD and IPC (with a compression of 60 to 80 mmHg); control group, undergoing MLD and a sham IPC (with compression of <30 mmHg). The primary outcome was the lower limb lymphedema reduction, assessed by the circumferential method (CM). Secondary outcomes were: passive range of motion (pROM) of hip, knee, and ankle; quality of life; laboratory exams as fasting plasma glucose and HbA1c. At baseline (T0) and at the end of the 1-month rehabilitative treatment (T1), all the outcome measures were assessed, except for the Hb1Ac evaluated after three months. Results: Out of 66 T2DM patients recruited, only 30 respected the eligibility criteria and were randomly allocated into 2 groups: experimental group (n = 15; mean age: 54.2 ± 4.9 years) and control group (n = 15; mean age: 54.0 ± 5.5 years). At the intra-group analysis, the experimental group showed a statistically significant improvement of all outcome measures (p < 0.05). The between-group analysis showed a statistically significant improvement in pROM of the hip, knee, ankle, EQ-VAS, and EQ5D3L index at T1. Conclusions: A multimodal approach consisting of IPC and MLD showed to play a role in reducing lower limb lymphedema, with an increase of pROM and HRQoL. Since these are preliminary data, further studies are needed.

Background: Rigorous study of ventricular fibrillation (VF) is not feasible in humans. The spatiotemporal characteristics of prolonged VF remain undefined, limiting our understanding of this lethal rhythm. Methods: VF was mapped in 4 canines. The endocardial and epicardial left ventricle (LV) and right ventricle (RV) were sequentially mapped at 0 to 15, 15 to 30, 30 to 45, and 45 to 60 minutes post-induction. Ten consecutive beats were used to determine the average cycle length and regularity index of ventricular and His-Purkinje system signals in discrete regions during each time interval. Results: Average VF time was 58±12 minutes. The shortest ventricular cycle length was present in the RV apical region (70±10 msec) at 0 to 15 minutes and at 15 to 30 minutes (89±31 msec) and LV apical region at 45 to 60 minutes (242±163 msec). The His-Purkinje system cycle length was the shortest at the RV outflow tract (75±3 msec) at 0 to 15 minutes, RV inflow and free wall (89±12 msec) at 15 to 30 minutes, LV apical region (83±14 msec) at 30 to 45 minutes, and inferior and inferolateral LV (145±23 msec) at 45 to 60 minutes. Regularity index was the highest in the RV inflow and free wall (78%) at 0 to 15 minutes, RV apical region (86%) at 15 to 30 minutes, LV septum and epicardial anterior RV (80%) at 30 to 45 minutes, and anterior and anterolateral LV (75%) at 45 to 60 minutes. Conclusions: These data suggest significant regional changes in electrical activity throughout VF in canines. A transition of fastest electrical activity from RV to LV apical regions across VF was observed. These novel insights of the temporal and spatial changes of VF merit further evaluation in diseased hearts to assess for reproducibility of findings.