Follow-up to Adolescence after Early Peanut Introduction for Allergy Prevention.

BACKGROUND: A randomized trial demonstrated consumption of peanut from infancy to age 5 years prevented the development of peanut allergy. An extension of that trial demonstrated the effect persisted after 1 year of peanut avoidance. This follow-up trial examined the durability of peanut tolerance at age 144 months after years of ad libitum peanut consumption. METHODS: Participants from a randomized peanut consumption trial were assessed for peanut allergy following an extended period of eating or avoiding peanuts as desired. The primary end point was the rate of peanut allergy at age 144 months. RESULTS: We enrolled 508 of the original 640 participants (79.4%); 497 had complete primary end point data. At age 144 months, peanut allergy remained significantly more prevalent in participants in the original peanut avoidance group than in the original peanut consumption group (15.4% [38 of 246 participants] vs. 4.4% [11 of 251 participants]; P<0.001). Participants in both groups reported avoiding peanuts for prolonged periods of time between 72 and 144 months. Participants at 144 months in the peanut consumption group had levels of Ara h2-specific immunoglobulin E (a peanut allergen associated with anaphylaxis) of 0.03 ± 3.42 kU/l and levels of peanut-specific immunoglobulin G4 of 535.5 ± 4.98 µg/l, whereas participants in the peanut avoidance group had levels of Ara h2-specific immunoglobulin E of 0.06 ± 11.21 kU/l and levels of peanut-specific immunoglobulin G4 of 209.3 ± 3.84 µg/l. Adverse events were uncommon, and the majority were related to the food challenge. CONCLUSIONS: Peanut consumption, starting in infancy and continuing to age 5 years, provided lasting tolerance to peanut into adolescence irrespective of subsequent peanut consumption, demonstrating that long-term prevention and tolerance can be achieved in food allergy. (Funded by the National Institute of Allergy and Infectious Diseases and others; ITN070AD, ClinicalTrials.gov number, NCT03546413.).

Relationships between lung function, allergy, and wheezing in urban children.

BACKGROUND: Allergic sensitization and low lung function in early childhood are risk factors for subsequent wheezing and asthma. However, it is unclear how allergic sensitization affects lung function over time. OBJECTIVE: We sought to test whether allergy influences lung function and whether these factors synergistically increase the risk of continued wheezing in childhood. METHODS: We analyzed longitudinal measurements of lung function (spirometry and impulse oscillometry) and allergic sensitization (aeroallergen skin tests and serum allergen-specific IgE) throughout early childhood in the Urban Environmental and Childhood Asthma study, which included high-risk urban children living in disadvantaged neighborhoods. Intraclass correlation coefficients were calculated to assess lung function stability. Cluster analysis identified low, medium, and high allergy trajectories, which were compared with lung function and wheezing episodes in linear regression models. A variable selection model assessed predictors at age 5 years for continued wheezing through age 12 years. RESULTS: Lung function adjusted for growth was stable (intraclass correlation coefficient, 0.5-0.7) from age 5 to 12 years and unrelated to allergy trajectory. Lung function and allergic sensitization were associated with wheezing episodes in an additive fashion. In children with asthma, measuring lung function at age 5 years added little to the medical history for predicting future wheezing episodes through age 12 years. CONCLUSIONS: In high-risk urban children, age-related trajectories of allergic sensitization were not associated with lung function development; however, both indicators were related to continued wheezing. These results underscore the importance of understanding early-life factors that negatively affect lung development and suggest that treating allergic sensitization may not alter lung function development in early to mid-childhood.

Top journals publishing articles related to drowning prevention: a bibliometric analysis 2000-2022.

BACKGROUND: Drowning is a worldwide problem. Scholarly publications about drowning prevention play a crucial role in bringing data to policy makers and prevention specialists. This study presents a bibliometric analysis of published articles related to unintentional drowning prevention included in the comprehensive, curated injury literature database, SafetyLit®. METHODS: Thorough searches of drowning-related search terms in English and non- English translations identified articles published in journals between 2000 and 2022. RESULTS: There was a 3-fold increase in publications between 2000 and 2022, with 2,937 articles published in 941 journals. Articles were published in 20 different languages. Five journals published 16% of the articles and sixty-one top journals published 50% of the articles. Eighty-nine percent of the top journals were included in PubMed; 82% were indexed in MEDLINE®; and professional areas of expertise of article authors spanned 18 categories. CONCLUSIONS: This study can facilitate journal selection for drowning researchers to ultimately increase the publication of scientific literature globally.

Caregiver water safety knowledge and views of toddler water competency.

BACKGROUND: Drowning is the leading cause of death for toddlers. When caregivers are knowledgeable about water safety, they can provide the best protection against drowning. The aim of this study is to survey caregivers of toddlers to better understand factors associated with water safety knowledge, attitudes about pool supervision, and toddler water competency skills. METHODS: An online survey of 650 parents/caregivers of 1-4-year-old toddlers asked about the caregiver's water safety and swimming background and views on pool supervision. Surveys included a true/false section of ten basic water safety knowledge questions. Caregivers also reported on toddler swim lesson history and whether their toddler could perform six standard water competency skills. Linear regression identified factors predictive of water safety knowledge. RESULTS: On average, caregivers selected the correct answer on six out of ten water safety knowledge questions. Water safety knowledge was predicted by the relationship of the caregiver to the toddler, gender, race, education, prior CPR training, caregiver swim capability, and reported pool supervision style. On average, caregivers reported that their toddler could perform half of the water competency skills. The majority of the toddlers had taken swimming lessons. One third of caregivers believed that after a toddler has had swimming lessons, they don't need to be watched as closely when they are in a pool. CONCLUSIONS: Findings suggest that water safety knowledge is poor and that there are misconceptions about toddler supervision needs. Efforts are needed to improve water safety knowledge and to change perceptions about supervision among caregivers of toddlers.

Drowning is fast, silent, and preventable: a Texas example of research in action.

Drowning is a major public health issue internationally. In August 2022, a report was released by members of the Central Texas Drowning Prevention Action Team that provided data on drowning fatalities in Texas between 2006 and 2020 and offered recommendations for drowning prevention actions. The information in the Texas drowning report is an important contribution to the field of injury prevention. The aim of this editorial is to allow the information in the report to be available to a wider audience and potentially used as a model for other states.

Acquired predator recognition via epidermal alarm cues but not dietary alarm cues by isolated pupfish.

We tested whether Shoshone pupfish Cyprinodon nevadensis shoshone and Amargosa River pupfish C. n. amargosae respond behaviourally to conspecific chemical alarm cues released when epidermal tissue is damaged by a predator. We found that both subspecies reduced activity and vertical position in the water column in response to alarm cues. We then tested if pupfish can use alarm cue to acquire recognition of a novel predator. We trained pupfish with (1) water + odour of largemouth bass fed a diet of earthworms, (2) alarm cues from skin extract (epidermal alarm cues) + odour of bass fed a diet of earthworms, or (3) water + odour of bass fed a diet of pupfish (dietary alarm cues). Pupfish responded to epidermal alarm cues but not to dietary alarm cues. Pupfish were retested with the odour of bass that were fed an earthworm diet. Pupfish that had previously received epidermal alarm cues reduced vertical position and activity relative to the other two treatments. This is the first demonstration of acquired recognition of a novel predator by a pupfish, the first report of partial predator naiveté, and opens the possibility of predator-recognition training as a tool for management and conservation of endangered desert fishes.

Altered coordination strategies during upright stance and gait in teachers of the Alexander Technique.

Deterioration in movement and posture often occurs with aging. Yet there may be approaches to movement training that can maintain posture and movement coordination patterns as we age. The Alexander Technique is a non-exercise-based approach that aims to improve everyday movement and posture by increasing awareness and modulating whole-body postural muscle activity. This study assessed whether nineteen 55-72-year-old Alexander Technique teachers showed different posture and movement coordination patterns than twenty age-matched controls during a standing and walking protocol using 3D inertial sensors. During upright stance, Alexander Technique teachers showed lower centroidal sway frequency at the ankle (p = .04) and lower normalized jerk at the sternum (p = .05) than controls. During gait, Alexander Technique teachers had more symmetrical gait cycles (p = .04), more symmetrical arm swing velocity (p = .01), greater arm swing velocity (p < .01), greater arm swing range of motion (p = .02), and lower range of acceleration of the torso in the frontal plane (p = .03) than controls. Smoother control of upright posture, more stable torso motion, and less restrained arm mobility suggest that Alexander Technique training may counter movement degradation that is found with aging. Results highlight the important balance between mobility and stability within the torso and limbs.

Impact of caregiver swimming capability on perceptions of swimming pool supervision of toddlers.

BACKGROUND: Drowning is a leading cause of unintentional injury-related death for toddlers within the USA. Keeping toddlers within arm's reach while swimming is recommended, yet many caregivers do not. Possibly, caregivers' attitudes are shaped by their expectations about whether they could quickly save a child. The aims of this study are to 1) explore caregivers' views of arm's reach pool supervision in various scenarios and 2) understand whether perceptions of arm's reach pool supervision are impacted by the caregiver's self-reported capability to swim the length of a standard pool. RESULTS: Caregivers generally showed agreement with arm's reach pool supervision; however, arm's reach supervision was viewed as less necessary when a toddler was in shallow water, wearing a flotation device, or with an older child or teen. There was a significant effect of caregiver swimming capability on perceptions of arm's reach pool supervision, with non-swimmers and the strongest swimmers showing more positive perceptions of arm's reach pool supervision than caregivers reporting poor swimming capability. Female caregivers showed significantly more agreement with arm's reach pool supervision compared with male caregivers. Grandparents and parents showed significantly more agreement with arm's reach pool supervision than siblings. CONCLUSIONS: Caregivers' views about what constitutes appropriate supervision are impacted by gender, the relationship to the toddler, and the caregiver's swimming capability. Findings suggest that a caregiver's ability to offer close supervision or respond in an emergency may influence their attitudes about what constitutes appropriate supervision. Caregivers may view arm's reach pool supervision as less necessary when additional layers of protection are in place.

Quantitative single-cell transcriptome-based ranking of engineered AAVs in human retinal explants.

Gene therapy is a rapidly developing field, and adeno-associated viruses (AAVs) are a leading viral-vector candidate for therapeutic gene delivery. Newly engineered AAVs with improved abilities are now entering the clinic. It has proven challenging, however, to predict the translational potential of gene therapies developed in animal models due to cross-species differences. Human retinal explants are the only available model of fully developed human retinal tissue and are thus important for the validation of candidate AAV vectors. In this study, we evaluated 18 wild-type and engineered AAV capsids in human retinal explants using a recently developed single-cell RNA sequencing (RNA-seq) AAV engineering pipeline (scAAVengr). Human retinal explants retained the same major cell types as fresh retina, with similar expression of cell-specific markers except for a photoreceptor population with altered expression of photoreceptor-specific genes. The efficiency and tropism of AAVs in human explants were quantified with single-cell resolution. The top-performing serotypes, K91, K912, and 7m8, were further validated in non-human primate and human retinal explants. Together, this study provides detailed information about the transcriptome profiles of retinal explants and quantifies the infectivity of leading AAV serotypes in human retina, accelerating the translation of retinal gene therapies to the clinic.

Somatic whole genome dynamics of precancer in Barrett's esophagus reveals features associated with disease progression.

While the genomes of normal tissues undergo dynamic changes over time, little is understood about the temporal-spatial dynamics of genomes in premalignant tissues that progress to cancer compared to those that remain cancer-free. Here we use whole genome sequencing to contrast genomic alterations in 427 longitudinal samples from 40 patients with stable Barrett's esophagus compared to 40 Barrett's patients who progressed to esophageal adenocarcinoma (ESAD). We show the same somatic mutational processes are active in Barrett's tissue regardless of outcome, with high levels of mutation, ESAD gene and focal chromosomal alterations, and similar mutational signatures. The critical distinction between stable Barrett's versus those who progress to cancer is acquisition and expansion of TP53-/- cell populations having complex structural variants and high-level amplifications, which are detectable up to six years prior to a cancer diagnosis. These findings reveal the timing of common somatic genome dynamics in stable Barrett's esophagus and define key genomic features specific to progression to esophageal adenocarcinoma, both of which are critical for cancer prevention and early detection strategies.

Transesophageal Echocardiography Performed by Intensivist and Emergency Physicians-A 5-Year, Single-Center Experience.

Purpose: Data on the use of transesophageal echocardiography (TEE) by intensivist physicians (IP) and emergency physicians (EP) are limited. This study aims to characterize the use of TEE by IPs and EPs in critically ill patients at a single center in the United States. Materials and Methods: Retrospective chart review of all critical care TEEs performed from January 1, 2016 to January 31, 2021. The personnel performing the exams, location of the exams, characteristics of exams, complications, and outcome of the patients were reviewed. Results: A total of 396 examinations was reviewed. TEE was performed by IPs (92%) and EPs (9%). The location of TEE included: intensive care unit (87%), emergency department (11%), and prehospital (2%) settings. The most common indications for TEE were: hemodynamic instability/shock (44%), cardiac arrest (23%), and extracorporeal membrane oxygenation (ECMO) facilitation, adjustment, or weaning (21%). The most common diagnosis based on TEE were: normal TEE (25%), left ventricular dysfunction (19%), and vasodilatory shock (15%). A management change resulted from 89% of exams performed. Complications occurred in 2% of critical care TEEs. Conclusion: TEE can be successfully performed by IPs and EPs on critically ill patients in multiple clinical settings. TEE frequently informed management changes with few complications.

Evaluation of the WAVE Drowning Detection SystemTM for use with children's summer camp groups in swimming pools: A prospective observational study.

Background: Groups of children swimming during summer camp or child care are generally monitored by a small number of lifeguards and staff. The high child-to-staff ratio can make pool monitoring less effective, increasing drowning risk. The aim of this study is to evaluate novel drowning detection technology that could supplement pool monitoring. Methods: The WAVE™ Drowning Detection System was deployed at a camp pool for 8 weeks. The WAVE™ Drowning Detection System entails headbands worn by swimmers that send alerts to vibrating staff bracelets and audible alarms when submerged for a period of time. Data on the number of alerts were collected, and staff were surveyed. Results: One or two alerts were initiated every hour. Staff reported that risky underwater play and exiting the pool area were top reasons for alerts. Staff found the awareness brought to risky pool behavior useful and had a neutral attitude about false alarms. Staff found the system easy to learn and use but suggested headband fit and comfort could be improved. Staff believed the system could help save someone's life. Conclusions: The WAVE system is low-risk, easy-to-use technology that may supplement lifeguard monitoring of large groups of children in pools.

scAAVengr, a transcriptome-based pipeline for quantitative ranking of engineered AAVs with single-cell resolution.

Background: Adeno-associated virus (AAV)-mediated gene therapies are rapidly advancing to the clinic, and AAV engineering has resulted in vectors with increased ability to deliver therapeutic genes. Although the choice of vector is critical, quantitative comparison of AAVs, especially in large animals, remains challenging. Methods: Here, we developed an efficient single-cell AAV engineering pipeline (scAAVengr) to simultaneously quantify and rank efficiency of competing AAV vectors across all cell types in the same animal. Results: To demonstrate proof-of-concept for the scAAVengr workflow, we quantified - with cell-type resolution - the abilities of naturally occurring and newly engineered AAVs to mediate gene expression in primate retina following intravitreal injection. A top performing variant identified using this pipeline, K912, was used to deliver SaCas9 and edit the rhodopsin gene in macaque retina, resulting in editing efficiency similar to infection rates detected by the scAAVengr workflow. scAAVengr was then used to identify top-performing AAV variants in mouse brain, heart, and liver following systemic injection. Conclusions: These results validate scAAVengr as a powerful method for development of AAV vectors. Funding: This work was supported by funding from the Ford Foundation, NEI/NIH, Research to Prevent Blindness, Foundation Fighting Blindness, UPMC Immune Transplant and Therapy Center, and the Van Sloun fund for canine genetic research.

Gene therapy is an experimental approach to treating disease that involves altering faulty genes or replacing them with new, working copies. Most often, the new genetic material is delivered into cells using a modified virus that no longer causes disease, called a viral vector. Virus-mediated gene therapies are currently being explored for degenerative eye diseases, such as retinitis pigmentosa, and neurological disorders, like Alzheimer's and Parkinson's disease. A number of gene therapies have also been approved for treating some rare cancers, blood disorders and a childhood form of motor neuron disease. Despite the promise of virus-mediated gene therapy, there are significant hurdles to its widespread success. Viral vectors need to deliver enough genetic material to the right cells without triggering an immune response or causing serious side effects. Selecting an optimal vector is key to achieving this. A type of viruses called adeno-associated viruses (AAV) are prime candidates, partly because they can be easily engineered. However, accurately comparing the safety and efficacy of newly engineered AAVs is difficult, due to variation between test subjects and the labor and cost involved in careful testing. Öztürk et al. addressed this issue by developing an experimental pipeline called scAAVengr for comparing gene therapy vectors head-to-head. The process involves tagging potential AAV vectors with unique genetic barcodes, which can then be detected and quantified in individual cells using a technique called single-cell RNA sequencing. This means that when several vectors are used to infect lab-grown cells or a test animal at the same time, they can be tracked. The vectors can then be ranked on their ability to infect specific cell types and deliver useful genetic material. Using scAAVengr, Öztürk et al. compared viral vectors designed to target the light-sensitive cells of the retina, which allow animals to see. First, a set of promising viral vectors were evaluated using the scAAVengr pipeline in the eyes of marmosets and macaques, two small primates. Precise levels and locations of gene delivery were quantified. The top-performing vector was then identified and used to deliver Cas9, a genome editing tool, to primate retinas. Öztürk et al. also used scAAVengr to compare viral vectors in mice, analysing the vectors' ability to deliver their genetic cargo to the brain, heart, and liver. These experiments demonstrated that scAAVengr can be used to evaluate vectors in multiple tissues and in different organisms. In summary, this work outlines a method for identifying and precisely quantifying the performance of top-performing viral vectors for gene therapy. By aiding the selection of optimal viral vectors, the scAAVengr pipeline could help to improve the success of preclinical studies and early clinical trials testing gene therapies.

Predictors of swimming pool supervision for caregivers of toddlers.

BACKGROUND: In the U.S., drowning is a leading cause of death for toddlers. One important layer of protection against submersion injuries and fatalities is parent or caregiver supervision. The aims of this study are to explore current supervisory behavior of caregivers, determine how caregivers view com-mon supervision distractions, like cell phones and grilling, and identify what factors shape the quality of supervision that is given when swimming with their toddler at a swimming pool. METHODS: This cross-sectional study used the MTurk online platform to survey 650 caregivers of toddlers (1-4 yrs old) about their supervision behavior, their drowning knowledge, their perceptions of arm's reach supervision, the water competency of their toddler, and other background information. Regression analysis was used to identify factors that predicted report-ed supervision behavior. RESULTS: The average supervision behavior score for caregivers indicated an attitude between neutral and disagreement with allowing distractions for themselves while supervising their toddler in a swimming pool. High water safety knowledge and positive perceptions of arm's reach supervision were the biggest predictors of attentive supervision behavior. Having a home pool, higher education level, and believing their toddler had greater water competency were predictive of less attentive supervision behavior. CONCLUSIONS: Results suggest that supervision behavior while toddlers are in a swimming pool may be inade-quate. Low water safety knowledge and attitudes about what constitutes quality supervision are related to pool supervision behavior and changing these may reduce drowning risk. Caregivers should be encouraged to not reduce supervision as their toddlers gain water competency and if they have a home pool.

Drugs of Abuse-Opioids, Sedatives, Hypnotics.

Over the last 2 decades, prescription and nonprescription substance use has significantly increased. In this article, 3 particular drug classes-opioids, sedatives, and hypnotics-are discussed. For each class, a brief history of the agent, a description of relevant pharmacology, the clinical presentation of overdose, the management of specific drug overdoses, and a summary of salient points are presented. The intent is to provide a clinically relevant and comprehensive approach to understanding these potential substance exposures in order to provide a framework for management of opioid, sedative, and hypnotic overdoses.

Deep whole-genome sequencing of 3 cancer cell lines on 2 sequencing platforms.

To test the performance of a new sequencing platform, develop an updated somatic calling pipeline and establish a reference for future benchmarking experiments, we performed whole-genome sequencing of 3 common cancer cell lines (COLO-829, HCC-1143 and HCC-1187) along with their matched normal cell lines to great sequencing depths (up to 278x coverage) on both Illumina HiSeqX and NovaSeq sequencing instruments. Somatic calling was generally consistent between the two platforms despite minor differences at the read level. We designed and implemented a novel pipeline for the analysis of tumor-normal samples, using multiple variant callers. We show that coupled with a high-confidence filtering strategy, the use of combination of tools improves the accuracy of somatic variant calling. We also demonstrate the utility of the dataset by creating an artificial purity ladder to evaluate the somatic pipeline and benchmark methods for estimating purity and ploidy from tumor-normal pairs. The data and results of the pipeline are made accessible to the cancer genomics community.

Organoid Profiling Identifies Common Responders to Chemotherapy in Pancreatic Cancer.

Pancreatic cancer is the most lethal common solid malignancy. Systemic therapies are often ineffective, and predictive biomarkers to guide treatment are urgently needed. We generated a pancreatic cancer patient-derived organoid (PDO) library that recapitulates the mutational spectrum and transcriptional subtypes of primary pancreatic cancer. New driver oncogenes were nominated and transcriptomic analyses revealed unique clusters. PDOs exhibited heterogeneous responses to standard-of-care chemotherapeutics and investigational agents. In a case study manner, we found that PDO therapeutic profiles paralleled patient outcomes and that PDOs enabled longitudinal assessment of chemosensitivity and evaluation of synchronous metastases. We derived organoid-based gene expression signatures of chemosensitivity that predicted improved responses for many patients to chemotherapy in both the adjuvant and advanced disease settings. Finally, we nominated alternative treatment strategies for chemorefractory PDOs using targeted agent therapeutic profiling. We propose that combined molecular and therapeutic profiling of PDOs may predict clinical response and enable prospective therapeutic selection.Significance: New approaches to prioritize treatment strategies are urgently needed to improve survival and quality of life for patients with pancreatic cancer. Combined genomic, transcriptomic, and therapeutic profiling of PDOs can identify molecular and functional subtypes of pancreatic cancer, predict therapeutic responses, and facilitate precision medicine for patients with pancreatic cancer. Cancer Discov; 8(9); 1112-29. ©2018 AACR.See related commentary by Collisson, p. 1062This article is highlighted in the In This Issue feature, p. 1047.

Use of a Novel Memory Aid to Educate Perioperative Team Members on Proper Patient Positioning Technique.

Interdisciplinary collaboration is key to safe surgical positioning. Although the surgical procedure dictates the patient's position, surgeons, anesthesia care providers, intraoperative nurses, and ancillary staff members must work together to achieve the goal of safe positioning. Correct patient positioning includes the provision of adequate access to the surgical site for the surgeon and surgical assistants. Surgical positions may put the patient at risk of injury. Understanding human anatomy, including the nerves commonly affected by each surgical position, can help the surgical team prevent accidental and irreversible patient injury. A lack of knowledge of proper positioning practices can result in serious patient injury, such as permanent paralysis, blindness, tissue necrosis, burns, bone fracture, and even death. This article reviews surgical positioning and introduces a learning module that involves the use of mnemonics as memory aids for perioperative team members who are learning proper positioning techniques.

Identification of Head and Neck Cancer Subtypes Based on Human Papillomavirus Presence and E2F-Regulated Gene Expression.

Human papillomavirus (HPV) is present in a subset of head and neck squamous cell carcinomas (HNSCCs). The cell cycle regulatory Rb-E2F pathway is a major target of HPV and is perturbed by these viruses in cell culture and animal models, as well as in human tumors. In this study, we examined differences in the Rb-E2F pathway displayed by HPV-positive (HPV+) and HPV-negative (HPV-) HNSCC tumors. We created a computational approach that effectively categorizes gene expression as unchanged, downregulated, or upregulated by comparing the gene's mRNA levels in the tumor to the corresponding mRNA levels across normal tissue samples. Our findings suggest that there are three major HNSCC subtypes, defined by differences in the presence of HPV and in E2F-regulated gene expression. Most HPV+ HNSCC tumors show upregulation of E2F-regulated genes, which is consistent with inactivation of Rb by the virus-encoded E7 protein. In contrast, many HPV- HNSCCs show little or no change in the Rb-E2F pathway. However, we also identified a set of tumors that show alterations in the Rb-E2F pathway in the absence of HPV. Thus, one class of HPV- HNSCCs arise without significant alterations of the Rb-E2F pathway, while a second class of tumors appear to deregulate this pathway independently of the presence of HPV. IMPORTANCE Cancer is a complex disease that can be caused by a multitude of factors. HNSCC is complicated because some of these cancers are clearly associated with HPV, while others have no viral involvement. Determining the pathways that are commonly altered in both types of HNSCC, as well as those that are unique to viral and nonviral tumors, is important for a basic understanding of how these cancers arise and progress and critical to the development of targeted therapies. In this work, we show that all HPV-associated tumors have increased expression of E2F target genes, indicating that the tumor suppressor function of Rb is blocked. Importantly, Rb is also inhibited in a subset of nonviral tumors, suggesting that mutations present in these cancers mimic the action of the HPV E6 and E7 oncogenes.

Disseminated histoplasmosis in a patient with common variable immunodeficiency: A coincidence or the result of T cell defects?

BACKGROUND: In endemic regions, histoplasmosis is often seen in hosts with defective cell mediated immunity. We report a case of disseminated histoplasmosis in a patient with common variable immunodeficiency (CVID), a disorder mainly characterized by B cell defects. CASE: A 35 year old male with CVID developed fever, headache, dyspnea and pancytopenia within few weeks of swimming in the Tennessee River. After a non-revealing initial evaluation he was transferred to a tertiary facility for fever of unknown origin, where massive splenomegaly was noted. Clinical course was complicated by hypoxia from extensive bilateral lung infiltrates requiring non-invasive ventilation. Urine and serum Histoplasma antigens were positive. He was treated with liposomal amphotericin B followed by itraconazole after clinical improvement within 48 h and discharged home by day 6. Fungal blood cultures sent on day 1 grew Histoplasma capsulatum on day 19. After 5 months splenomegaly completely resolved and he successfully completed one year of treatment with itraconazole. CONCLUSIONS: Our case highlights the significance of T cell defects in CVID. More research focusing on T cell defects in CVID is required to understand the extent of vulnerability to such intracellular pathogens in CVID.