Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Background Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. Methods RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov , NCT00541047 . Findings Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Interpretation Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Funding Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society

Changes in symptomatology, reinfection, and transmissibility associated with the SARS-CoV-2 variant B.1.1.7: an ecological study

Background The SARS-CoV-2 variant B.1.1.7 was first identified in December, 2020, in England. We aimed to investigate whether increases in the proportion of infections with this variant are associated with differences in symptoms or disease course, reinfection rates, or transmissibility. Methods We did an ecological study to examine the association between the regional proportion of infections with the SARS-CoV-2 B.1.1.7 variant and reported symptoms, disease course, rates of reinfection, and transmissibility. Data on types and duration of symptoms were obtained from longitudinal reports from users of the COVID Symptom Study app who reported a positive test for COVID-19 between Sept 28 and Dec 27, 2020 (during which the prevalence of B.1.1.7 increased most notably in parts of the UK). From this dataset, we also estimated the frequency of possible reinfection, defined as the presence of two reported positive tests separated by more than 90 days with a period of reporting no symptoms for more than 7 days before the second positive test. The proportion of SARS-CoV-2 infections with the B.1.1.7 variant across the UK was estimated with use of genomic data from the COVID-19 Genomics UK Consortium and data from Public Health England on spike-gene target failure (a non-specific indicator of the B.1.1.7 variant) in community cases in England. We used linear regression to examine the association between reported symptoms and proportion of B.1.1.7. We assessed the Spearman correlation between the proportion of B.1.1.7 cases and number of reinfections over time, and between the number of positive tests and reinfections. We estimated incidence for B.1.1.7 and previous variants, and compared the effective reproduction number, Rt, for the two incidence estimates. Findings From Sept 28 to Dec 27, 2020, positive COVID-19 tests were reported by 36 920 COVID Symptom Study app users whose region was known and who reported as healthy on app sign-up. We found no changes in reported symptoms or disease duration associated with B.1.1.7. For the same period, possible reinfections were identified in 249 (0·7% [95% CI 0·6–0·8]) of 36 509 app users who reported a positive swab test before Oct 1, 2020, but there was no evidence that the frequency of reinfections was higher for the B.1.1.7 variant than for pre-existing variants. Reinfection occurrences were more positively correlated with the overall regional rise in cases (Spearman correlation 0·56–0·69 for South East, London, and East of England) than with the regional increase in the proportion of infections with the B.1.1.7 variant (Spearman correlation 0·38–0·56 in the same regions), suggesting B.1.1.7 does not substantially alter the risk of reinfection. We found a multiplicative increase in the Rt of B.1.1.7 by a factor of 1·35 (95% CI 1·02–1·69) relative to pre-existing variants. However, Rt fell below 1 during regional and national lockdowns, even in regions with high proportions of infections with the B.1.1.7 variant. Interpretation The lack of change in symptoms identified in this study indicates that existing testing and surveillance infrastructure do not need to change specifically for the B.1.1.7 variant. In addition, given that there was no apparent increase in the reinfection rate, vaccines are likely to remain effective against the B.1.1.7 variant. Funding Zoe Global, Department of Health (UK), Wellcome Trust, Engineering and Physical Sciences Research Council (UK), National Institute for Health Research (UK), Medical Research Council (UK), Alzheimer's Society

Genetic association between APOE*4 and neuropsychiatric symptoms in patients with probable Alzheimer's disease is dependent on the psychosis phenotype

Abstract Background Neuropsychiatric symptoms such as psychosis are prevalent in patients with probable Alzheimer’s disease (AD) and are associated with increased morbidity and mortality. Because these disabling symptoms are generally not well tolerated by caregivers, patients with these symptoms tend to be institutionalized earlier than patients without them. The identification of protective and risk factors for neuropsychiatric symptoms in AD would facilitate the development of more specific treatments for these symptoms and thereby decrease morbidity and mortality in AD. The E4 allele of the apolipoprotein E (APOE) gene is a well-documented risk factor for the development of AD. However, genetic association studies of the APOE 4 allele and BPS in AD have produced conflicting findings. Methods This study investigates the association between APOE and neuropsychiatric symptoms in a large sample of clinically well-characterized subjects with probable AD (n=790) who were systematically evaluated using the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) Behavioral Rating Scale for Dementia (BRSD). Results Our study found that hallucinations were significantly more likely to occur in subjects with no APOΕ4 alleles than in subjects with two Ε4 alleles (15% of subjects and 5% of subjects, respectively; p=.0066), whereas there was no association between the occurrence of delusions, aberrant motor behavior, or agitation and the number of Ε4 alleles. However, 94% of the subjects with hallucinations also had delusions (D+H). Conclusion These findings suggest that in AD the Ε4 allele is differentially associated with D+H but not delusions alone. This is consistent with the hypothesis that distinct psychotic subphenotypes may be associated with the APOE allele.</p

Sexually Transmitted Infection Positivity Among Adolescents With or at High-Risk for Human Immunodeficiency Virus Infection in Los Angeles and New Orleans.

BackgroundGay, bisexual, and transgender youth and homeless youth are at high risk for sexually transmitted infections (STIs). However, little recent data exist describing STI positivity by anatomical site among those groups. We determined the positivity of Chlamydia trachomatis (CT) infection, Neisseria gonorrhoeae (NG) infection, and syphilis antibody reactivity among lesbian, gay, bisexual, transgender, and homeless youth.MethodsWe recruited 1,264 adolescents with high risk behavior aged 12 to 24 years from homeless shelters, lesbian, gay, bisexual, and transgender organizations, community health centers, and using social media and online dating apps in Los Angeles, California and New Orleans, Louisiana from May 2017 to February 2019. Participants received point-of-care pharyngeal, rectal, and urethral/vaginal CT and NG testing and syphilis antibody testing. We calculated STI positivity by anatomical site and compared positivity by participant subgroups based on human immunodeficiency virus (HIV) status, sex assigned at birth, and gender identity.ResultsCT and NG positivity and syphilis antibody reactivity was higher among HIV-infected adolescent men who have sex with men (MSM) than HIV-uninfected adolescent MSM (40.2% vs. 19%, P &lt; 0.05), particularly CT or NG rectal infection (28% vs. 12.3%, P &lt; 0.05). Of participants with positive CT or NG infections, 65% had extragenital-only infections, 20% had both extragenital and urogenital infections, and 15% had urogenital-only infections.ConclusionsSexually transmitted infection positivity was high, particularly among transgender women and MSM. The high proportion of rectal and pharyngeal infections highlights the importance of both urogenital and extragenital STI screening. More accessible STI testing is necessary for high-risk adolescent populations

Sexually Transmitted Infection Positivity Among Adolescents With or at High-Risk for Human Immunodeficiency Virus Infection in Los Angeles and New Orleans.

BackgroundGay, bisexual, and transgender youth and homeless youth are at high risk for sexually transmitted infections (STIs). However, little recent data exist describing STI positivity by anatomical site among those groups. We determined the positivity of Chlamydia trachomatis (CT) infection, Neisseria gonorrhoeae (NG) infection, and syphilis antibody reactivity among lesbian, gay, bisexual, transgender, and homeless youth.MethodsWe recruited 1,264 adolescents with high risk behavior aged 12 to 24 years from homeless shelters, lesbian, gay, bisexual, and transgender organizations, community health centers, and using social media and online dating apps in Los Angeles, California and New Orleans, Louisiana from May 2017 to February 2019. Participants received point-of-care pharyngeal, rectal, and urethral/vaginal CT and NG testing and syphilis antibody testing. We calculated STI positivity by anatomical site and compared positivity by participant subgroups based on human immunodeficiency virus (HIV) status, sex assigned at birth, and gender identity.ResultsCT and NG positivity and syphilis antibody reactivity was higher among HIV-infected adolescent men who have sex with men (MSM) than HIV-uninfected adolescent MSM (40.2% vs. 19%, P &lt; 0.05), particularly CT or NG rectal infection (28% vs. 12.3%, P &lt; 0.05). Of participants with positive CT or NG infections, 65% had extragenital-only infections, 20% had both extragenital and urogenital infections, and 15% had urogenital-only infections.ConclusionsSexually transmitted infection positivity was high, particularly among transgender women and MSM. The high proportion of rectal and pharyngeal infections highlights the importance of both urogenital and extragenital STI screening. More accessible STI testing is necessary for high-risk adolescent populations