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More than 75% of patients presenting to level I trauma centers in the United States with suspicion of TBI sufficient to require a clinical computed tomography scan report injury-related symptoms 3 months later. There are currently no approved treatments, and few clinical trials have evaluated possible treatments. Efficient trials will require subject inclusion and exclusion criteria that balance cost-effective recruitment with enrolling individuals with a higher chance of benefiting from the interventions. Using data from the

Objective: Aberrantly methylated DNA may be used to detect minimal residual disease or early recurrence in breast cancer. As a 1st step, we aimed to develop an MDM panel to delineate between healthy women, stage I-III breast cancer in remission with no evidence of disease (NED), and metastatic breast cancer (MBC). Methods: We prospectively enrolled patients into 3 groups: healthy controls (adult females with a normal mammogram in past 12 months with no history of breast cancer), NED [stage I-III breast cancer with no clinical evidence of recurrence 6 months - 3 years post-treatment (adjuvant endocrine therapy allowed)], and MBC (collected either at initial diagnosis of untreated metastatic disease or radiographic progression). DNA was extracted from 6 mL of plasma derived from blood collected in LBgard tubes (Exact Sciences Corp., San Diego CA), and was bisulfite-treated and assayed by target enrichment long-probe quantitative amplified signal (TELQASTM) method for a panel of 15 previously identified MDMs [Table], normalized by the control gene, B3GALT6. Areas under the receiver operating characteristic curve (AUC) were calculated for each MDM to assess discrimination of MBC from other groups. With 60 patients per group, we had greater than 80% power to detect a difference of 0.20 from the null AUC of 0.7. Results: We tested samples from 60 MBC (10 untreated, 50 recurrent), 60 NED, and 60 healthy women. The median age was 63 (IQR, 55-72) and was not different between groups. The NED group was all hormone-receptor (HR) positive, with 47 (78%) being human epidermal growth factor receptor 2 negative (HER2-) and 13 (22%) HER2+; 48 (80%) were stage I and 9 (15%) were N+. The MBC group had 35 (58%) patients with HR+/HER2- tumors, 11 (18%) HR+/HER2+, and 6 (10%) HR-/HER2-, 4 (7%) HR-/HER2+, with 4 (7%) unknown. Of the 41 MBC whose original stage and nodal status were known 9 (22%) were stage I and 22 (54%) were N+. The markers were able to discriminate between MBC and NED patient samples with AUCs from 0.97 to 0.72. AUCs for 10/15 MDMs (ITPRIPL1, EMX1, C17orf64, OSR2, TRIM67, CHST2, IFFO1, TRH, FAM59B, and MPZ) were >0.90. No difference in MDMs was observed between the healthy and NED groups. Conclusions: MDMs, assayed from plasma, appear highly discriminant for metastatic breast cancer cases in comparison to control patients with NED or healthy controls. Further clinical validation of this MDM panel in a larger cohort is warranted. Table 1. Plasma MDM discrimination of metastatic breast cancer (MBC) from healthy controls and previously treated breast cancer patients with no evidence of disease (NED) Citation Format: Karthik V. Giridhar, Fergus J. Couch, Jason P. Sinnwell, Seth W. Slettedahl, William R. Taylor, Douglas W. Mahoney, Patrick H. Foote, Maria C. O’Connell, Mariah J. Robran, Mary E. Devens, Anna M. Gonser, Nicole Larson, Karen A. Doering, Kelli N. Burger, Michael Kaiser, Hatim Allawi, Kathryn Ruddy, Janet Olson, John B. Kisiel. Plasma assay of methylated DNA markers (MDM) detects patients with metastatic breast cancer (MBC) compared to healthy controls and treated breast cancer patients with no evidence of disease [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-11-06.

Context The mental health crisis in medicine cannot be explained by burnout alone. Physicians are not immune to this crisis and are known to have higher rates of suicide and depression than the general population. A high prevalence of mental health symptoms has been observed in early medical training. Objectives This study was completed to characterize medical students’ mental well-being and provide guidance for timely intervention. Methods An annual prospective, voluntary, anonymous, cross-sectional survey of medical students was completed over a 4-year period in medical school from 2016 to 2019. The survey was created based on standardized psychiatric screening tools assessing symptoms of depression, anxiety, burnout, and sleep problems. In each of those years, 1,257 (2016), 1,254 (2017), 1,221 (2018), and 1,220 (2019) enrolled students, respectively, were invited to participate. Data on students’ mental health were analyzed in relation to their year of school separately for each survey year utilizing SAS 9.4. Results A total of 973 students in 2016, 889 students in 2017, 547 students in 2018, and 606 students in 2019 participated in the study. For depression and burnout subscales, an increase in symptom scores were observed every survey year (2016, 2017, 2018, and 2019) by the second or third year of medical school with a clinically significant effect size. Persistently high levels of anxiety were observed throughout medical school, with significant increases after the first year noted in the 2016 and 2017 surveys, but not in the 2018 or 2019 surveys. Similarly, significant changes in sleep disturbance were found in the 2016 and 2017 surveys, but not in 2018 or 2019. Conclusions Symptoms of burnout, depression, and anxiety were observed throughout all four years of medical school, with increases starting after the first year. Early intervention is needed to support students’ mental health and increase access to care and resources.

In response to climate change, biodiversity patterns in the oceans are predicted to shift rapidly, thus increasing the need for efficient monitoring methods. Environmental DNA (eDNA) metabarcoding recently emerged as a potent and cost-effective candidate to answer this challenge. We targeted three molecular markers to determine multicellular metazoan communities from two timepoints across a long-standing transect in the Southern Hemisphere, the Munida Observational Time Series. We detected four community types across the successive water masses—neritic, sub-tropical, frontal, and sub-Antarctic—crossed by the transect, together with important community differences between the two sampling points. From indicator species analysis, we found diversity patterns were mostly driven by planktonic organisms. Mesopelagic communities differed from surface-water communities in the sub-Antarctic water mass, with at-depth communities dominated by single-cellular organisms. We evaluate the ability of eDNA to detect species-compositional changes across surface and depth gradients and lay the foundations for using this technique in multi-trophic environmental monitoring efforts across long time series. We observed community differences across time and space. More intensive sampling will be critical to fully capture diversity across marine gradients, but this multi-trophic method represents an invaluable opportunity to understand shifts in marine biota.

BackgroundThe coronavirus disease 2019 pandemic led to increased pressure on health services, which, combined with variable social restrictions, led to decreased referrals for head and neck cancer. This study assessed whether there were lasting changes to head and neck cancer referrals during different stages of the pandemic response in 2020 and 2021.MethodsA retrospective review was conducted of all cases referred for suspected head and neck cancer to our institution in January 2020, April 2020, April 2021 and June 2021.ResultsThere was a rebound 91 per cent increase in referrals between April 2020 and April 2021 following the 59 per cent decrease in referrals between January 2020 and April 2020. Males made up 47.1 per cent of referrals in January 2020, 40 per cent in April 2020 and 37.82 per cent in April 2021.ConclusionFurther research is recommended to investigate the reasons why there is a continued decline in male referrals and the effect this has on their outcomes.

OBJECTIVE A carefully selected subset of civilian cranial gunshot wound (CGSW) patients may be treated with simple wound closure (SWC) as a proactive therapy, but the appropriate clinical scenario for using this strategy is unknown. The aim of this study was to compare SWC and surgery patients in terms of their neurological outcomes and complications, including infections, seizures, and reoperations. METHODS This was a single-center, retrospective review of the prospectively maintained institutional traumatic brain injury and trauma registries. Included were adults who sustained an acute CGSW defined as suspected or confirmed dural penetration. Excluded were nonfirearm penetrating injuries, patients with an initial Glasgow Coma Scale (GCS) score of 3, patients with an initial GCS score of 4 and nonreactive pupils, and patients who died within 48 hours of presentation. RESULTS A total of 67 patients were included; 17 (25.4%) were treated with SWC and 50 (74.6%) were treated with surgery. The SWC group had a lower incidence of radiographic mass effect (3/17 [17.6%] SWC vs 31/50 [62%] surgery; absolute difference 44.4, 95% CI −71.9 to 16.8; p = 0.002) and lower incidence of involvement of the frontal sinus (0/17 [0%] SWC vs 14/50 [28%] surgery; absolute difference 28, 95% CI −50.4 to 5.6; p = 0.01). There were no differences in the frequency of Glasgow Outcome Scale–Extended scores ≥ 5 between the SWC and surgery groups at 30 days (4/11 [36.4%] SWC vs 12/35 [34.3%] surgery; OR 1.1, 95% CI 0.3–4.5; p > 0.99), 60 days (2/7 [28.6%] SWC vs 8/26 [30.8%] surgery; OR 0.9, 95% CI 0.3–3.4; p > 0.99), and 90 days (3/8 [37.5%] SWC vs 12/26 [46.2%] surgery; OR 0.7, 95% CI 0.1–3.6; p > 0.99). There were no differences in the incidence of infections (1/17 [5.9%] SWC vs 6/50 [12%] surgery; OR 0.5, 95% CI 0.1–4.1; p = 0.67), CSF fistulas (2/11 [11.6%] SWC vs 3/50 [6%] surgery; OR 2.1, 95% CI 0.3–13.7; p = 0.60), seizures (3/17 [17.6%] SWC vs 9/50 [18%] surgery; OR 1, 95% CI 0.2–4.1; p > 0.99), and reoperations (3/17 [17.6%] SWC vs 4/50 [8%] surgery; OR 2.5, 95% CI 0.5–12.4; p = 0.36) between the SWC and surgery groups. CONCLUSIONS There were important clinically relevant differences between the SWC and surgery groups. SWC can be considered a safe and efficacious proactive therapy in a carefully selected subset of civilian CGSW patients.

The ice shelf–ocean boundary current has an important control on heat delivery to the base of an ice shelf. Climate and regional models that include a representation of ice shelf cavities often use a coarse grid, and results have a strong dependence on resolution near the ice shelf–ocean interface. This study models the ice shelf–ocean boundary current with a nonhydrostatic z-level configuration at turbulence-permitting resolution (1 m). The z-level model performs well when compared against state-of-the-art large-eddy simulations, showing its capability in representing the correct physics. We show that theoretical results from a one-dimensional model with parameterized turbulence reproduce the z-level model results to a good degree, indicating possible utility as a turbulence closure. The one-dimensional model evolves to a state of marginal instability, and we use the z-level model to demonstrate how this is represented in three dimensions. Instabilities emerge that regulate the strength of the pycnocline and coexist with persistent Ekman rolls, which are identified prior to the flow becoming intermittently unstable. When resolution of the z-level model is degraded to understand the gridscale dependencies, the degradation is dominated by the established problem of excessive numerical diffusion. We show that at intermediate resolutions (2–4 m), the boundary layer structure can be partially recovered by tuning diffusivities. Last, we compare replacing prescribed melting with interactive melting that is dependent on the local ocean conditions. Interactive melting results in a feedback such that the system evolves more slowly, which is exaggerated at lower resolution.

During neurovascular development, brain endothelial cells (BECs) respond to secreted signals from the neuroectoderm that regulate CNS angiogenesis, the formation of new blood vessels in the brain, and barriergenesis, the acquisition of blood-brain barrier (BBB) properties. Wnt/β-catenin signaling and Vegf signaling are both required for CNS angiogenesis; however, the relationship between these pathways is not understood. Furthermore, while Wnt/β-catenin signaling is essential for barriergenesis, the role of Vegf signaling in this vital process remains unknown. Here, we provide the first direct evidence, to our knowledge, that Vegf signaling is not required for barriergenesis and that activation of Wnt/β-catenin in BECs is independent of Vegf signaling during neurovascular development. Using double transgenic glut1b:mCherry and plvap:EGFP zebrafish (Danio rerio) to visualize the developing brain vasculature, we performed a forward genetic screen and identified a new mutant allele of kdrl, an ortholog of mammalian Vegfr2. The kdrl mutant lacks CNS angiogenesis but, unlike the Wnt/β-catenin pathway mutant gpr124, acquires BBB properties in BECs. To examine Wnt/β-catenin pathway activation in BECs, we chemically inhibited Vegf signaling and found robust expression of the Wnt/β-catenin transcriptional reporter line 7xtcf-Xla.Siam:EGFP. Taken together, our results establish that Vegf signaling is essential for CNS angiogenesis but is not required for Wnt/β-catenin-dependent barriergenesis. Given the clinical significance of either inhibiting pathological angiogenesis or stimulating neovascularization, our study provides valuable new insights that are critical for the development of effective therapies that target the vasculature in neurological disorders.

Malignant peripheral nerve sheath tumor (MPNST), an aggressive soft-tissue sarcoma, occurs in people with neurofibromatosis type 1 (NF1) and sporadically. Whole-genome and multiregional exome sequencing, transcriptomic, and methylation profiling of 95 tumor samples revealed the order of genomic events in tumor evolution. Following biallelic inactivation of NF1, loss of CDKN2A or TP53 with or without inactivation of polycomb repressive complex 2 (PRC2) leads to extensive somatic copy-number aberrations (SCNA). Distinct pathways of tumor evolution are associated with inactivation of PRC2 genes and H3K27 trimethylation (H3K27me3) status. Tumors with H3K27me3 loss evolve through extensive chromosomal losses followed by whole-genome doubling and chromosome 8 amplification, and show lower levels of immune cell infiltration. Retention of H3K27me3 leads to extensive genomic instability, but an immune cell-rich phenotype. Specific SCNAs detected in both tumor samples and cell-free DNA (cfDNA) act as a surrogate for H3K27me3 loss and immune infiltration, and predict prognosis.Significance:MPNST is the most common cause of death and morbidity for individuals with NF1, a relatively common tumor predisposition syndrome. Our results suggest that somatic copy-number and methylation profiling of tumor or cfDNA could serve as a biomarker for early diagnosis and to stratify patients into prognostic and treatment-related subgroups.This article is highlighted in the In This Issue feature, p. 517

DNA-peptide conjugates offer an opportunity to marry the benefits of both biomolecular classes, combining the high level of programmability found with DNA, with the chemical diversity of peptides. These hybrid systems offer potential in fields such as therapeutics, nanotechnology, and robotics. Using the first DNA-β-turn peptide conjugate, we present three studies investigating the self-assembly of DNA-peptide conjugates over a period of 28 days. Time-course studies, such as these have not been previously conducted for DNA-peptide conjugates, although they are common in pure peptide assembly, for example in amyloid research. By using aging studies to assess the structures produced, we gain insights into the dynamic nature of these systems. The first study explores the influence varying amounts of DNA-peptide conjugates have on the self-assembly of our parent peptide. Study 2 explores how DNA and peptide can work together to change the structures observed during aging. Study 3 investigates the presence of orthogonality within our system by switching the DNA and peptide control on and off independently. These results show that two orthogonal self-assemblies can be combined and operated independently or in tandem within a single macromolecule, with both spatial and temporal effects upon the resultant nanostructures.

International audience; Genomic epidemiology has guided research and policy for various viral pathogens and there has been a parallel effort towards using genomic epidemiology to combat diseases that are caused by eukaryotic pathogens, such as the malaria parasite. However, the central concept of viral genomic epidemiology, namely that of measurably mutating pathogens, does not apply easily to sexually recombining parasites. Here we introduce the related but different concept of measurably recombining malaria parasites to promote convergence around a unifying theoretical framework for malaria genomic epidemiology. Akin to viral phylodynamics, we anticipate that an inferential framework developed around recombination will help guide practical research and thus realize the full public health potential of genomic epidemiology for malaria parasites and other sexually recombining pathogens.

Obesity is a worldwide epidemic and is associated with an increased risk of hypertension, diabetes, and obstructive sleep apnea. Pregnant patients with obesity experience a higher risk of maternal and fetal complications. Anesthesia also poses higher risks for obese parturients and may be more technically challenging due to body habitus. Safe anesthesia practice for these patients must take into consideration the unique challenges associated with the combination of pregnancy and obesity.

In study abroad programs, overall student participation and the representation of minoritized students continue to rise, but barriers to participation for minoritized students persist, especially in engineering. As we strive to broaden participation in engineering study abroad programs, we must critically examine the experiences of minoritized students who engage in these programs so we can facilitate supportive educational environments. This study examines the experiences of minoritized students in a global engineering study abroad program, using the concept of habitus, a student’s collection of identities and embodied cultural capital. We find that students draw on various forms of habitus while studying abroad, connecting their new experiences abroad to their prior experiences. Based on these findings, we make recommendations for designing more equitable and inclusive study abroad programming elements.

Balsam fir (Abies balsamea) is one of the most abundant softwood species in eastern Canada but is projected to be adversely affected by climate change. Balsam fir decline could occur due to a combination of reduced germination and regeneration, lower growth and competitive ability, and higher rates of mortality. However, tree regeneration represents one of the most vulnerable stages to climate-induced stress. In this paper, we synthesize potential and observed effects of climate change on balsam fir regeneration. Recent studies have shown no detrimental effects of increased temperatures on either germination or seedling growth of balsam fir, but clear deleterious effects of decreased water availability. Balsam fir seeds require 28–60 days of cold stratification to become germinable, and such conditions should still be met under climate change across most of the species’ range. Sampling along a north-south climatic gradient throughout the Acadian Forest Region of eastern Canada indicated effects are complex and do not suggest a clear decline under warmer, drier conditions for the species. Thus, effects of global warming on balsam fir may be more gradual than projected in modeling studies and occur primarily via reduced competitive ability and/or higher mortality in overstory trees, rather than regeneration failure.

HDAC inhibitors are an attractive class of cytotoxic agents for the design of hybrid molecules. Several HDAC hybrids have emerged over the years, but none combines HDAC inhibition with ferroptosis, a combination which is being extensively studied because it leads to enhanced cytotoxicity and attenuated neuronal toxicity. We combined the pharmacophores of

Purpose: Succinate dehydrogenase (dSDH)-deficient tumors, including pheochromocytoma/paraganglioma, hereditary leiomyomatosis and renal cell cancer–associated renal cell carcinoma (HLRCC-RCC), and gastrointestinal stromal tumors (GIST) without KIT or platelet-derived growth factor receptor alpha mutations are often resistant to cytotoxic chemotherapy, radiotherapy, and many targeted therapies. We evaluated guadecitabine, a dinucleotide containing the DNA methyltransferase inhibitor decitabine, in these patient populations. Patients and Methods: Phase II study of guadecitabine (subcutaneously, 45 mg/m2/day for 5 consecutive days, planned 28-day cycle) to assess clinical activity (according to RECISTv.1.1) across three strata of patients with dSDH GIST, pheochromocytoma/paraganglioma, or HLRCC-RCC. A Simon optimal two-stage design (target response rate 30% rule out 5%) was used. Biologic correlates (methylation and metabolites) from peripheral blood mononuclear cells (PBMC), serum, and urine were analyzed. Results: Nine patients (7 with dSDH GIST, 1 each with paraganglioma and HLRCC-RCC, 6 females and 3 males, age range 18–57 years) were enrolled. Two patients developed treatment-limiting neutropenia. No partial or complete responses were observed (range 1–17 cycles of therapy). Biologic activity assessed as global demethylation in PBMCs was observed. No clear changes in metabolite concentrations were observed. Conclusions: Guadecitabine was tolerated in patients with dSDH tumors with manageable toxicity. Although 4 of 9 patients had prolonged stable disease, there were no objective responses. Thus, guadecitabine did not meet the target of 30% response rate across dSDH tumors at this dose, although signs of biologic activity were noted.

Primaquine is an important antimalarial drug for malaria transmission blocking and radical cure, but it is not currently available in child-friendly formulations in appropriate doses. Adult-strength tablets are often crushed and dissolved in water to obtain the required dose, which exposes the drug’s bitter taste. As part of the developing paediatric primaquine (DPP) project, this study adopted a responsive sensory pharmaceutics approach by integrating real-time formulation development and pre-clinical taste assessment to develop palatable, flavour-infused primaquine tablets. A design of experiment (DoE) approach was used to screen different taste-masking agents and excipient blends with trained, expert sensory assessors, with quinine hydrochloride as a model bitter tastant. The taste-masking efficacy of selected prototype formulation blends was validated with naïve assessors using the highest 15 mg primaquine dose. The mean bitterness intensity rating, measured on a discrete 11-point scale, was halved from 7.04 for the unflavoured control to 2.74–3.70 for the formulation blends. Sucralose had the biggest impact on bitterness suppression and improving palatability. Two different flavouring systems have been developed, and their acceptability in paediatric patients will be assessed as part of upcoming validation field clinical trials in Africa.

This article provides a course of correction in the discourse surrounding human-centric AI by elucidating the philosophical underpinning that serves to create a view that AI is divorced from human-centric values. Next, we espouse the need to explicitly designate stakeholder- or community-centric values which are needed to resolve the issue of alignment. To achieve this, we present two frameworks, Ubuntu and maximum feasible participation. Finally, we demonstrate how employing the aforementioned frameworks in AI can benefit society by flattening the current top-down social hierarchies as AI is currently being utilized. Implications are discussed.

Experimental knee implant wear testing according to ISO 14243 is a standard procedure, but it inherently possesses limitations for preclinical evaluations due to extended testing periods and costly infrastructure. In an effort to overcome these limitations, we hereby develop and experimentally validate a finite element (FE) based algorithm, including a novel cross-shear and contact pressure dependent wear and creep model, and apply it towards understanding the sensitivity of wear outcomes to the applied boundary conditions.Specifically, we investigated the application of in vivo data for level walking from the publicly available “Stan” dataset, which contains single representative tibiofemoral loads and kinematics derived from in vivo measurements of six subjects, and compared wear outcomes against those obtained using the ISO standard boundary conditions. To provide validation of the numerical models, this comparison was reproduced experimentally on a six-station knee wear simulator over 5 million cycles, testing the same implant Stan’s data was obtained from.Experimental implementation of Stan’s boundary conditions in displacement control resulted in approximately three times higher wear rates (4.4 vs. 1.6 mm3per million cycles) and a more anterior wear pattern compared to the ISO standard in force control. While a force-controlled ISO FE model was unable to reproduce the bench test kinematics, and thus wear rate, displacement-controlled FE models accurately predicted the laboratory wear tests for both ISO and Stan boundary conditions. The credibility of the in silico wear and creep model was further established per the ASME V&V-40 standard. The model is thus suitable for supporting future patient specific models and development of novel implant designs.

Opioids have been used to manage pain for thousands of years, but they have significant potential for abuse. Prescription opioids, like oxycodone, are associated with 32% of overdoses, that have reached a total of 75,673 deaths in 2021. A major challenge is maximizing their therapeutic potential while minimizing the negative side effects including opioid use disorder (OUD). The Ketogenic Diet (KD) has been reported to reduce pain and decrease the severity of alcohol use disorder, yet its effects on oxycodone responses remain unknown. KD mice displayed increased oxycodone-induced locomotor activity and enhanced antinociceptive effects of oxycodone, suggesting a dietary effect on opiate sensitivity. Male KD mice exposed to chronic oxycodone exhibited increased naloxone-induced jumps, suggesting a sex-specific effect of diet on opioid withdrawal. Consistent with this, male KD mice self-administered less oxycodone while female KD mice did not differ from controls. Finally, no effect of KD on motivation to obtain oxycodone was observed during a progressive ratio schedule. These data suggest sex-biased effects of KD on responses to opioids that should be considered and potentially leveraged in both clinical pain management and treatment of OUD.

Metabolic cross-feeding plays vital roles in promoting ecological diversity. While some microbes depend on exchanges of essential nutrients for growth, the forces driving the extensive cross-feeding needed to support the coexistence of free-living microbes are poorly understood. Here we characterize bacterial physiology under self-acidification and establish that extensive excretion of key metabolites following growth arrest provides a collaborative, inter-species mechanism of stress resistance. This collaboration occurs not only between species isolated from the same community, but also between unrelated species with complementary (glycolytic vs. gluconeogenic) modes of metabolism. Cultures of such communities progress through distinct phases of growth-dilution cycles, comprising of exponential growth, acidification-triggered growth arrest, collaborative deacidification, and growth recovery, with each phase involving different combinations of physiological states of individual species. Our findings challenge the steady-state view of ecosystems commonly portrayed in ecological models, offering an alternative dynamical view based on growth advantages of complementary species in different phases., Nature Communications, 14 (1), ISSN:2041-1723

As of August 2022, clusters of acute severe hepatitis of unknown aetiology in children have been reported from 35 countries, including the USA1,2. Previous studies have found human adenoviruses (HAdVs) in the blood from patients in Europe and the USA3-7, although it is unclear whether this virus is causative. Here we used PCR testing, viral enrichment-based sequencing and agnostic metagenomic sequencing to analyse samples from 16 HAdV-positive cases from 1 October 2021 to 22 May 2022, in parallel with 113 controls. In blood from 14 cases, adeno-associated virus type 2 (AAV2) sequences were detected in 93% (13 of 14), compared to 4 (3.5%) of 113 controls (P