Access to Care Considerations for the Endodontic Treatment of Immature Permanent Teeth: A National Survey of Pediatric Dentists and Endodontists.

INTRODUCTION: This study aimed to investigate access to care and financial considerations associated with the endodontic treatment of immature permanent teeth. METHODS: Surveys were distributed to endodontists (n = 2,457) and pediatric dentists (n = 3,974) in the United States. Data were analyzed using X2 analysis and logistic regression. The level of significance was set to 0.05. RESULTS: The response rate was 13% (n = 840). Respondent specialist groups were similar by age and years since specialty residency completion, but significantly different with regard to primary practice setting (eg private practice, Federally Qualified Health Center, hospital), (P = .001). The majority (91%) of respondents reported participation with dental insurance. Pediatric dentists (69%) were significantly more likely than endodontists (17%) to participate with public-payer dental insurance (P < .001). The majority of respondents (82%) indicated that patients reported economic factors (time or money) as a barrier to accessing endodontic treatment. Pediatric dentists were significantly more likely to consider economic factors when planning for treatment (P < .001). Pediatric dentists were more likely than endodontists to have the opinion that endodontic procedures for treatment of necrotic immature permanent teeth should cost less than root canal therapy (apexification, P < .001; regenerative endodontic procedures, P = .002). Pediatric dentists (33%) reported encountering barriers when attempting to refer their patients to an endodontist. Inability to find an endodontist that participates with dental insurance was the most frequently cited barrier. CONCLUSIONS: Limited clinician participation with dental insurance and gaps in insurance coverage for endodontic procedures appear to contribute to access to care barriers for pediatric patients.

Effects of Side Flattening on Torsional and Cyclic Fracture Resistance of Nickel-Titanium File.

INTRODUCTION: The purpose of this study was to evaluate the effect of side flattening of cutting flutes on the cyclic resistance and torsional resistance of nickel-titanium files. METHODS: Both novel flattened Platinum V.EU (PL) and standard nonflattened CC Premium V.EU (CC) rotaries were tested. For cyclic fatigue tests, all the files were rotated in an artificial root canal with a curvature of 45° and a radius of 6.06 mm at 300 rpm (n = 15 in each group). The number of cycles to failure (NCF) was calculated. For torsional tests, the files were rotated at 2 rpm clockwise until fracture occurred. The maximum torque value at fracture was measured and the toughness and distortion angle were computed. Subsequently, 5 fragments were randomly selected in each experiment, the cross-section and longitudinal direction of the fragments were photographed using a scanning electron microscope. An unpaired t-test was performed at a significance level of 95%. RESULTS: There was a statistically significant difference in NCF between CC and PL (P < .05). CC showed higher NCF than PL. There was no statistically significant difference between CC and PL with regards to the parameters related to torsional resistance (distortion angle, ultimate strength, and toughness) (P > .05). CONCLUSION: Within the limitations of this study, side flattening of the file did not improve cyclic resistance or torsional resistance of the files. As side flattening may reduce a file's cyclic resistance, such files should be used with caution in clinical practice.

A population-based survey of FBN1 variants in Iceland reveals underdiagnosis of Marfan syndrome.

Marfan syndrome (MFS) is an autosomal dominant condition characterized by aortic aneurysm, skeletal abnormalities, and lens dislocation, and is caused by variants in the FBN1 gene. To explore causes of MFS and the prevalence of the disease in Iceland we collected information from all living individuals with a clinical diagnosis of MFS in Iceland (n = 32) and performed whole-genome sequencing of those who did not have a confirmed genetic diagnosis (27/32). Moreover, to assess a potential underdiagnosis of MFS in Iceland we attempted a genotype-based approach to identify individuals with MFS. We interrogated deCODE genetics' database of 35,712 whole-genome sequenced individuals to search for rare sequence variants in FBN1. Overall, we identified 15 pathogenic or likely pathogenic variants in FBN1 in 44 individuals, only 22 of whom were previously diagnosed with MFS. The most common of these variants, NM_000138.4:c.8038 C > T p.(Arg2680Cys), is present in a multi-generational pedigree, and was found to stem from a single forefather born around 1840. The p.(Arg2680Cys) variant associates with a form of MFS that seems to have an enrichment of abdominal aortic aneurysm, suggesting that this may be a particularly common feature of p.(Arg2680Cys)-associated MFS. Based on these combined genetic and clinical data, we show that MFS prevalence in Iceland could be as high as 1/6,600 in Iceland, compared to 1/10,000 based on clinical diagnosis alone, which indicates underdiagnosis of this actionable genetic disorder.

Variants at the Interleukin 1 Gene Locus and Pericarditis.

Importance: Recurrent pericarditis is a treatment challenge and often a debilitating condition. Drugs inhibiting interleukin 1 cytokines are a promising new treatment option, but their use is based on scarce biological evidence and clinical trials of modest sizes, and the contributions of innate and adaptive immune processes to the pathophysiology are incompletely understood. Objective: To use human genomics, transcriptomics, and proteomics to shed light on the pathogenesis of pericarditis. Design, Setting, and Participants: This was a meta-analysis of genome-wide association studies of pericarditis from 5 countries. Associations were examined between the pericarditis-associated variants and pericarditis subtypes (including recurrent pericarditis) and secondary phenotypes. To explore mechanisms, associations with messenger RNA expression (cis-eQTL), plasma protein levels (pQTL), and CpG methylation of DNA (ASM-QTL) were assessed. Data from Iceland (deCODE genetics, 1983-2020), Denmark (Copenhagen Hospital Biobank/Danish Blood Donor Study, 1977-2022), the UK (UK Biobank, 1953-2021), the US (Intermountain, 1996-2022), and Finland (FinnGen, 1970-2022) were included. Data were analyzed from September 2022 to August 2023. Exposure: Genotype. Main Outcomes and Measures: Pericarditis. Results: In this genome-wide association study of 4894 individuals with pericarditis (mean [SD] age at diagnosis, 51.4 [17.9] years, 2734 [67.6%] male, excluding the FinnGen cohort), associations were identified with 2 independent common intergenic variants at the interleukin 1 locus on chromosome 2q14. The lead variant was rs12992780 (T) (effect allele frequency [EAF], 31%-40%; odds ratio [OR], 0.83; 95% CI, 0.79-0.87; P = 6.67 × 10-16), downstream of IL1B and the secondary variant rs7575402 (A or T) (EAF, 45%-55%; adjusted OR, 0.89; 95% CI, 0.85-0.93; adjusted P = 9.6 × 10-8). The lead variant rs12992780 had a smaller odds ratio for recurrent pericarditis (0.76) than the acute form (0.86) (P for heterogeneity = .03) and rs7575402 was associated with CpG methylation overlapping binding sites of 4 transcription factors known to regulate interleukin 1 production: PU.1 (encoded by SPI1), STAT1, STAT3, and CCAAT/enhancer-binding protein ß (encoded by CEBPB). Conclusions and Relevance: This study found an association between pericarditis and 2 independent sequence variants at the interleukin 1 gene locus. This finding has the potential to contribute to development of more targeted and personalized therapy of pericarditis with interleukin 1-blocking drugs.

Actionable Genotypes and Their Association with Life Span in Iceland.

BACKGROUND: In 2021, the American College of Medical Genetics and Genomics (ACMG) recommended reporting actionable genotypes in 73 genes associated with diseases for which preventive or therapeutic measures are available. Evaluations of the association of actionable genotypes in these genes with life span are currently lacking. METHODS: We assessed the prevalence of coding and splice variants in genes on the ACMG Secondary Findings, version 3.0 (ACMG SF v3.0), list in the genomes of 57,933 Icelanders. We assigned pathogenicity to all reviewed variants using reported evidence in the ClinVar database, the frequency of variants, and their associations with disease to create a manually curated set of actionable genotypes (variants). We assessed the relationship between these genotypes and life span and further examined the specific causes of death among carriers. RESULTS: Through manual curation of 4405 sequence variants in the ACMG SF v3.0 genes, we identified 235 actionable genotypes in 53 genes. Of the 57,933 participants, 2306 (4.0%) carried at least one actionable genotype. We found shorter median survival among persons carrying actionable genotypes than among noncarriers. Specifically, we found that carrying an actionable genotype in a cancer gene was associated with survival that was 3 years shorter than that among noncarriers, with causes of death among carriers attributed primarily to cancer-related conditions. Furthermore, we found evidence of association between carrying an actionable genotype in certain genes in the cardiovascular disease group and a reduced life span. CONCLUSIONS: On the basis of the ACMG SF v3.0 guidelines, we found that approximately 1 in 25 Icelanders carried an actionable genotype and that carrying such a genotype was associated with a reduced life span. (Funded by deCODE Genetics-Amgen.).

Rare variants with large effects provide functional insights into the pathology of migraine subtypes, with and without aura.

Migraine is a complex neurovascular disease with a range of severity and symptoms, yet mostly studied as one phenotype in genome-wide association studies (GWAS). Here we combine large GWAS datasets from six European populations to study the main migraine subtypes, migraine with aura (MA) and migraine without aura (MO). We identified four new MA-associated variants (in PRRT2, PALMD, ABO and LRRK2) and classified 13 MO-associated variants. Rare variants with large effects highlight three genes. A rare frameshift variant in brain-expressed PRRT2 confers large risk of MA and epilepsy, but not MO. A burden test of rare loss-of-function variants in SCN11A, encoding a neuron-expressed sodium channel with a key role in pain sensation, shows strong protection against migraine. Finally, a rare variant with cis-regulatory effects on KCNK5 confers large protection against migraine and brain aneurysms. Our findings offer new insights with therapeutic potential into the complex biology of migraine and its subtypes.

Apexification Outcomes in the United States: A Retrospective Cohort Study.

INTRODUCTION: This epidemiological analysis used procedure codes from dental insurance claims data to identify apexification cases and evaluate survival at the tooth-level. METHODS: Dental insurance claims data from New York State (2006-2019) and Massachusetts (2013-2018) were used in an observational, retrospective cohort study to evaluate the provision and treatment outcomes of apexification. Statistical analyses included Kaplan-Meier survival estimates and Cox proportional hazards regression. Cox proportional hazard regression was used to evaluate the hazard of adverse event occurrence by age, gender, tooth type, placement of permanent restoration, and dental provider type. A sensitivity analysis evaluated potential bias in the survival estimates and adjusted hazard ratios (aHRs) due to differential loss to follow-up. Robust standard errors were used to account for potential dependence between teeth within an individual. RESULTS: The analytic cohort of 575 individuals included 632 teeth, with an average follow-up time of 64 months. The survival rates of apexification procedures were 95% at 1 year; 93% at 2 years; 90% at 3 years; and 86% at 5 years. Tooth retention following apexification was 98% at 1 year; 96% at 2 years; 95% at 3 years; and 90% at 5 years. Tooth type and subsequent placement of a permanent restoration were significant predictors of survival after apexification. CONCLUSIONS: The procedural and tooth survival outcomes of apexification were high and comparable to studies that analyzed clinical data on tooth survival following apexification.

Effect of Periodic Changes in Rotation Speed on Torsional Stress and Screw-in Force by Alternative Rotation Technique.

INTRODUCTION: This study evaluated the effect of periodic changes in rotation speed on torsional stress and screw-in force using the dedicated alternative rotation technique (ART) motion of the EQ-M (Metabiomed, Cheongju, Korea) endodontic motor. METHODS: Two ART modes of the EQ-M motor in 2 alternative techniques (ART30 and ART50) and continuous rotation were compared using ProTaper Next X2 (Dentsply Sirona, Charlotte, NC) files and simulated resin blocks (n = 12 per group). ART30 and ART50 were operated by continuous rotation of 350 rpm for 360° and then rotated at 30% increased speed from the base speed for 180° and at 50% increased speed for 180°, respectively. Before the test, the simulated resin blocks were pre-enlarged using ProTaper Gold S1 and S2 (Dentsply Sirona) and fixed on a metal stage connected to the force- and torque-measuring unit. During shaping the simulated canal in an automatic up-and-down manner, the parameters of maximum torque, sum of torque, maximum screw-in force, and maximum apical force were measured. The data were statistically analyzed using 1-way analysis of variance and the Tukey post hoc comparison test at the 95% significance level. RESULTS: The ART30 and ART50 groups showed a lower maximum torque, sum of torques, screw-in force, and apical drive force than the continuous rotation group. There was no significant difference between the ART30 and ART50 groups (P > .05). When the screw-in force increased suddenly, the torque correspondently increased. CONCLUSIONS: Under the limitations of this study, the ART mode could reduce the torsional stress and apical forces of the screw-in during instrumentation in comparison with continuous rotation.

The population genomic legacy of the second plague pandemic.

Human populations have been shaped by catastrophes that may have left long-lasting signatures in their genomes. One notable example is the second plague pandemic that entered Europe in ca. 1,347 CE and repeatedly returned for over 300 years, with typical village and town mortality estimated at 10%-40%.1 It is assumed that this high mortality affected the gene pools of these populations. First, local population crashes reduced genetic diversity. Second, a change in frequency is expected for sequence variants that may have affected survival or susceptibility to the etiologic agent (Yersinia pestis).2 Third, mass mortality might alter the local gene pools through its impact on subsequent migration patterns. We explored these factors using the Norwegian city of Trondheim as a model, by sequencing 54 genomes spanning three time periods: (1) prior to the plague striking Trondheim in 1,349 CE, (2) the 17th-19th century, and (3) the present. We find that the pandemic period shaped the gene pool by reducing long distance immigration, in particular from the British Isles, and inducing a bottleneck that reduced genetic diversity. Although we also observe an excess of large FST values at multiple loci in the genome, these are shaped by reference biases introduced by mapping our relatively low genome coverage degraded DNA to the reference genome. This implies that attempts to detect selection using ancient DNA (aDNA) datasets that vary by read length and depth of sequencing coverage may be particularly challenging until methods have been developed to account for the impact of differential reference bias on test statistics.

Outcomes of primary root canal therapy: An updated systematic review of longitudinal clinical studies published between 2003 and 2020.

BACKGROUND: A comprehensive effort to evaluate outcomes of primary root canal therapy (RCT) between 1966 and 2002 was published by Ng et al. (2007, International Endodontic Journal, 40, 921; 2008, International Endodontic Journal, 41, 6). Changes in endodontic materials and treatment methods warrant an updated analysis of outcomes. OBJECTIVES: This study aimed to (1) quantify the success rates of primary RCT published between 2003 and 2020; and (2) investigate the influence of some characteristics known/suspected to be associated with treatment outcomes. METHODS: An electronic search was performed in the following databases (01-01-2003 to 12-31-2020): Pubmed, Embase, CINHAL, Cochrane and Web of Science. Included study designs were longitudinal clinical studies (randomized control trials, cohort studies, retrospective observational studies). Studies with at least twelve-months of post-operative review and success rates based on clinical and radiographic criteria were analysed. The terms 'strict' (complete resolution of periapical lesion) or 'loose' (reduction in size of existing periapical lesion) were used to describe the outcome criteria. Weighted, pooled success rates were calculated. Random effects meta-regression models were used to investigate potential sources of statistical heterogeneity. The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach was used to evaluate for quality assessment of the included studies. RESULTS: Forty-two studies were included in the review. Meta-analyses showed that the weighted pooled success rates were estimated to be 92.6% (95% CI: 90.5%-94.8%) under 'loose criteria' and 82.0% (95% CI: 79.3%-84.8%) under 'strict' criteria. The most significant areas of study heterogeneity were year of publication and qualification of operator. The majority (64.29%) of studies were considered to be of low quality of evidence. DISCUSSION: Biological factors continue to have the most significant impact on RCT outcomes. The technological method of instrumentation had no significant effect. The quality of evidence was based primarily on study design and only randomized control trials were considered to be 'high' quality of evidence. CONCLUSIONS: The reported success rates show improvement over time. Weighted success rates for studies with a minimum of four-years follow-up had better outcomes, compared to those with less than four years, when 'strict criteria' were used. REGISTRATION: PROSPERO database (CRD42021226311).

Bupivacaine for Root Canal Treatment - Practitioner Behaviors and Patient Perspectives: Survey Studies.

INTRODUCTION AND OBJECTIVES: Local anesthesia is essential in dentistry in providing intraoperative analgesia and anesthesia. However, knowledge related to its use for management of post-operative pain is limited. Perioperative pain management is especially important for root canal treatment (ie, endodontic therapy), performed by endodontists. In this study, we sought to better understand endodontists' attitudes regarding the use of long-lasting anesthetic, namely 0.5% bupivacaine HCl with 1:200,000 epinephrine, for the management of post-endodontic pain. Additionally, we aimed to understand the perspectives of dental patients about receiving longer lasting anesthesia for endodontic therapy and to determine factors that affect their anesthetic preferences within the orofacial region. METHODS: An email invitation to participate in an anonymous online survey was sent to members of the American Association of Endodontists. Also, 82 patients attending an in-person visit to an endodontic clinic were recruited to the study. RESULTS: Data from 474 endodontic practitioners and 82 patients included in analysis. Among practitioners, the majority reported to either never (33.31%) or rarely (34.84%) using bupivacaine. Most chose "I don't think I need it" (47%) and "patient discomfort because of longer duration of soft tissue anesthesia" (30.81%) as reasons for not preferring the use of bupivacaine. Of the practitioners who reported at least rare use, most chose bupivacaine for post-operative pain management (78.02%). Conversely, 52% of patients reported that they were likely/most likely to request long-lasting anesthetics for post-operative pain control. CONCLUSION: Bupivacaine is rarely used as a post-operative pain management strategy for endodontic therapy. Specifically, bupivacaine is not preferred not because of adverse events, toxicity, or slow onset concerns, but rather, because of longer duration of soft tissue anesthesia. However, our data suggest that patients may be willing to receive long-lasting anesthesia. Further patient-centered research should investigate the use of long-lasting anesthetic agents for management of post-endodontic pain.

Reconstruction of a large-scale outbreak of SARS-CoV-2 infection in Iceland informs vaccination strategies.

OBJECTIVES: The spread of SARS-CoV-2 is dependent on several factors, both biological and behavioural. The effectiveness of nonpharmaceutical interventions can be attributed largely to changes in human behaviour, but quantifying this effect remains challenging. Reconstructing the transmission tree of the third wave of SARS-CoV-2 infections in Iceland using contact tracing and viral sequence data from 2522 cases enables us to directly compare the infectiousness of distinct groups of persons. METHODS: The transmission tree enables us to model the effect that a given population prevalence of vaccination would have had on the third wave had one of three different vaccination strategies been implemented before that time. This allows us to compare the effectiveness of the strategies in terms of minimizing the number of cases, deaths, critical cases, and severe cases. RESULTS: We found that people diagnosed outside of quarantine (Rˆ=1.31) were 89% more infectious than those diagnosed while in quarantine (Rˆ=0.70) and that infectiousness decreased as a function of time spent in quarantine before diagnosis, with people diagnosed outside of quarantine being 144% more infectious than those diagnosed after ≥3 days in quarantine (Rˆ=0.54). People of working age, 16 to 66 years (Rˆ=1.08), were 46% more infectious than those outside of that age range (Rˆ=0.74). DISCUSSION: We found that vaccinating the population in order of ascending age or uniformly at random would have prevented more infections per vaccination than vaccinating in order of descending age, without significantly affecting the expected number of deaths, critical cases, or severe cases.

Epidemiological evaluation of the outcomes of initial root canal therapy in permanent teeth of a publicly insured paediatric population.

BACKGROUND: Previously published epidemiological outcome studies of nonsurgical root canal therapy (NSRCT) in the United States utilize data only from a single, private dental insurer for adult populations. AIM: This study aimed to investigate the outcomes of initial NSRCT, performed on permanent teeth, in a publicly insured paediatric population. DESIGN: New York State Medicaid administrative claims were used to follow 77 741 endodontic procedures in 51 545 patients aged 6-18, from the time of initial NSRCT until the occurrence of an untoward event (retreatment, apicoectomy, and extraction). The initial treatment and untoward events were identified by Current Dental Terminology codes. The Kaplan-Meier survival estimates were calculated at 1, 3, and 5 years. Hazard ratios for time to permanent restoration and restoration type were calculated using the Cox proportional hazards model. RESULTS: The median follow-up time was 44 months [range: 12-158 months]. Procedural, NSRCT, survival was 98% at 1 year, 93% at 3 years, and 88% at 5 years. Extraction was the most common untoward event. Teeth permanently restored with cuspal coverage had the most favorable treatment outcomes. CONCLUSIONS: Overall, 89% of teeth were retained and remained functional over a minimum follow-up time of 5 years. These results elucidate the expected outcomes of NSRCT in permanent teeth for paediatric patients with public-payer dental benefits.

Large-Scale Screening for Monogenic and Clinically Defined Familial Hypercholesterolemia in Iceland.

Objective: Familial hypercholesterolemia (FH) is traditionally defined as a monogenic disease characterized by severely elevated LDL-C (low-density lipoprotein cholesterol) levels. In practice, FH is commonly a clinical diagnosis without confirmation of a causative mutation. In this study, we sought to characterize and compare monogenic and clinically defined FH in a large sample of Icelanders. Approach and Results: We whole-genome sequenced 49 962 Icelanders and imputed the identified variants into an overall sample of 166 281 chip-genotyped Icelanders. We identified 20 FH mutations in LDLR, APOB, and PCSK9 with combined prevalence of 1 in 836. Monogenic FH was associated with severely elevated LDL-C levels and increased risk of premature coronary disease, aortic valve stenosis, and high burden of coronary atherosclerosis. We used a modified version of the Dutch Lipid Clinic Network criteria to screen for the clinical FH phenotype among living adult participants (N=79 058). Clinical FH was found in 2.2% of participants, of whom only 5.2% had monogenic FH. Mutation-negative clinical FH has a strong polygenic basis. Both individuals with monogenic FH and individuals with mutation-negative clinical FH were markedly undertreated with cholesterol-lowering medications and only a minority attained an LDL-C target of <2.6 mmol/L (<100 mg/dL; 11.0% and 24.9%, respectively) or <1.8 mmol/L (<70 mg/dL; 0.0% and 5.2%, respectively), as recommended for primary prevention by European Society of Cardiology/European Atherosclerosis Society cholesterol guidelines. Conclusions: Clinically defined FH is a relatively common phenotype that is explained by monogenic FH in only a minority of cases. Both monogenic and clinical FH confer high cardiovascular risk but are markedly undertreated.

Molecular benchmarks of a SARS-CoV-2 epidemic.

A pressing concern in the SARS-CoV-2 epidemic and other viral outbreaks, is the extent to which the containment measures are halting the viral spread. A straightforward way to assess this is to tally the active cases and the recovered ones throughout the epidemic. Here, we show how epidemic control can be assessed with molecular information during a well characterized epidemic in Iceland. We demonstrate how the viral concentration decreased in those newly diagnosed as the epidemic transitioned from exponential growth phase to containment phase. The viral concentration in the cases identified in population screening decreased faster than in those symptomatic and considered at high risk and that were targeted by the healthcare system. The viral concentration persists in recovering individuals as we found that half of the cases are still positive after two weeks. We demonstrate that accumulation of mutations in SARS-CoV-2 genome can be exploited to track the rate of new viral generations throughout the different phases of the epidemic, where the accumulation of mutations decreases as the transmission rate decreases in the containment phase. Overall, the molecular signatures of SARS-CoV-2 infections contain valuable epidemiological information that can be used to assess the effectiveness of containment measures.

Loss-of-Function Variants in the Tumor-Suppressor Gene PTPN14 Confer Increased Cancer Risk.

The success of genome-wide association studies (GWAS) in identifying common, low-penetrance variant-cancer associations for the past decade is undisputed. However, discovering additional high-penetrance cancer mutations in unknown cancer predisposing genes requires detection of variant-cancer association of ultra-rare coding variants. Consequently, large-scale next-generation sequence data with associated phenotype information are needed. Here, we used genotype data on 166,281 Icelanders, of which, 49,708 were whole-genome sequenced and 408,595 individuals from the UK Biobank, of which, 41,147 were whole-exome sequenced, to test for association between loss-of-function burden in autosomal genes and basal cell carcinoma (BCC), the most common cancer in Caucasians. A total of 25,205 BCC cases and 683,058 controls were tested. Rare germline loss-of-function variants in PTPN14 conferred substantial risks of BCC (OR, 8.0; P = 1.9 × 10-12), with a quarter of carriers getting BCC before age 70 and over half in their lifetime. Furthermore, common variants at the PTPN14 locus were associated with BCC, suggesting PTPN14 as a new, high-impact BCC predisposition gene. A follow-up investigation of 24 cancers and three benign tumor types showed that PTPN14 loss-of-function variants are associated with high risk of cervical cancer (OR, 12.7, P = 1.6 × 10-4) and low age at diagnosis. Our findings, using power-increasing methods with high-quality rare variant genotypes, highlight future prospects for new discoveries on carcinogenesis. SIGNIFICANCE: This study identifies the tumor-suppressor gene PTPN14 as a high-impact BCC predisposition gene and indicates that inactivation of PTPN14 by germline sequence variants may also lead to increased risk of cervical cancer.

Lifelong Reduction in LDL (Low-Density Lipoprotein) Cholesterol due to a Gain-of-Function Mutation in LDLR.

BACKGROUND: Loss-of-function mutations in the LDL (low-density lipoprotein) receptor gene (LDLR) cause elevated levels of LDL cholesterol and premature cardiovascular disease. To date, a gain-of-function mutation in LDLR with a large effect on LDL cholesterol levels has not been described. Here, we searched for sequence variants in LDLR that have a large effect on LDL cholesterol levels. METHODS: We analyzed whole-genome sequencing data from 43 202 Icelanders. Single-nucleotide polymorphisms and structural variants including deletions, insertions, and duplications were genotyped using whole-genome sequencing-based data. LDL cholesterol associations were carried out in a sample of >100 000 Icelanders with genetic information (imputed or whole-genome sequencing). Molecular analyses were performed using RNA sequencing and protein expression assays in Epstein-Barr virus-transformed lymphocytes. RESULTS: We discovered a 2.5-kb deletion (del2.5) overlapping the 3' untranslated region of LDLR in 7 heterozygous carriers from a single family. Mean level of LDL cholesterol was 74% lower in del2.5 carriers than in 101 851 noncarriers, a difference of 2.48 mmol/L (96 mg/dL; P=8.4×10-8). Del2.5 results in production of an alternative mRNA isoform with a truncated 3' untranslated region. The truncation leads to a loss of target sites for microRNAs known to repress translation of LDLR. In Epstein-Barr virus-transformed lymphocytes derived from del2.5 carriers, expression of alternative mRNA isoform was 1.84-fold higher than the wild-type isoform (P=0.0013), and there was 1.79-fold higher surface expression of the LDL receptor than in noncarriers (P=0.0086). We did not find a highly penetrant detrimental impact of lifelong very low levels of LDL cholesterol due to del2.5 on health of the carriers. CONCLUSIONS: Del2.5 is the first reported gain-of-function mutation in LDLR causing a large reduction in LDL cholesterol. These data point to a role for alternative polyadenylation of LDLR mRNA as a potent regulator of LDL receptor expression in humans.

Humoral Immune Response to SARS-CoV-2 in Iceland.

BACKGROUND: Little is known about the nature and durability of the humoral immune response to infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). METHODS: We measured antibodies in serum samples from 30,576 persons in Iceland, using six assays (including two pan-immunoglobulin [pan-Ig] assays), and we determined that the appropriate measure of seropositivity was a positive result with both pan-Ig assays. We tested 2102 samples collected from 1237 persons up to 4 months after diagnosis by a quantitative polymerase-chain-reaction (qPCR) assay. We measured antibodies in 4222 quarantined persons who had been exposed to SARS-CoV-2 and in 23,452 persons not known to have been exposed. RESULTS: Of the 1797 persons who had recovered from SARS-CoV-2 infection, 1107 of the 1215 who were tested (91.1%) were seropositive; antiviral antibody titers assayed by two pan-Ig assays increased during 2 months after diagnosis by qPCR and remained on a plateau for the remainder of the study. Of quarantined persons, 2.3% were seropositive; of those with unknown exposure, 0.3% were positive. We estimate that 0.9% of Icelanders were infected with SARS-CoV-2 and that the infection was fatal in 0.3%. We also estimate that 56% of all SARS-CoV-2 infections in Iceland had been diagnosed with qPCR, 14% had occurred in quarantined persons who had not been tested with qPCR (or who had not received a positive result, if tested), and 30% had occurred in persons outside quarantine and not tested with qPCR. CONCLUSIONS: Our results indicate that antiviral antibodies against SARS-CoV-2 did not decline within 4 months after diagnosis. We estimate that the risk of death from infection was 0.3% and that 44% of persons infected with SARS-CoV-2 in Iceland were not diagnosed by qPCR.