Defining stage-specific activity of potent new inhibitors of Cryptosporidium parvum growth in vitro

Currently, nitazoxanide is the only FDA-approved treatment for cryptosporidiosis; unfortunately, it is ineffective in immunocompromised patients, has varied efficacy in immunocompetent individuals, and is not approved in infants under 1 year of age. Identifying new inhibitors for the treatment of cryptosporidiosis requires standardized and quantifiable in vitro assays for assessing potency, selectivity, timing of activity, and reversibility. Here, we provide new protocols for defining which stages of the life cycle are susceptible to four highly active compound classes that likely inhibit different targets in the parasite. We also utilize a newly developed long-term culture system to define assays for monitoring reversibility as a means of defining cidal activity as a function of concentration and time of treatment. These assays should provide valuable in vitro parameters to establish conditions for efficacious in vivo treatment.Cryptosporidium parvum and Cryptosporidium hominis have emerged as major enteric pathogens of infants in the developing world, in addition to their known importance in immunocompromised adults. Although there has been recent progress in identifying new small molecules that inhibit Cryptosporidium sp. growth in vitro or in animal models, we lack information about their mechanism of action, potency across the life cycle, and cidal versus static activities. Here, we explored four potent classes of compounds that include inhibitors that likely target phosphatidylinositol 4 kinase (PI4K), phenylalanine-tRNA synthetase (PheRS), and several potent inhibitors with unknown mechanisms of action. We utilized monoclonal antibodies and gene expression probes for staging life cycle development to define the timing of when inhibitors were active during the life cycle of Cryptosporidium parvum grown in vitro. These different classes of inhibitors targeted different stages of the life cycle, including compounds that blocked replication (PheRS inhibitors), prevented the segmentation of daughter cells and thus blocked egress (PI4K inhibitors), or affected sexual-stage development (a piperazine compound of unknown mechanism). Long-term cultivation of C. parvum in epithelial cell monolayers derived from intestinal stem cells was used to distinguish between cidal and static activities based on the ability of parasites to recover from treatment. Collectively, these approaches should aid in identifying mechanisms of action and for designing in vivo efficacy studies based on time-dependent concentrations needed to achieve cidal activity

Analysis of the Space Shuttle Orbiter skin panels under simulated hydrodynamic loads

The Space Shuttle orbiter skin panels were analyzed under pressure loads simulating hydrodynamic loads to determine their capability to sustain a potential ditching and to determine pressures that typically would produce failures. Two Dynamic Crash Analysis of Structures (DYCAST) finite element models were used. One model was used to represent skin panels (bays) in the center body, while a second model was used to analyze a fuselage bay in the wing region of the orbiter. From an assessment of the DYCAST nonlinear computer results, it is concluded that the probability is extremely high that most, if not all, of the lower skin panels would rupture under ditching conditions. Extremely high pressure loads which are produced under hydrodynamic planning conditions far exceed the very low predicted failure pressures for the skin panels. Consequently, a ditching of the orbiter is not considered to have a high probability of success and should not be considered a means of emergency landing unless no other option exists

An overview of the crash dynamics failure behavior of metal and composite aircraft structures

An overview of failure behavior results is presented from some of the crash dynamics research conducted with concepts of aircraft elements and substructure not necessarily designed or optimized for energy absorption or crash loading considerations. Experimental and analytical data are presented that indicate some general trends in the failure behavior of a class of composite structures that includes fuselage panels, individual fuselage sections, fuselage frames, skeleton subfloors with stringers and floor beams without skin covering, and subfloors with skin added to the frame stringer structure. Although the behavior is complex, a strong similarity in the static/dynamic failure behavior among these structures is illustrated through photographs of the experimental results and through analytical data of generic composite structural models

Oculocutaneous Albinism in a Finetooth Shark, Carcharhinus isodon, from Mobile Bay, Alabama

Albinism has been documented in numerous species of teleosts (Dawson, 1964, 1966, 1971; Dawson and Heal, 1971). However, published accounts of oculocutaneous albino elasmobranches are relatively rare. Oculocutaneous albinism is a deficiency of the melanocyte system, resulting in a lack of skin pigment and pink eyes. Coad and Gilhen (2002) reviewed the literature and found published reports of 24 cases of albinism in 20 species with only eight of those being oculocutaneous albinos, 12 being piebaldistic (partial albinos), and 4 not clearly defined. Coloration in piebaldistic specimens includes partially white dorsal or ventral surfaces, lack of diagnostic markings (such as ocellae), or leucistic (yellow) coloration

A qualitative study of Western Australian women's perceptions of using a Snoezelen room for breastfeeding during their postpartum hospital stay

<p>Abstract</p> <p>Background</p> <p>There is limited evidence on the use of the Snoezelen concept for maternity clients. Snoezelen, a Dutch concept, initiated in the 1970s as a leisure activity for severely disabled people, involves creating an indoor environment using controllable stimuli to enhance comfort and relaxation. These specially designed rooms expose the user to multiple sensory stimulations combining vision, touch, sounds and aromas. The aim of this study was to provide insight into breastfeeding women's experience of using a Snoezelen room during hospitalisation.</p> <p>Methods</p> <p>A qualitative exploratory design was chosen to reveal women's perceptions of using the Snoezelen room. Osborne Park Hospital, the study setting is the second largest public provider of obstetric services in Western Australia. A purposive sample was drawn from breastfeeding women who used the Snoezelen room during their postpartum stay from March 2006 to March 2007. Saturation was achieved after eleven breastfeeding women were interviewed six weeks post discharge. Data analysis involved the constant comparison method.</p> <p>Results</p> <p>Participants entered the room feeling tired and emotional with an unsettled baby and breastfeeding issues aggravated by maternal stress and anxiety. All women indicated they were able to achieve relaxation while in the room and would recommend its use to other breastfeeding mothers. Two key themes revealed how the Snoezelen room facilitated maternal relaxation, which ultimately enhanced the breastfeeding experience. The first theme, "Finding Relaxation for the Breastfeeding Mother" incorporates three subthemes: 'Time out' for mother; Control in own personal space; and a Quiet/calm environment with homelike atmosphere. The second theme, "Enabling Focus on Breastfeeding", occurred after relaxation was achieved and involved four subthemes: Able to get one-on-one attention; Not physically exposed to others; Away from prying, judgemental eyes and Able to safely attempt breastfeeding alone knowing help is nearby.</p> <p>Conclusion</p> <p>Insight into how the Snoezelen room promoted relaxation also highlights what contributes to maternal anxiety during breastfeeding experiences in hospital. The findings offer health professionals the opportunity to consider adopting strategies such as a Snoezelen room in their hospital or being innovative in modifying the postpartum setting to promote relaxation for breastfeeding women.</p

Effects of floor location on response of composite fuselage frames

Experimental and analytical results are presented which show the effect of floor placement on the structural response and strength of circular fuselage frames constructed of graphite-epoxy composite material. The research was conducted to study the behavior of conventionally designed advanced composite aircraft components. To achieve desired new designs which incorporate improved energy absorption capabilities requires an understanding of how these conventional designs behave under crash type loadings. Data are presented on the static behavior of the composite structure through photographs of the frame specimen, experimental strain distributions, and through analytical data from composite structural models. An understanding of this behavior can aid the dynamist in predicting the crash behavior of these structures and may assist the designer in achieving improved designs for energy absorption and crash behavior of future structures

Increased risk for other cancers in individuals with Ewing sarcoma and their relatives.

BackgroundThere are few reports of the association of other cancers with Ewing sarcoma in patients and their relatives. We use a resource combining statewide genealogy and cancer reporting to provide unbiased risks.MethodsUsing a combined genealogy of 2.3 million Utah individuals and the Utah Cancer Registry (UCR), relative risks (RRs) for cancers of other sites were estimated in 143 Ewing sarcoma patients using a Cox proportional hazards model with matched controls; however, risks in relatives were estimated using internal cohort-specific cancer rates in first-, second-, and third-degree relatives.ResultsCancers of three sites (breast, brain, complex genotype/karyotype sarcoma) were observed in excess in Ewing sarcoma patients. No Ewing sarcoma patients were identified among first-, second-, or third-degree relatives of Ewing sarcoma patients. Significantly increased risk for brain, lung/bronchus, female genital, and prostate cancer was observed in first-degree relatives. Significantly increased risks were observed in second-degree relatives for breast cancer, nonmelanoma eye cancer, malignant peripheral nerve sheath cancer, non-Hodgkin lymphoma, and translocation sarcomas. Significantly increased risks for stomach cancer, prostate cancer, and acute lymphocytic leukemia were observed in third-degree relatives.ConclusionsThis analysis of risk for cancer among Ewing sarcoma patients and their relatives indicates evidence for some increased cancer predisposition in this population which can be used to individualize consideration of potential treatment of patients and screening of patients and relatives

Isolation and characterization of the herpes simplex virus 1 terminase complex

During herpes simplex virus 1 (HSV-1) infection, empty procapsids are assembled and subsequently filled with the viral genome by means of a protein complex called the terminase, which is comprised of the HSV-1 UL15, UL28, and UL33 proteins. Biochemical studies of the terminase proteins have been hampered by the inability to purify the intact terminase complex. In this study, terminase complexes were isolated by tandem-affinity purification (TAP) using recombinant viruses expressing either a full-length NTAP-UL28 fusion protein (vFH476) or a C-terminally truncated NTAP-UL28 fusion protein (vFH499). TAP of the UL28 protein from vFH476-infected cells, followed by silver staining, Western blotting, and mass spectrometry, identified the UL15, UL28, and UL33 subunits, while TAP of vFH499-infected cells confirmed previous findings that the C terminus of UL28 is required for UL28 interaction with UL33 and UL15. Analysis of the oligomeric state of the purified complexes by sucrose density gradient ultracentrifugation revealed that the three proteins formed a complex with a molecular mass that is consistent with the formation of a UL15-UL28-UL33 heterotrimer. In order to assess the importance of conserved regions of the UL15 and UL28 proteins, recombinant NTAP-UL28 viruses with mutations of the putative UL28 metal-binding domain or within the UL15 nuclease domain were generated. TAP of UL28 complexes from cells infected with each domain mutant demonstrated that the conserved cysteine residues of the putative UL28 metal-binding domain and conserved amino acids within the UL15 nuclease domain are required for the cleavage and packaging functions of the viral terminase, but not for terminase complex assembly

Understanding engagement in digital mental health and well-being programs for women in the perinatal period: Systematic review without meta-analysis

Background: Pregnancy and the postnatal period can be a time of increased psychological distress, which can be detrimental to both the mother and the developing child. Digital interventions are cost-effective and accessible tools to support positive mental health in women during the perinatal period. Although studies report efficacy, a key concern regarding web-based interventions is the lack of engagement leading to drop out, lack of participation, or reduced potential intervention benefits. Objective: This systematic review aimed to understand the reporting and levels of engagement in studies of digital psychological mental health or well-being interventions administered during the perinatal period. Specific objectives were to understand how studies report engagement across 4 domains specified in the Connect, Attend, Participate, and Enact (CAPE) model, make recommendations on best practices to report engagement in digital mental health interventions (DMHIs), and understand levels of engagement in intervention studies in this area. To maximize the utility of this systematic review, we intended to develop practical tools for public health use: to develop a logic model to reference the theory of change, evaluate the studies using the CAPE framework, and develop a guide for future data collection to enable consistent reporting in digital interventions. Methods: This systematic review used the Cochrane Synthesis Without Meta-analysis reporting guidelines. This study aimed to identify studies reporting DMHIs delivered during the perinatal period in women with subclinical mood symptoms. A systematic database search was used to identify relevant papers using the Ovid Platform for MEDLINE, PsycINFO, EMBASE, Scopus, Web of Science, and Medical Subject Headings on Demand for all English-language articles published in the past 10 years. Results: Searches generated a database of 3473 potentially eligible studies, with a final selection of 16 (0.46%) studies grouped by study design. Participant engagement was evaluated using the CAPE framework and comparable variables were described. All studies reported at least one engagement metric. However, the measures used were inconsistent, which may have contributed to the wide-ranging results. There was insufficient reporting for enactment (ie, participants\u27 real-world use of intervention skills), with only 38% (6/16) of studies clearly recording longer-term practice through postintervention interviews. The logic model proposes ways of conceptualizing and reporting engagement details in DMHIs more consistently in the future. Conclusions: The perinatal period is the optimal time to intervene with strength-based digital tools to build positive mental health. Despite the growing number of studies on digital interventions, few robustly explore engagement, and there is limited evidence of long-term skill use beyond the intervention period. Our results indicate variability in the reporting of both short- and long-term participant engagement behaviors, and we recommend the adoption of standardized reporting metrics in future digital interventions. Trial Registration: PROSPERO CRD42020162283; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=162283

Adverse Childhood Life Events and Postpartum Mood Episodes in Bipolar Disorder

Background: The early postpartum has been established as a period of increased vulnerability for psychiatric mood illness. Women with bipolar disorder (BD) in particular are at elevated risk of postnatal depression (PND) and of postpartum psychosis (PP). Though adverse childhood life events (ACLEs) have been implicated in the aetiology of PND, this has rarely been studied in relation to PP. Furthermore, despite being at high risk of relapse following childbirth, little research has assessed the relationship between ACLEs and postnatal mood episodes (PNEs) exclusively in women with BD. Therefore, our aim was to explore associations between ACLEs and occurrence of both PND and PP in a large sample of women with BD. Methods: Participants were 665 parous women with BD who had been recruited into the Bipolar Disorder Research Network study. Diagnoses and lifetime psychopathology were obtained via a semi-structured interview (SCAN). Postnatal psychiatric history and experience of 7 ACLEs were also assessed. Where available, all information obtained at interview was confirmed from psychiatric case notes. Women were classified into three groups according to postnatal psychiatric history: 1) those who had experienced no postnatal mood episode (no PNE, n=224), 2) women with a history of PND (n=223) and 3) women who had experienced PP (n=208). A Pearson’s chi-square test was used to compare the prevalence of each type of ACLE between women in the no PNE group and those with a history of PND or PP. Results: Women with PND were significantly more likely to have experienced emotional, sexual or physical abuse in childhood compared with women who had no history of a PNE (p<0.05). In particular, childhood sexual abuse was reported significantly more in the PND than the no PNE group (P<0.05). In contrast, there were no significant differences in the frequency of reporting of any ACLEs between women who had no PNE and those with PP. Conclusions: Our findings indicate that childhood abuse, sexual abuse in particular, is associated with PND among women with BD. In contrast, we found no evidence for an association between any ACLE and PP, suggesting that biological factors are likely to play a more important role in the aetiology of psychosis in the early postpartum