Activity

3% and 97.1%), no statistically significant differences were found among the 3 groups in mean and minimum SpO

adjusting for age and sex (

= .183 and

= .464, respectively, ANOVA). With respect to the presence of an abnormally low oxygen saturation (SpO

 ≤ 94%), 4.4% of the CRSsNP, 10.9% of the CRScNP and 7.3% of the control patients demonstrated a low oxygen saturation (

= .013).

CRS alone does not objectively contribute to systemic hypoxemia, although a subset of CRScNP patients may have abnormally low SpO

, possibly warranting SpO

assessment in this group of patients.

3.

3.

Frontal sinus surgery is considered one of the more challenging aspects of Functional Endoscopic Sinus Surgery, due to the complex variations in normal sinus anatomy but also increased morbidity due to the close proximity of critical structures such as the anterior cranial fossa and orbits. We aim to investigate the medial canthal point (MCP) as an anatomical landmark for safe frontal sinus access.

The MCP intranasally is identified during surgery with non-tooth forceps, with one limb just anterior to the medial canthus and the other intranasally in the same coronal plane along the skull base. This point was identified on 100 paranasal sinus computed tomography (CT) scan reconstructions. The distance between the anterior cranial fossa and MCP was measured on imaging-medial canthal point distance (MCPD). The maximal anterior-posterior (AP) distance was measured on all scans.

The average MCPD for males was 13.0 mm (8.7-20.4 mm) and for females 12.0 mm (6.8-22.8 mm). Mean AP distance for males was 12.0 mm (4.5-20.2 mm) and for females 10.4 mm (3.8-15.9 mm). Mean distance for all 100 patients was 12.6 mm (range 7.5-22.8 mm). In all cases, the MCP was anterior to the cranial fossa. Mixed effects modelling analysis showed a significant correlation between the MCPD and AP distance (

= .006).

The MCP is a consistent anatomical landmark that can serve as an adjunct to safe frontal sinus access alongside the first olfactory fiber and CT navigation systems. However, patient selection continues to be very important, with larger well pneumatized frontal sinuses being ideal to tackle earlier in a surgeon’s career.

NA.

NA.How much life in the United States is lost to encounters with the police? I build on a demographic life table model by Edwards, Lee, and Esposito to estimate, for race- and gender-specific populations, how many years of life are lost in two categories of police encounter (1) encounters involving officer use of force, and (2) all deaths involving police encounters. Average life years lost by individuals who are killed ranges from 39 years (white men) to 52 years (Native women). The loss of years per 100,000 people over their collective lifetimes is largest for Black men, with 5,696 years of life lost to all encounters with police, of which 3,772 years are lost to police use of force. This implies a loss of roughly 16,000 years of life for recent cohorts of Black men. #link# These results provide context for current debates surrounding the cost and necessity of protests.

To expand the genetic spectrum of hereditary spastic paraparesis by a treatable condition and to evaluate the therapeutic effects of biotin supplementation in an adult patient with biotinidase deficiency (BD).

We performed exome sequencing (ES) in a patient with the clinical diagnosis of complex hereditary spastic paraparesis. The patient was examined neurologically, including functional rating scales. We performed ophthalmologic examinations and metabolic testing.

A 41-year-old patient presented with slowly progressive lower limb spasticity combined with optic atrophy. link2 He was clinically diagnosed with complex hereditary spastic paraparesis. The initial panel diagnostics did not reveal the disease-causing variant; therefore, ES was performed. ES revealed biallelic pathogenic variants in the

gene leading to the genetic diagnosis of BD. BD is an autosomal recessive metabolic disorder causing a broad spectrum of neurologic symptoms, optic atrophy, and dermatologic abnormalities. When treatment is initiatients and those born in countries without newborn screening programs for BD are at risk of being missed. Therapeutic success depends on early diagnosis and presymptomatic treatment.

To further clarify the molecular pathogenesis of RNA polymerase III (Pol III)-related leukodystrophy caused by biallelic

variants at a cellular level and potential effects on its downstream genes.

Exome analysis and molecular functional studies using cell expression and long-read sequencing analyses were performed on 1 family with hypomyelinating leukodystrophy showing no clinical and MRI findings characteristic of Pol III-related leukodystrophy other than hypomyelination.

Biallelic novel

alterations, c.167T>A, p.M56K and c.595A>T, p.I199F, were identified as causal variants. Functional analyses showed that these variants not only resulted in altered protein subcellular localization and decreased protein expression but also caused abnormal inclusion of introns in 85% of the

transcripts in patient cells. Unexpectedly, allelic segregation analysis in each carrier parent revealed that each heterozygous variant also caused the inclusion of introns on both mutant and wild-type alleles. These findings suggest that the abnormal splicing is not direct consequences of the variants, but rather reflect the downstream effect of the variants in dysregulating splicing of

, and potentially other target genes.

The lack of characteristic clinical findings in this family confirmed the broad clinical spectrum of Pol III-related leukodystrophy. Molecular studies suggested that dysregulation of splicing is the potential downstream pathomechanism for

variants.

The lack of characteristic clinical findings in this family confirmed the broad clinical spectrum of Pol III-related leukodystrophy. Molecular studies suggested that dysregulation of splicing is the potential downstream pathomechanism for POLR1C variants.

To expand the clinical phenotype of

mutations by assessing the functional consequences of a missense and a splicing acceptor mutation.

We performed whole-exome sequencing for identification of likely pathogenic mutations in a 9-year-old female patient with severe generalized dystonia, metabolic acidosis, leukocytosis, hypotonia, and dysphagia. Brain MRI showed basal ganglia atrophy and presence of lactate and lipid peaks by [

H]-magnetic resonance spectroscopy. Expression levels of Pol III target genes were measured by quantitative real-time (qRT)-PCR to study the pathogenicity of the biallelic mutations in patient fibroblasts.

The patient is a compound heterozygous for a novel missense c.3721G>A (p.Val1241Met) and the splicing region c.1771-6C>G mutation in

, the gene coding for the catalytic subunit of RNA polymerase III (Pol III). this website was observed for the c.1771-6C>G mutation. Decreased RNA expression levels of Pol III targets (HNRNPH2, ubiquitin B, lactotransferrin, and eased Lactate.

To delineate the phenotype associated with biallelic

variants.

We describe 2 new patients with

-related disorder diagnosed by whole-exome sequencing and compare their phenotype to 6 previous patients.

Patients 1 and 2 had a similar distinctive phenotype comprising congenital stiffness of limbs, absent spontaneous movements, weak sucking, and hypoventilation. Both had absent brainstem evoked auditory responses (BEARs). Patient 1 carried the homozygous p.(His357Argfs*15) variant in

. In the light of the finding in patient 1, a second reading of exome data for patient 2 revealed the novel homozygous p.(Gly128Val) variant.

Analysis of the phenotypes of these 2 patients and of the 6 previous cases showed that biallelic

mutations are responsible for a unique congenital encephalopathy likely comprising absent BEAR, different from hyperekplexia and other conditions with neonatal hypertonia.

Analysis of the phenotypes of these 2 patients and of the 6 previous cases showed that biallelic ATAD1 mutations are responsible for a unique congenital encephalopathy likely comprising absent BEAR, different from hyperekplexia and other conditions with neonatal hypertonia.

To determine whether transcriptional risk scores (TRSs), a summation of polarized expression levels of functional genes, reflect the risk of Alzheimer disease (AD).

Blood transcriptome data were from Caucasian participants, which included AD, mild cognitive impairment, and cognitively normal controls (CN) in the Alzheimer’s Disease Neuroimaging Initiative (ADNI, n = 661) and AddNeuroMed (n = 674) cohorts. To calculate TRSs, we selected functional genes that were expressed under the control of the AD risk loci and were identified as being responsible for AD by using Bayesian colocalization and mendelian randomization methods. Regression was used to investigate the association of the TRS with diagnosis (AD vs CN) and MRI biomarkers (entorhinal thickness and hippocampal volume). Regression was also used to evaluate whether expression of each functional gene was associated with AD diagnosis.

The TRS was significantly associated with AD diagnosis, hippocampal volume, and entorhinal cortical thickness in the ADNI. The association of the TRS with AD diagnosis and entorhinal cortical thickness was also replicated in AddNeuroMed. Among functional genes identified to calculate the TRS,

and

were significantly upregulated, and

was significantly downregulated in patients with AD compared with CN, all of which were identified in the ADNI and replicated in AddNeuroMed.

The blood-based TRS is significantly associated with AD diagnosis and neuroimaging biomarkers. In blood,

and

were known to be associated with uptake of β-amyloid and herpes simplex virus 1 infection, respectively, both of which may play a role in the pathogenesis of AD.

The study is rated Class III because of the case control design and the risk of spectrum bias.

The study is rated Class III because of the case control design and the risk of spectrum bias.

Our aim was to study a Hungarian family with autosomal dominantly inherited neurodegeneration with brain iron accumulation (NBIA) with markedly different intrafamilial expressivity.

Targeted sequencing and multiplex ligation-dependent probe amplification (MLPA) of known NBIA-associated genes were performed in many affected and unaffected members of the family. In addition, a trio whole-genome sequencing was performed to find a potential explanation of phenotypic variability. Neuropathologic analysis was performed in a single affected family member.

The clinical phenotype was characterized by 3 different syndromes-1 with rapidly progressive dystonia-parkinsonism with cognitive deterioration, 1 with mild parkinsonism associated with dementia, and 1 with predominantly psychiatric symptoms along with movement disorder. A heterozygous stop-gain variation in the

gene segregated with the phenotype. Targeted sequencing of all known NBIA genes, and MLPA of

and

genes, as well as whole-genome sequencing in a trio from the family, revealed a unique constellation of oligogenic burden in 3 NBIA-associated genes (

p.Trp112Ter,

p.Val105PhefsTer5, and

dup(ex14)). Neuropathologic analysis of a single case (39-year-old man) showed a complex pattern of alpha-synucleinopathy and tauopathy, both involving subcortical and cortical areas and the hippocampus.

Our study expands the number of cases reported with autosomal dominant mitochondrial membrane protein-associated neurodegeneration and emphasizes the complexity of the genetic architecture, which might contribute to intrafamilial phenotypic variability.

Our study expands the number of cases reported with autosomal dominant mitochondrial membrane protein-associated neurodegeneration and emphasizes the complexity of the genetic architecture, which might contribute to intrafamilial phenotypic variability.