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Several intravenous iron complexes are available for the treatment of iron deficiency anemia (IDA). Iron dextran (DEX) is associated with an elevated risk of potentially serious anaphylactic reactions, whereas others must be administered in several small infusions to avoid labile iron reactions. Ferric carboxymaltose (FCM) is a nondextran intravenous iron which can be administered in high single doses. A randomized, open label, and multicenter comparison of FCM to DEX in adults with IDA and baseline hemoglobin of ≤11.0 g/dL was conducted. A total of 160 patients were in the safety population (FCM n=82; DEX n=78). Adverse events, including immune system disorders (0% in FCM versus 10.3% in DEX, P=0.003) and skin disorders (7.3% in FCM versus 24.4% in DEX, P=0.004), were less frequently observed in the FCM group. A greater portion of patients in the FCM group experienced a transient, asymptomatic decrease in phosphate compared to patients in the DEX group (8.5% in FCM versus 0% in DEX, P=0.014). In the FCM arm, the change in hemoglobin from baseline to the highest observed level was 2.8 g/dL, whereas the DEX arm displayed a change of 2.4 g/dL (P=0.20). Treatment of IDA with FCM resulted in fewer hypersensitivity-related reactions than DEX.

Low-carbohydrate diets are frequently used as part of weight-loss programs. These are typically associated with increased fat intake. Therefore, cholesterol absorption inhibition is a logical therapeutic strategy to lower low-density lipoprotein cholesterol (LDL-C) in subjects following a low-carbohydrate diet. However, the efficacy of cholesterol absorption inhibition added to statin therapy has not been studied in this common clinical setting. We performed a randomized controlled trial to compare the effects of ezetimibe on LDL-C when added to simvastatin among subjects following a low-carbohydrate diet. We enrolled 65 subjects who were overweight or obese (body mass index 25-45 kg/m2) and had a moderately elevated LDL-C (130-190 mg/dL). During a 4-week diet run-in, subjects were instructed to restrict carbohydrate intake to <30 g/day. Subjects demonstrating adequate adherence to a low-carbohydrate diet (n = 58) were randomized to simvastatin (20 mg) or simvastatin (20 mg) plus ezetimibe (10 mg) for 8 weeks. Body weight decreased by 3.1% (95% CI 2.1%-4.0%, P < .0001), but the magnitude of weight change did not differ between the groups (P = .92). The LDL-C decreased by 32 mg/dL (95% CI 21-42 mg/dL) in the simvastatin arm and 60 mg/dL (95% CI 45-75 mg/dL) in the combined simvastatin-ezetimibe arm (P = .002). This corresponded to a 20.9% reduction (95% CI 14.5%-27.4%) in LDL-C on simvastatin alone, compared with a 37.4% reduction (95% CI 29.3%-45.6%) on simvastatin-ezetimibe (P = .002). A significant 15.8% reduction in triglycerides was observed among enrolled subjects, which did not differ between the groups. Among subjects following a low-carbohydrate diet, combined statin and cholesterol absorption inhibitor therapy is more effective than statin monotherapy for LDL-C lowering.

Cells from patients with Cockayne syndrome (CS) are hypersensitive to DNA-damaging agents and are unable to restore damage-inhibited RNA synthesis. On the basis of repair kinetics of different types of lesions in transcriptionally active genes, we hypothesized previously that impaired transcription in CS cells is a consequence of defective transcription initiation after DNA damage induction. Here, we investigated the effect of UV irradiation on transcription by using an in vitro transcription system that allowed uncoupling of initiation from elongation events. Nuclear extracts prepared from UV-irradiated or mock-treated normal human and CS cells were assayed for transcription activity on an undamaged β -globin template. Transcription activity in nuclear extracts closely mimicked kinetics of transcription in intact cells: extracts from normal cells prepared 1 h after UV exposure showed a strongly reduced activity, whereas transcription activity was fully restored in extracts prepared 6 h after treatment. Extracts from CS cells exhibited reduced transcription activity at any time after UV exposure. Reduced transcription activity in extracts coincided with a strong reduction of RNA polymerase II (RNAPII) containing hypophosphorylated C-terminal domain, the form of RNAPII known to be recruited to the initiation complex. These results suggest that inhibition of transcription after UV irradiation is at least partially caused by repression of transcription initiation and not solely by blocked elongation at sites of lesions. Generation of hypophosphorylated RNAPII after DNA damage appears to play a crucial role in restoration of transcription. CS proteins may be required for this process in a yet unknown way.

Damage to actively transcribed DNA is preferentially repaired by the transcription-coupled repair (TCR) system. TCR requires RNA polymerase II (Pol II), but the mechanism by which repair enzymes preferentially recognize and repair DNA lesions on Pol II-transcribed genes is incompletely understood. Herein we demonstrate that a fraction of the large subunit of Pol II (Pol II LS) is ubiquitinated after exposing cells to UV-radiation or cisplatin but not several other DNA damaging agents. This novel covalent modification of Pol II LS occurs within 15 min of exposing cells to UV-radiation and persists for about 8-12 hr. Ubiquitinated Pol II LS is also phosphorylated on the C-terminal domain. UV-induced ubiquitination of Pol II LS is deficient in fibroblasts from individuals with two forms of Cockayne syndrome (CS-A and CS-B), a rare disorder in which TCR is disrupted. UV-induced ubiquitination of Pol II LS can be restored by introducing cDNA constructs encoding the CSA or CSB genes, respectively, into CS-A or CS-B fibroblasts. These results suggest that ubiquitination of Pol II LS plays a role in the recognition and/or repair of damage to actively transcribed genes. Alternatively, these findings may reflect a role played by the CSA and CSB gene products in transcription.

Affected neurons of Alzheimer disease (AD) brain are distinguished by the presence of the cell cycle cdc2 kinase and mitotic phosphoepitopes. A significant body of previous data has documented a decrease in neuronal RNA levels and nucleolar volume in AD brain. Here we present evidence that integrates these seemingly distinct findings and offers an explanation for the degenerative outcome of the disease. During mitosis cdc2 phosphorylates and inhibits the major transcriptional regulator RNA polymerase II (RNAP II). We therefore investigated cdc2 phosphorylation of RNAP II in AD brain. Using the H5 and H14 monoclonal antibodies specific for the cdc2-phosphorylated sites in RNAP II, we found that the polymerase is highly phosphorylated in AD. Moreover, RNAP II in AD translocates from its normally nuclear compartment to the cytoplasm of affected neurons, where it colocalizes with cdc2. These M phase-like changes in RNAP II correlate with decreased levels of poly-A RNA in affected neurons. Significantly, they precede tau phosphorylation and neurofibrillary tangle formation. Our data support the hypothesis that inappropriate activation of the cell cycle cdc2 kinase in differentiated neurons contributes to neuronal dysfunction and degeneration in part by inhibiting RNAP II and cellular processes dependent on transcription.

Bortezomib, lenalidomide, and dexamethasone (VRd) is a preferred first-line treatment option for patients with newly diagnosed multiple myeloma. Whether the addition of the anti-CD38 monoclonal antibody isatuximab to the VRd regimen would reduce the risk of disease progression or death among patients ineligible to undergo transplantation is unclear. In an international, open-label, phase 3 trial, we randomly assigned, in a 3:2 ratio, patients 18 to 80 years of age with newly diagnosed multiple myeloma who were ineligible to undergo transplantation to receive either isatuximab plus VRd or VRd alone. The primary efficacy end point was progression-free survival. Key secondary end points included a complete response or better and minimal residual disease (MRD)-negative status in patients with a complete response. A total of 446 patients underwent randomization. At a median follow-up of 59.7 months, the estimated progression-free survival at 60 months was 63.2% in the isatuximab-VRd group, as compared with 45.2% in the VRd group (hazard ratio for disease progression or death, 0.60; 98.5% confidence interval, 0.41 to 0.88; P<0.001). The percentage of patients with a complete response or better was significantly higher in the isatuximab-VRd group than in the VRd group (74.7% vs. 64.1%, P = 0.01), as was the percentage of patients with MRD-negative status and a complete response (55.5% vs. 40.9%, P = 0.003). No new safety signals were observed with the isatuximab-VRd regimen. The incidence of serious adverse events during treatment and the incidence of adverse events leading to discontinuation were similar in the two groups. Isatuximab-VRd was more effective than VRd as initial therapy in patients 18 to 80 years of age with newly diagnosed multiple myeloma who were ineligible to undergo transplantation. (Funded by Sanofi and a Cancer Center Support Grant; IMROZ ClinicalTrials.gov number, NCT03319667.).

With a population of forty million and substantial geographic variation in sociodemographics and health services, California is an important setting in which to study disparities. Its population (37.5 percent White, 39.1 percent Latino, 5.3 percent Black, and 14.4 percent Asian) experienced 59,258 COVID-19 deaths through April 14, 2021-the most of any state. We analyzed California's racial/ethnic disparities in COVID-19 exposure risks, testing rates, test positivity, and case rates through October 2020, combining data from 15.4 million SARS-CoV-2 tests with subcounty exposure risk estimates from the American Community Survey. We defined \"high-exposure-risk\" households as those with one or more essential workers and fewer rooms than inhabitants. Latino people in California are 8.1 times more likely to live in high-exposure-risk households than White people (23.6 percent versus 2.9 percent), are overrepresented in cumulative cases (3,784 versus 1,112 per 100,000 people), and are underrepresented in cumulative testing (35,635 versus 48,930 per 100,000 people). These risks and outcomes were worse for Latino people than for members of other racial/ethnic minority groups. Subcounty disparity analyses can inform targeting of interventions and resources, including community-based testing and vaccine access measures. Tracking COVID-19 disparities and developing equity-focused public health programming that mitigates the effects of systemic racism can help improve health outcomes among California's populations of color.

Background and purpose The European Academy of Neurology (EAN) has adhered to the global plan for reducing the burden of neurological disorders and promoting brain health launched by the World Health Organisation (WHO), the WHO Intersectoral Global Action Plan on Epilepsy and Other Neurological Disorders. This study reports the results of an EAN survey among national neurological societies (NNSs) on their awareness of brain health policies. Methods The EAN survey on the current state of national brain health policies was conducted among the 47 presidents of the NNSs affiliated with the EAN, with the aim of developing the best strategy for close collaboration among stakeholders. Results From June 2023 to February 2024, 36/47 responses (77%) were collected. Among respondents, 67% were in contact with their Ministry of Health and 78% were aware of and in contact with one or more national neurological patient organisation, while 17% had no contacts with any association. Ninety‐two percent declared a high to medium degree of awareness of the need to support brain health and of brain health plans and strategies in their country. Conclusions Our findings suggest good awareness of the importance of brain health and of the strategies implemented at the national level among the EAN‐affiliated NNSs and representatives. Efforts towards improvement may be directed towards cooperation between NNSs and political institutions, as well as patient organisations, to optimise brain and global public health and neurological care in each country.

We tested the hypothesis that de novo copy number variation (CNV) is associated with autism spectrum disorders (ASDs). We performed comparative genomic hybridization (CGH) on the genomic DNA of patients and unaffected subjects to detect copy number variants not present in their respective parents. Candidate genomic regions were validated by higher-resolution CGH, paternity testing, cytogenetics, fluorescence in situ hybridization, and microsatellite genotyping. Confirmed de novo CNVs were significantly associated with autism (P = 0.0005). Such CNVs were identified in 12 out of 118 (10%) of patients with sporadic autism, in 2 out of 77 (3%) of patients with an affected first-degree relative, and in 2 out of 196 (1%) of controls. Most de novo CNVs were smaller than microscopic resolution. Affected genomic regions were highly heterogeneous and included mutations of single genes. These findings establish de novo germline mutation as a more significant risk factor for ASD than previously recognized.

While genetic evidence shows that the Nav1.7 voltage-gated sodium ion channel is a key regulator of pain, it is unclear exactly how Nav1.7 governs neuronal firing and what biophysical, physiological, and distribution properties of a pharmacological Nav1.7 inhibitor are required to produce analgesia. Here we characterize a series of aminotriazine inhibitors of Nav1.7 in vitro and in rodent models of pain and test the effects of the previously reported \"compound 52\" aminotriazine inhibitor on the spiking properties of nociceptors in vivo. Multiple aminotriazines, including some with low terminal brain to plasma concentration ratios, showed analgesic efficacy in the formalin model of pain. Effective concentrations were consistent with the in vitro potency as measured on partially-inactivated Nav1.7 but were far below concentrations required to inhibit non-inactivated Nav1.7. Compound 52 also reversed thermal hyperalgesia in the complete Freund's adjuvant (CFA) model of pain. To study neuronal mechanisms, electrophysiological recordings were made in vivo from single nociceptive fibers from the rat tibial nerve one day after CFA injection. Compound 52 reduced the spontaneous firing of C-fiber nociceptors from approximately 0.7 Hz to 0.2 Hz and decreased the number of action potentials evoked by suprathreshold tactile and heat stimuli. It did not, however, appreciably alter the C-fiber thresholds for response to tactile or thermal stimuli. Surprisingly, compound 52 did not affect spontaneous activity or evoked responses of Aδ-fiber nociceptors. Results suggest that inhibition of inactivated states of TTX-S channels, mostly likely Nav1.7, in the peripheral nervous system produces analgesia by regulating the spontaneous discharge of C-fiber nociceptors.