Screening and Testing for Hepatitis B Virus Infection: CDC Recommendations - United States, 2023.

Chronic hepatitis B virus (HBV) infection can lead to substantial morbidity and mortality. Although treatment is not considered curative, antiviral treatment, monitoring, and liver cancer surveillance can reduce morbidity and mortality. Effective vaccines to prevent hepatitis B are available. This report updates and expands CDC's previously published Recommendations for Identification and Public Health Management of Persons with Chronic Hepatitis B Virus Infection (MMWR Recomm Rep 2008;57[No. RR-8]) regarding screening for HBV infection in the United States. New recommendations include hepatitis B screening using three laboratory tests at least once during a lifetime for adults aged ≥18 years. The report also expands risk-based testing recommendations to include the following populations, activities, exposures, or conditions associated with increased risk for HBV infection: persons incarcerated or formerly incarcerated in a jail, prison, or other detention setting; persons with a history of sexually transmitted infections or multiple sex partners; and persons with a history of hepatitis C virus infection. In addition, to provide increased access to testing, anyone who requests HBV testing should receive it, regardless of disclosure of risk, because many persons might be reluctant to disclose stigmatizing risks.

The landscape of BRCA1 and BRCA2 large rearrangements in an international cohort of over 20 000 ovarian tumors identified using next-generation sequencing.

BACKGROUND: Approximately half of ovarian tumors have defects within the homologous recombination repair pathway. Tumors carrying pathogenic variants (PVs) in BRCA1/BRCA2 are more likely to respond to poly-ADP ribose polymerase (PARP) inhibitor treatment. Large rearrangements (LRs) are a challenging class of variants to identify and characterize in tumor specimens and may therefore be underreported. This study describes the prevalence of pathogenic BRCA1/BRCA2 LRs in ovarian tumors and discusses the importance of their identification using a comprehensive testing strategy. METHODS: Sequencing and LR analyses of BRCA1/BRCA2 were conducted in 20 692 ovarian tumors received between March 18, 2016 and February 14, 2023 for MyChoice CDx testing. MyChoice CDx uses NGS dosage analysis to detect LRs in BRCA1/BRCA2 genes using dense tiling throughout the coding regions and limited flanking regions. RESULTS: Of the 2217 PVs detected, 6.3% (N = 140) were LRs. Overall, 0.67% of tumors analyzed carried a pathogenic LR. The majority of detected LRs were deletions (89.3%), followed by complex LRs (5.7%), duplications (4.3%), and retroelement insertions (0.7%). Notably, 25% of detected LRs encompassed a single or partial single exon. This study identified 84 unique LRs, 2 samples each carried 2 unique LRs in the same gene. We identified 17 LRs that occurred in multiple samples, some of which were specific to certain ancestries. Several cases presented here illustrate the intricacies involved in characterizing LRs, particularly when multiple events occur within the same gene. CONCLUSIONS: Over 6% of PVs detected in the ovarian tumors analyzed were LRs. It is imperative for laboratories to utilize testing methodologies that will accurately detect LRs at a single exon resolution to optimize the identification of patients who may benefit from PARP inhibitor treatment.

Concordance of BRCA mutation detection in tumor versus blood, and frequency of bi-allelic loss of BRCA in tumors from patients in the phase III SOLO2 trial.

OBJECTIVE: Maintenance olaparib provided a progression-free survival benefit in the phase III SOLO2 trial (NCT01874353) in patients with platinum-sensitive relapsed ovarian cancer and a BRCA mutation (BRCAm). However, questions remain regarding tumor versus germline BRCA testing and the impact of heterozygous versus bi-allelic loss of BRCA1 or BRCA2 in the tumor. METHODS: Blood and tumor samples were analyzed. A concordance analysis of germline BRCAm status (BRACAnalysis® CLIA test) and tumor BRCAm status (myChoice® CDx test) was conducted (Myriad Genetic Laboratories, Inc.). Bi-allelic loss of BRCA1 and BRCA2 and a genomic instability score (GIS) (myChoice® CDx test) were also determined. RESULTS: 289 of 295 enrolled patients had a germline BRCAm confirmed centrally and tumor BRCAm status was evaluable in 241 patients. There was 98% and 100% concordance between tumor and germline testing for BRCA1m and BRCA2m, respectively, with discordance found in four cases. Of 210 tumor samples evaluable for BRCA zygosity, 100% of germline BRCA1-mutated tumors (n = 144) and 98% of germline BRCA2-mutated tumors (n = 66) had bi-allelic loss of BRCA. One patient with a heterozygous BRCA2m had a GIS of 53, was progression free for 911 days and remained on olaparib at data cut-off. CONCLUSIONS: Very high concordance was demonstrated between tumor and germline BRCA testing, supporting wider implementation of tumor BRCA testing in ovarian cancer. Near 100% rates of bi-allelic loss of BRCA in platinum-sensitive relapsed ovarian tumors suggest routine testing for BRCA zygosity is not required in this population and reflects BRCA loss being a driver of tumorigenesis.

Outcomes Among Patients Referred to Outpatient Rehabilitation Clinics After COVID-19 diagnosis - United States, January 2020-March 2021.

As of June 30, 2021, 33.5 million persons in the United States had received a diagnosis of COVID-19 (1). Although most patients infected with SARS-CoV-2, the virus that causes COVID-19, recover within a few weeks, some experience post-COVID-19 conditions. These range from new or returning to ongoing health problems that can continue beyond 4 weeks. Persons who were asymptomatic at the time of infection can also experience post-COVID-19 conditions. Data on post-COVID-19 conditions are emerging and information on rehabilitation needs among persons recovering from COVID-19 is limited. Using data acquired during January 2020-March 2021 from Select Medical* outpatient rehabilitation clinics, CDC compared patient-reported measures of health, physical endurance, and health care use between patients who had recovered from COVID-19 (post-COVID-19 patients) and patients needing rehabilitation because of a current or previous diagnosis of a neoplasm (cancer) who had not experienced COVID-19 (control patients). All patients had been referred to outpatient rehabilitation. Compared with control patients, post-COVID-19 patients had higher age- and sex-adjusted odds of reporting worse physical health (adjusted odds ratio [aOR] = 1.8), pain (aOR = 2.3), and difficulty with physical activities (aOR = 1.6). Post-COVID-19 patients also had worse physical endurance, measured by the 6-minute walk test† (6MWT) (p<0.001) compared with control patients. Among patients referred to outpatient rehabilitation, those recovering from COVID-19 had poorer physical health and functional status than those who had cancer, or were recovering from cancer but not COVID-19. Patients recovering from COVID-19 might need additional clinical support, including tailored physical and mental health rehabilitation services.

Long-Term Symptoms Among Adults Tested for SARS-CoV-2 - United States, January 2020-April 2021.

Long-term symptoms often associated with COVID-19 (post-COVID conditions or long COVID) are an emerging public health concern that is not well understood. Prevalence of post-COVID conditions has been reported among persons who have had COVID-19 (range = 5%-80%), with differences possibly related to different study populations, case definitions, and data sources (1). Few studies of post-COVID conditions have comparisons with the general population of adults with negative test results for SARS-CoV-2, the virus that causes COVID-19, limiting ability to assess background symptom prevalence (1). CDC used a nonprobability-based Internet panel established by Porter Novelli Public Services* to administer a survey to a nationwide sample of U.S. adults aged ≥18 years to compare the prevalence of long-term symptoms (those lasting >4 weeks since onset) among persons who self-reported ever receiving a positive SARS-CoV-2 test result with the prevalence of similar symptoms among persons who reported always receiving a negative test result. The weighted prevalence of ever testing positive for SARS-CoV-2 was 22.2% (95% confidence interval [CI] = 20.6%-23.8%). Approximately two thirds of respondents who had received a positive test result experienced long-term symptoms often associated with SARS-CoV-2 infection. Compared with respondents who received a negative test result, those who received a positive test result reported a significantly higher prevalence of any long-term symptom (65.9% versus 42.9%), fatigue (22.5% versus 12.0%), change in sense of smell or taste (17.3% versus 1.7%), shortness of breath (15.5% versus 5.2%), cough (14.5% versus 4.9%), headache (13.8% versus 9.9%), and persistence (>4 weeks) of at least one initially occurring symptom (76.2% versus 69.6%). Compared with respondents who received a negative test result, a larger proportion of those who received a positive test result reported believing that receiving a COVID-19 vaccine made their long-term symptoms better (28.7% versus 15.7%). Efforts to address post-COVID conditions should include helping health care professionals recognize the most common post-COVID conditions and optimize care for patients with persisting symptoms, including messaging on potential benefits of COVID-19 vaccination.

Combining DNA damaging therapeutics with immunotherapy: more haste, less speed.

The idea that chemotherapy can be used in combination with immunotherapy may seem somewhat counterproductive, as it can theoretically eliminate the immune cells needed for antitumour immunity. However, much preclinical work has now demonstrated that in addition to direct cytotoxic effects on cancer cells, a proportion of DNA damaging agents may actually promote immunogenic cell death, alter the inflammatory milieu of the tumour microenvironment and/or stimulate neoantigen production, thereby activating an antitumour immune response. Some notable combinations have now moved forward into the clinic, showing promise in phase I-III trials, whereas others have proven toxic, and challenging to deliver. In this review, we discuss the emerging data of how DNA damaging agents can enhance the immunogenic properties of malignant cells, focussing especially on immunogenic cell death, and the expansion of neoantigen repertoires. We discuss how best to strategically combine DNA damaging therapeutics with immunotherapy, and the challenges of successfully delivering these combination regimens to patients. With an overwhelming number of chemotherapy/immunotherapy combination trials in process, clear hypothesis-driven trials are needed to refine the choice of combinations, and determine the timing and sequencing of agents in order to stimulate antitumour immunological memory and improve maintained durable response rates, with minimal toxicity.

Trends in Clinical Severity of Hospitalized Patients With Coronavirus Disease 2019-Premier Hospital Dataset, April 2020-April 2021.

BACKGROUND: Clinical severity of coronavirus disease 2019 (COVID-19) may vary over time; trends in clinical severity at admission during the pandemic among hospitalized patients in the United States have been incompletely described, so a historical record of severity over time is lacking. METHODS: We classified 466677 hospital admissions for COVID-19 from April 2020 to April 2021 into 4 mutually exclusive severity grades based on indicators present on admission (from most to least severe): Grade 4 included intensive care unit (ICU) admission and invasive mechanical ventilation (IMV); grade 3 included non-IMV ICU and/or noninvasive positive pressure ventilation; grade 2 included diagnosis of acute respiratory failure; and grade 1 included none of the above indicators. Trends were stratified by sex, age, race/ethnicity, and comorbid conditions. We also examined severity in states with high vs low Alpha (B.1.1.7) variant burden. RESULTS: Severity tended to be lower among women, younger adults, and those with fewer comorbidities compared to their counterparts. The proportion of admissions classified as grade 1 or 2 fluctuated over time, but these less-severe grades comprised a majority (75%-85%) of admissions every month. Grades 3 and 4 consistently made up a minority of admissions (15%-25%), and grade 4 showed consistent decreases in all subgroups, including states with high Alpha variant burden. CONCLUSIONS: Clinical severity among hospitalized patients with COVID-19 has varied over time but has not consistently or markedly worsened over time. The proportion of admissions classified as grade 4 decreased in all subgroups. There was no consistent evidence of worsening severity in states with higher vs lower Alpha prevalence.

First-in-Human Study of AT13148, a Dual ROCK-AKT Inhibitor in Patients with Solid Tumors.

PURPOSE: AT13148 is an oral AGC kinase inhibitor, which potently inhibits ROCK and AKT kinases. In preclinical models, AT13148 has been shown to have antimetastatic and antiproliferative activity. PATIENTS AND METHODS: The trial followed a rolling six design during dose escalation. An intrapatient dose escalation arm to evaluate tolerability and a biopsy cohort to study pharmacodynamic effects were later added. AT13148 was administered orally three days a week (Mon-Wed-Fri) in 28-day cycles. Pharmacokinetic profiles were assessed using mass spectrometry and pharmacodynamic studies included quantifying p-GSK3ß levels in platelet-rich plasma (PRP) and p-cofilin and p-MLC2 levels in tumor biopsies. RESULTS: Fifty-one patients were treated on study. The safety of 5-300 mg of AT13148 was studied. Further, the doses of 120-180-240 mg were studied in an intrapatient dose escalation cohort. The dose-limiting toxicities included hypotension (300 mg), pneumonitis, and elevated liver enzymes (240 mg), and skin rash (180 mg). The most common side effects were fatigue, nausea, headaches, and hypotension. On the basis of tolerability, 180 mg was considered the maximally tolerated dose. At 180 mg, mean C max and AUC were 400 nmol/L and 13,000 nmol/L/hour, respectively. At 180 mg, ≥50% reduction of p-cofilin was observed in 3 of 8 posttreatment biopsies. CONCLUSIONS: AT13148 was the first dual potent ROCK-AKT inhibitor to be investigated for the treatment of solid tumors. The narrow therapeutic index and the pharmacokinetic profile led to recommend not developing this compound further. There are significant lessons learned in designing and testing agents that simultaneously inhibit multiple kinases including AGC kinases in cancer.

Phase I Trial of First-in-Class ATR Inhibitor M6620 (VX-970) as Monotherapy or in Combination With Carboplatin in Patients With Advanced Solid Tumors.

PURPOSE: Preclinical studies demonstrated that ATR inhibition can exploit synthetic lethality (eg, in cancer cells with impaired compensatory DNA damage responses through ATM loss) as monotherapy and combined with DNA-damaging drugs such as carboplatin. PATIENTS AND METHODS: This phase I trial assessed the ATR inhibitor M6620 (VX-970) as monotherapy (once or twice weekly) and combined with carboplatin (carboplatin on day 1 and M6620 on days 2 and 9 in 21-day cycles). Primary objectives were safety, tolerability, and maximum tolerated dose; secondary objectives included pharmacokinetics and antitumor activity; exploratory objectives included pharmacodynamics in timed paired tumor biopsies. RESULTS: Forty patients were enrolled; 17 received M6620 monotherapy, which was safe and well tolerated. The recommended phase II dose (RP2D) for once- or twice-weekly administration was 240 mg/m2. A patient with metastatic colorectal cancer harboring molecular aberrations, including ATM loss and an ARID1A mutation, achieved RECISTv1.1 complete response and maintained this response, with a progression-free survival of 29 months at last assessment. Twenty-three patients received M6620 with carboplatin, with mechanism-based hematologic toxicities at higher doses, requiring dose delays and reductions. The RP2D for combination therapy was M6620 90 mg/m2 with carboplatin AUC5. A patient with advanced germline BRCA1 ovarian cancer achieved RECISTv1.1 partial response and Gynecologic Cancer Intergroup CA125 response despite being platinum refractory and PARP inhibitor resistant. An additional 15 patients had RECISTv1.1 stable disease as best response. Pharmacokinetics were dose proportional and exceeded preclinical efficacious levels. Pharmacodynamic studies demonstrated substantial inhibition of phosphorylation of CHK1, the downstream ATR substrate. CONCLUSION: To our knowledge, this report is the first of an ATR inhibitor as monotherapy and combined with carboplatin. M6620 was well tolerated, with target engagement and preliminary antitumor responses observed.

Upward spirals of positive emotion and coping: Replication, extension, and initial exploration of neurochemical substrates.

The broaden-and-build theory (Fredrickson, 1998, 2001) predicts that positive emotions broaden the scopes of attention and cognition, thereby facilitating the building of personal resources and initiating upward spirals toward increasing emotional well-being. This study attempts to replicate and extend previous empirical support for this model. Using a sample of 185 undergraduates, we assessed whether positive affect and broad-minded coping, interpersonal trust, and social support reciprocally and prospectively predict one another over a two-month period, and whether this upward spiral might be partially based in changes in dopaminergic functioning. As hypothesized, PA and positive coping did mutually build on one another, as did PA and interpersonal trust. Contrary to expectation, PA did not demonstrate an upward spiral relation with social support. Results suggest further study of the relationship between PA and changes in dopamine metabolite levels over time is warranted.

Examination of racial differences on the MMPI-2 clinical and restructured clinical scales in an outpatient sample.

The current study examined the possibility of differential predictive accuracy of selected Minnesota Multiphasic Personality Inventory-Second Edition (MMPI-2) clinical and Restructured Clinical (RC) scales in a group of Black and White mental health center clients. Results indicate that Black clients scored higher than White clients on one non-K-corrected clinical scale and 4 RC scales. All these differences produced medium effect sizes and were clinically significant according to Greene's (1987) criterion. These differences, however, were not accompanied by differential predictive accuracy of the scales in Black versus White clients. Although additional research is needed, especially on the RC scales, this study indicates that the MMPI-2 is not a biased predictor of symptomatology for Black versus White test takers.

Childhood physical and sexual abuse and lifetime number of suicide attempts: a persistent and theoretically important relationship.

BACKGROUND: Research to date has indicated that childhood abuse is associated with suicide, though little research has examined the unique contribution of specific types of abuse to suicidal behavior. We predict that childhood physical and violent sexual abuse will have a greater effect on suicide attempts than molestation and verbal abuse. METHODS: The National Comorbidity Survey data were used to test these predictions while controlling for a number of psychiatric and psychosocial variables. RESULTS: As expected, childhood physical and violent sexual abuse showed similar effects on lifetime suicide attempts, which were stronger than the effects of molestation and verbal abuse. LIMITATIONS: This was a cross-sectional, retrospective study, so true causality cannot be shown. Some measurement limitations exist. Additionally, effect sizes were small but still significant. CONCLUSIONS: While all forms of childhood abuse are troubling and create risk for future psychopathology and suicidality, the present study indicates that childhood physical and violent sexual abuse should be seen as greater risk factors for future suicide attempts than molestation and verbal abuse.

Maximising the potential of AKT inhibitors as anti-cancer treatments.

PI3K/AKT signalling is commonly disrupted in human cancers, with AKT being a central component of the pathway, influencing multiple processes that are directly involved in tumourigenesis. Targeting AKT is therefore a highly attractive anti-cancer strategy with multiple AKT inhibitors now in various stages of clinical development. In this review, we summarise the role and regulation of AKT signalling in normal cellular physiology. We highlight the mechanisms by which AKT signalling can be hyperactivated in cancers and discuss the past, present and future clinical strategies for AKT inhibition in oncology.

Targeting DNA Repair in Cancer: Beyond PARP Inhibitors.

Germline aberrations in critical DNA-repair and DNA damage-response (DDR) genes cause cancer predisposition, whereas various tumors harbor somatic mutations causing defective DDR/DNA repair. The concept of synthetic lethality can be exploited in such malignancies, as exemplified by approval of poly(ADP-ribose) polymerase inhibitors for treating BRCA1/2-mutated ovarian cancers. Herein, we detail how cellular DDR processes engage various proteins that sense DNA damage, initiate signaling pathways to promote cell-cycle checkpoint activation, trigger apoptosis, and coordinate DNA repair. We focus on novel therapeutic strategies targeting promising DDR targets and discuss challenges of patient selection and the development of rational drug combinations. SIGNIFICANCE: Various inhibitors of DDR components are in preclinical and clinical development. A thorough understanding of DDR pathway complexities must now be combined with strategies and lessons learned from the successful registration of PARP inhibitors in order to fully exploit the potential of DDR inhibitors and to ensure their long-term clinical success. Cancer Discov; 7(1); 20-37. ©2016 AACR.

Differentiation of obsessive-compulsive-, panic-, obsessive-compulsive personality-, and non-disordered individuals by variation in the promoter region of the serotonin transporter gene.

Past research investigating the role of the serotonin transporter gene in OCD has produced mixed findings. One possible reason for the mixed findings is comorbidity. In this study, non-comorbid OCD individuals were compared to non-disordered controls. A sample of panic disordered individuals was also compared to a non-disordered group. Finally, as an exploratory analysis, individuals were assessed for OCPD and their allelic frequencies were also compared to non-disordered individuals. Analyses revealed that there were higher frequencies of the s/s genotype among the OCD group when compared to non-disordered controls. There were no differences in allelic frequencies on the serotonin transporter gene between the panic disordered group, the OCPD group, and the non-disordered control group. This study found that non-comorbid OCD individuals tended to have a higher percentage of the homozygous short genotype than non-disordered individuals. The s/s genotype might serve as a contributory risk factor for OCD.

Ubiquitylation, neddylation and the DNA damage response.

Failure of accurate DNA damage sensing and repair mechanisms manifests as a variety of human diseases, including neurodegenerative disorders, immunodeficiency, infertility and cancer. The accuracy and efficiency of DNA damage detection and repair, collectively termed the DNA damage response (DDR), requires the recruitment and subsequent post-translational modification (PTM) of a complex network of proteins. Ubiquitin and the ubiquitin-like protein (UBL) SUMO have established roles in regulating the cellular response to DNA double-strand breaks (DSBs). A role for other UBLs, such as NEDD8, is also now emerging. This article provides an overview of the DDR, discusses our current understanding of the process and function of PTM by ubiquitin and NEDD8, and reviews the literature surrounding the role of ubiquitylation and neddylation in DNA repair processes, focusing particularly on DNA DSB repair.

Neddylation promotes ubiquitylation and release of Ku from DNA-damage sites.

The activities of many DNA-repair proteins are controlled through reversible covalent modification by ubiquitin and ubiquitin-like molecules. Nonhomologous end-joining (NHEJ) is the predominant DNA double-strand break (DSB) repair pathway in mammalian cells and is initiated by DSB ends being recognized by the Ku70/Ku80 (Ku) heterodimer. By using MLN4924, an anti-cancer drug in clinical trials that specifically inhibits conjugation of the ubiquitin-like protein, NEDD8, to target proteins, we demonstrate that NEDD8 accumulation at DNA-damage sites is a highly dynamic process. In addition, we show that depleting cells of the NEDD8 E2-conjugating enzyme, UBE2M, yields ionizing radiation hypersensitivity and reduced cell survival following NHEJ. Finally, we demonstrate that neddylation promotes Ku ubiquitylation after DNA damage and release of Ku and Ku-associated proteins from damage sites following repair. These studies provide insights into how the NHEJ core complex dissociates from repair sites and highlight its importance for cell survival following DSB induction.

Is there an association between serotonin transporter gene polymorphism and family history of depression?

BACKGROUND: To date, research examining the relationship between the serotonin transporter gene and depression has yielded both positive and negative results. This study will attempt to add further evidence to that body of literature by examining the relationship between the serotonin transporter gene and a family history of depression while controlling for a family history of completed suicide. METHODS: Forty-seven volunteers responded to questionnaires regarding family history of depression and suicide, and provided buccal swabs to allow for analysis of the 5-HTTLPR polymorphism. RESULTS: Individuals with the s/s genotype were significantly more likely to have two or more first-degree relatives with a history of depression even when controlling for a family history of completed suicides. LIMITATIONS: The small sample size, particularly in the group of individuals with the s/s genotype, is a limitation of this study. Assessment of family history was conducted in abbreviated fashion. Information regarding participants' personal history of depression and suicide was not collected, so no conclusions regarding participants' own mental health can be drawn. CONCLUSIONS: A significant relationship between family history of depression and the s/s genotype was found, despite the small sample size and while controlling for family history of suicide. Whatever risk short alleles may confer for depression may be distinct from the risk they confer for suicidality.

A test of the tripartite model's prediction of anhedonia's specificity to depression: patients with major depression versus patients with schizophrenia.

The tripartite model of depression and anxiety suggests that anhedonia represents a relatively specific marker of depression. A strong version of this view is that anhedonic symptoms would particularly characterize depressed patients, even when compared to another diagnostic group-schizophrenic patients-for whom anhedonic symptoms represent a well-studied feature. This prediction was tested among 102 VA psychiatric inpatients (95 men), ages 21-72 (M=43.56; S.D.=8.47), all of whom received diagnoses of either major depression (n=50) or schizophrenia (n=52) based on structured diagnostic interviews. As predicted, patients with major depression scored significantly higher on the anhedonic symptoms scale of the Beck Depression Inventory (BDI) than did patients with schizophrenia. However, there was no difference between the two groups on the BDI total score or the BDI non-anhedonic symptoms score. Consistent with the tripartite model, anhedonic symptoms were more related to depressive vs. schizophrenic diagnostic status, whereas non-anhedonic depressive symptoms were not. Within the study's limitations, results were interpreted as relatively strong support for the validity and extension of the tripartite model.