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Protecting replication fork integrity during DNA replication is essential for maintaining genome stability. Here, we report that SDE2, a PCNA-associated protein, plays a key role in maintaining active replication and counteracting replication stress by regulating the replication fork protection complex (FPC). SDE2 directly interacts with the FPC component TIMELESS (TIM) and enhances its stability, thereby aiding TIM localization to replication forks and the coordination of replisome progression. Like TIM deficiency, knockdown of SDE2 leads to impaired fork progression and stalled fork recovery, along with a failure to activate CHK1 phosphorylation. Moreover, loss of SDE2 or TIM results in an excessive MRE11-dependent degradation of reversed forks. Together, our study uncovers an essential role for SDE2 in maintaining genomic integrity by stabilizing the FPC and describes a new role for TIM in protecting stalled replication forks. We propose that TIM-mediated fork protection may represent a way to cooperate with BRCA-dependent fork stabilization. The fork protection complex (FPC), including the proteins TIMELESS and TIPIN, stabilizes the replisome to ensure unperturbed fork progression during DNA replication. Here the authors reveal that that SDE2, a PCNA-associated protein, plays an important role in maintaining active replication and protecting stalled forks by regulating the replication fork protection complex (FPC).

•University testing programs provide an opportunity to estimate vaccine effectiveness in community populations of healthy young adults, a population not well-represented in routine vaccine effectiveness studies.•In a university population, a COVID-19 mRNA monovalent booster dose after primary series provided increased protection against symptomatic SARS-CoV-2 infection with the Omicron variant compared to primary series vaccination alone.•Relative vaccine effectiveness was greater for individuals without any known prior SARS-CoV-2 infection versus those with a history of infection. Vaccine effectiveness (VE) studies utilizing the test-negative design are typically conducted in clinical settings, rather than community populations, leading to bias in VE estimates against mild disease and limited information on VE in healthy young adults. In a community-based university population, we utilized data from a large SARS-CoV-2 testing program to estimate relative VE of COVID-19 mRNA vaccine primary series and monovalent booster dose versus primary series only against symptomatic SARS-CoV-2 infection from September 2021 to July 2022. We used the test-negative design and logistic regression implemented via generalized estimating equations adjusted for age, calendar time, prior SARS-CoV-2 infection, and testing frequency (proxy for test-seeking behavior) to estimate relative VE. Analyses included 2,218 test-positive cases (59 % received monovalent booster dose) and 9,615 test-negative controls (62 %) from 9,066 individuals, with median age of 21 years, mostly students (71 %), White (56 %) or Asian (28 %), and with few comorbidities (3 %). More cases (23 %) than controls (6 %) had COVID-19-like illness. Estimated adjusted relative VE of primary series and monovalent booster dose versus primary series only against symptomatic SARS-CoV-2 infection was 40 % (95 % CI: 33–47 %) during the overall analysis period and 46 % (39–52 %) during the period of Omicron circulation. Relative VE was greater for those without versus those with prior SARS-CoV-2 infection (41 %, 34–48 % versus 33 %, 9 %–52 %, P < 0.001). Relative VE was also greater in the six months after receiving a booster dose (41 %, 33–47 %) compared to more than six months (27 %, 8–42 %), but this difference was not statistically significant (P = 0.06). In this relatively young and healthy adult population, an mRNA monovalent booster dose provided increased protection against symptomatic SARS-CoV-2 infection, overall and with the Omicron variant. University testing programs may be utilized for estimating VE in healthy young adults, a population that is not well-represented by routine VE studies.

ATM is an apical kinase that governs cellular responses to DNA replication-associated double strand breaks (DSBs) accumulated by the topoisomerase inhibitor anti-cancer therapy. Here we identify that TIPIN, a major constituent of the fork protection complex in the replisome, plays a key role in coordinating ATM signaling tied to DNA replication stress. We demonstrate that TIPIN amplifies ATM signaling to promote DNA end resection and homology-directed repair. TIPIN itself is phosphorylated by ATM, which is required for the recruitment of MDC1 to stalled forks to promote ATM-dependent NF-κB activation. Inhibition of the NF-κB pathway by MDC1 depletion impairs upregulation of anti-apoptotic regulator c-FLIP, thus potentiating caspase-8 activation and cytotoxicity of topoisomerase inhibition. Together, our study defines TIPIN as a master regulator of ATM-dependent DSB repair and NF-κB signaling. We propose that targeting MDC1, a key effector of ATM-TIPIN signaling, acts as a chemosensitizer that suppresses therapy-induced senescence and augments the effectiveness of genotoxic therapy. Identification and characterization of the DNA damage response and NF-κB signaling coordinated by the replication machinery offers a strategy to target its regulatory axis as a chemosensitizer for the topoisomerase inhibitor cancer therapy.

Abstract Objective Screening for pain in routine care is one of the efforts that the Veterans Health Administration has adopted in its national pain management strategy. We aimed to understand patients’ perspectives and preferences about the experience of being screened for pain in primary care. Design Semistructured interviews captured patient perceptions and preferences of pain screening, assessment, and management. Subjects We completed interviews with 36 patients: 29 males and seven females ranging in age from 28 to 94 years from three geographically distinct VA health care systems. Methods We evaluated transcripts using constant comparison and identified emergent themes. Results Theme 1: Pain screening can “determine the tone of the examination”; Theme 2: Screening can initiate communication about pain; Theme 3: Screening can facilitate patient recall and reflection; Theme 4: Screening for pain may help identify under-reported psychological pain, mental distress, and suicidality; Theme 5: Patient recommendations about how to improve screening for pain. Conclusion Our results indicate that patients perceive meaningful, positive impacts of routine pain screening that as yet have not been considered in the literature. Specifically, screening for pain may help capture mental health concerns that may otherwise not emerge.

Novel variants continue to emerge in the SARS-CoV-2 pandemic. University testing programs may provide timely epidemiologic and genomic surveillance data to inform public health responses. We conducted testing from September 2021 to February 2022 in a university population under vaccination and indoor mask mandates. A total of 3,048 of 24,393 individuals tested positive for SARS-CoV-2 by RT-PCR; whole genome sequencing identified 209 Delta and 1,730 Omicron genomes of the 1,939 total sequenced. Compared to Delta, Omicron had a shorter median serial interval between genetically identical, symptomatic infections within households (2 versus 6 days, P  = 0.021). Omicron also demonstrated a greater peak reproductive number (2.4 versus 1.8), and a 1.07 (95% confidence interval: 0.58, 1.57; P  < 0.0001) higher mean cycle threshold value. Despite near universal vaccination and stringent mitigation measures, Omicron rapidly displaced the Delta variant to become the predominant viral strain and led to a surge in cases in a university population. This study presents results from a SARS-CoV-2 genomic surveillance study at a university campus in which ~2,000 samples were sequenced over five months. The authors document the replacement of Delta with Omicron as the dominant variant, and describe clinical characteristics and transmission dynamics.

Few population-based studies have evaluated the importance of pre-existing respiratory syncytial virus (RSV) antibody on RSV susceptibility among children and adults. We conducted a prospective, community-based cohort study among individuals aged 6 months-50 years in Oregon and Washington State, USA (June 2022-May 2023), with weekly symptom surveys and swab collection regardless of symptoms. Swabs were tested for RSV using RT-qPCR. Enrollment sera were tested for RSV prefusion F IgG binding (all participants) and neutralizing antibodies (pediatric participants). We detected 305 RSV illnesses among 3237 participants from 1188 households. Using proportional hazards regression, higher RSV binding antibody titers were associated with a lower estimated hazard of RSV among pediatric participants (hazard ratio=0.66 per 1-unit difference in log 10 -RSV antibody titer; 95% CI: 0.56, 0.78). In a post-pandemic period, pre-existing RSV antibody titers were associated with a lower risk of RSV illness in children aged 6 months-17 years, which could inform vaccine development for this age group. This study found higher RSV antibody levels were associated with lower RSV risk in children outside the hospital. An earlier rise in incidence and higher incidence rates were observed among children <5 years compared to older children and adults.

Abstract Background We aimed to evaluate a testing program to facilitate control of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission at a large university and measure spread in the university community using viral genome sequencing. Methods Our prospective longitudinal study used remote contactless enrollment, daily mobile symptom and exposure tracking, and self-swab sample collection. Individuals were tested if the participant was exposed to a known SARS-CoV-2-infected person, developed new symptoms, or reported high-risk behavior (such as attending an indoor gathering without masking or social distancing), if a member of a group experiencing an outbreak, or at enrollment. Study participants included students, staff, and faculty at an urban public university during the Autumn quarter of 2020. Results We enrolled 16 476 individuals, performed 29 783 SARS-CoV-2 tests, and detected 236 infections. Seventy-five percent of positive cases reported at least 1 of the following: symptoms (60.8%), exposure (34.7%), or high-risk behaviors (21.5%). Greek community affiliation was the strongest risk factor for testing positive, and molecular epidemiology results suggest that specific large gatherings were responsible for several outbreaks. Conclusions A testing program focused on individuals with symptoms and unvaccinated persons who participate in large campus gatherings may be effective as part of a comprehensive university-wide mitigation strategy to control the spread of SARS-CoV-2.

Correspondence to Dr Chi Mun Natalie Lo; chimunnatalie.lo@nhs.scot The National Institute for Health and Care Excellence and Public Health England (PHE) recommend gastric biopsies for Helicobacter pylori (HP) culture and antimicrobial susceptibility testing (AST) in individuals with HP who have failed second-line eradication therapy, have limited treatment options due to drug hypersensitivities, or live in an area known to have high antimicrobial resistance rates.1 2 Tests that can identify HP in gastric biopsy samples include H&E, Giemsa and Gram stains. In January 2025, the UK Health Security Agency Gastrointestinal Bacterial Unit paused its national HP AST service.3 This pause provides an opportunity to review the clinical utility of gastric biopsies for AST in the management of refractory HP infection. Available: https://assets.publishing.service.gov.uk/media/5d6ceea740f0b607c946aa65/HP_Quick_Reference_Guide_v18.0_August_2019_change_highlighted.pdf 2 Recommendations | gastro-oesophageal reflux disease and dyspepsia in adults: investigation and management.

IntroductionCurrent clinical approach to persistent Helicobacter pylori (HP) infection in National Health Service (NHS) Lothian is to perform endoscopic gastric biopsies for HP culture and sensitivity testing, which is costly and invasive given limited NHS resources. We aimed to audit current practice and assess if our proposed new HP eradication protocol would obviate the need for endoscopy for HP culture.MethodsA retrospective case note review was performed using Unisoft and the Trak electronic patient record in all patients whose gastric biopsy samples were sent for HP culture and sensitivity between 1 January 2023 and 31 December 2023. Descriptive statistics were carried out using R studio. HP culture sensitivities were compared to our proposed new HP eradication protocol.Results51 patients were identified, with median age 50 years (range 15-84). 39 (71%) were female, and 11 (22%) were smokers. 13 (25%) had a reported penicillin allergy. The most common symptom was dyspepsia (42; 82%). The median number of HP eradication courses prior to endoscopy was 3 (IQR 2 – 7). HP was isolated in only 21 patients (41%). Culture was paired with Campylobacter-Like Organism (CLO) test in 24 patients (47%), 50% of which were positive. Culture was paired with histology in 18 patients (35%), of which 56% (n=10) showed positive infection. Of the 30 patients with negative culture, 5 (17%) had positive histology and 6 (20%) had positive CLO results. Following a positive culture result, 18 patients (86%) received a tailored antibiotic regime. All sensitivity profiles would have been covered by our proposed new HP eradication protocol. 12 of the 18 patients (67%) underwent post-treatment HP stool antigen testing to confirm eradication. Of these, only 3 (25%) had been successfully eradicated.ConclusionsGastric biopsies for HP culture were positive in less than half of cases who had an endoscopy. Our proposed new HP eradication protocol would be expected to cover the HP culture sensitivities without the need for endoscopic biopsies. We suggest focusing on patient compliance with HP eradication regimens to ensure successful eradication of HP.

The updated 2023–24 COVID-19 vaccine was available in the United States beginning September 2023. Our objective was to identify reasons for decisions related to vaccination of children in the household. In December 2023, adults in Oregon and Washington were asked whether they or their household children had received the 2023–24 COVID-19 vaccination. Adults with unvaccinated children were asked about intentions to vaccinate and to rank the top three reasons for their decision. Vaccine concordance between adults and household children was assessed. Among 1067 adult participants, 33 % (n = 352) of adults reported at least one unvaccinated household child: 23 % intended to vaccinate and 10 % did not intend to vaccinate. Among 243 adults who intended to vaccinate, 73 % selected “if there is more severe illness in my school or community”, as a primary reason; the highest ranked reason among those not intending to vaccinate was the belief that their child would not become severely ill (66 %). 78 % of adults made the same vaccine decisions for themselves and their children. Participant's perception of their child's individual risk from SARS-CoV-2 infection was the primary consideration impacting vaccine uptake and intent for 2023–24 COVID-19 vaccine.