The Elderly and Waterborne Cryptosporidium Infection: Gastroenteritis Hospitalizations before and during the 1993 Milwaukee Outbreak

We used the Temporal Exposure Response Surfaces modeling technique to examine the association between gastroenteritis-related emergency room visits and hospitalizations in the elderly and drinking water turbidity before and during the 1993 Milwaukee waterborne Cryptosporidium outbreak. Before the outbreak, the rate of such events increased with age in the elderly (p<0.002), suggesting that the elderly are at an increased risk. During the outbreak, strong associations between turbidity and gastroenteritis-related emergency room visits and hospitalizations occurred at temporal lags of 5–6 days (consistent with the Cryptosporidium incubation period). A pronounced second wave of these illnesses in the elderly peaked at 13 days. This wave represented approximately 40% of all excess cases in the elderly. Our findings suggest that the elderly had an increased risk of severe disease due to Cryptosporidium infection, with a shorter incubation period than has been previously reported in all adults and with a high risk for secondary person-to-person transmission

Bags, junctions, and networks of BPS and non-BPS defects

We investigate several models of coupled scalar fields that present discrete Z_2, Z_2 x Z_2, Z_3 and other symmetries. These models support topological domain wall solutions of the BPS and non-BPS type. The BPS solutions are stable, but the stability of the non-BPS solutions may depend on the parameters that specify the models. The BPS and non-BPS states give rise to bags, and also to three-junctions that may allow the presence of networks of topological defects. In particular, we show that the non-BPS defects of a specific model that engenders the Z_3 symmetry give rise to a stable regular hexagonal network of domain walls.Comment: Revtex, 16 pages, 6 ps figures; Shorter version to be published in Phys. Rev.

Spin Glass Ordering in Diluted Magnetic Semiconductors: a Monte Carlo Study

We study the temperature-dilution phase diagram of a site-diluted Heisenberg antiferromagnet on a fcc lattice, with and without the Dzyaloshinskii-Moriya anisotropic term, fixed to realistic microscopic parameters for $IIB_{1-x} Mn_x Te$ (IIB=Cd, Hg, Zn). We show that the dipolar Dzyaloshinskii-Moriya anisotropy induces a finite-temperature phase transition to a spin glass phase, at dilutions larger than 80%. The resulting probability distribution of the order parameter P(q) is similar to the one found in the cubic lattice Edwards-Anderson Ising model. The critical exponents undergo large finite size corrections, but tend to values similar to the ones of the Edwards-Anderson-Ising model.Comment: 4 pages plus 3 postscript figure

Event-Level Associations of Marijuana and Heavy Alcohol Use With Intercourse and Condom Use

OBJECTIVE: The associations substance use has with sex and condom use among college students appear to be well-documented and of clear public health significance. However, few event-level studies examine marijuana or heavy alcohol use, control for temporal patterns shared among these behaviors, or consider differences by relationship status. METHOD: We recruited 284 18 to 22 year old undergraduate men and women (79%), 61% of whom were in a serious relationship. For 24 consecutive days, participants reported on their prior day marijuana use, heavy alcohol use, vaginal intercourse, and condom use. RESULTS: Most intercourse events (86%) were reported by participants in a serious relationship, and most (62%) were not protected by a condom. Hierarchical generalized linear models indicated participants in a serious relationship were more likely to report intercourse than were others. Adjusting for weekly patterns in intercourse, odds of intercourse were higher on days participants reported marijuana or heavy alcohol use; the latter effect was stronger for single participants. Being drunk during sex, being in a serious relationship, and use of non-condom birth control were associated with less condom use. CONCLUSIONS: Models distinguish among multiple potential influences on undergraduates’ sexual behavior. Findings suggest greater attention to the relationship and other contexts of marijuana and alcohol use may be relevant to understanding young adults’ sexual behavior and preventing health-risking or nonconsensual sex

Evaluation of Force-Field Calculations of Lattice Energies on a Large Public Dataset, Assessment of Pharmaceutical Relevance, and Comparison to Density Functional Theory

Crystal lattice energy is a key property affecting the ease of processing pharmaceutical materials during manufacturing, as well as product performance. We present an extensive comparison of 324 force-field protocols for calculating the lattice energies of single component, organic molecular crystals (further restricted to Z′ less than or equal to one), corresponding to a wide variety of force-fields (DREIDING, Universal, CVFF, PCFF, COMPASS, COMPASSII), optimization routines, and other variations, which could be implemented as part of an automated workflow using the industry standard Materials Studio software. All calculations were validated using a large new dataset (SUB-BIG), which we make publicly available. This dataset comprises public domain sublimation data, from which estimated experimental lattice energies were derived, linked to 235 molecular crystals. Analysis of pharmaceutical relevance was performed according to two distinct methods based upon (A) public and (B) proprietary data. These identified overlapping subsets of SUB-BIG comprising (A) 172 and (B) 63 crystals, of putative pharmaceutical relevance, respectively. We recommend a protocol based on the COMPASSII force field for lattice energy calculations of general organic or pharmaceutically relevant molecular crystals. This protocol was the most highly ranked prior to subsetting and was either the top ranking or amongst the top 15 protocols (top 5%) following subsetting of the dataset according to putative pharmaceutical relevance. Further analysis identified scenarios where the lattice energies calculated using the recommended force-field protocol should either be disregarded (values greater than or equal to zero and/or the messages generated by the automated workflow indicate extraneous atoms were added to the unit cell) or treated cautiously (values less than or equal to −249 kJ/mol), as they are likely to be inaccurate. Application of the recommended force-field protocol, coupled with these heuristic filtering criteria, achieved an root mean-squared error (RMSE) around 17 kJ/mol (mean absolute deviation (MAD) around 11 kJ/mol, Spearman’s rank correlation coefficient of 0.88) across all 226 SUB-BIG structures retained after removing calculation failures and applying the filtering criteria. Across these 226 structures, the estimated experimental lattice energies ranged from −60 to −269 kJ/mol, with a standard deviation around 29 kJ/mol. The performance of the recommended protocol on pharmaceutically relevant crystals could be somewhat reduced, with an RMSE around 20 kJ/mol (MAD around 13 kJ/mol, Spearman’s rank correlation coefficient of 0.76) obtained on 62 structures retained following filtering according to pharmaceutical relevance method B, for which the distribution of experimental values was similar. For a diverse set of 17 SUB-BIG entries, deemed pharmaceutically relevant according to method B, this recommended force-field protocol was compared to dispersion corrected density functional theory (DFT) calculations (PBE + TS). These calculations suggest that the recommended force-field protocol (RMSE around 15 kJ/mol) outperforms PBE + TS (RMSE around 37 kJ/mol), although it may not outperform more sophisticated DFT protocols and future studies should investigate this. Finally, further work is required to compare our recommended protocol to other lattice energy calculation protocols reported in the literature, as comparisons based upon previously reported smaller datasets indicated this protocol was outperformed by a number of other methods. The SUB-BIG dataset provides a basis for these future studies and could support protocol refinement

NF2/Merlin mediates contact-dependent inhibition of EGFR mobility and internalization via cortical actomyosin

The proliferation of normal cells is inhibited at confluence, but the molecular basis of this phenomenon, known as contact-dependent inhibition of proliferation, is unclear. We previously identified the neurofibromatosis type 2 (NF2) tumor suppressor Merlin as a critical mediator of contact-dependent inhibition of proliferation and specifically found that Merlin inhibits the internalization of, and signaling from, the epidermal growth factor receptor (EGFR) in response to cell contact. Merlin is closely related to the membrane–cytoskeleton linking proteins Ezrin, Radixin, and Moesin, and localization of Merlin to the cortical cytoskeleton is required for contact-dependent regulation of EGFR. We show that Merlin and Ezrin are essential components of a mechanism whereby mechanical forces associated with the establishment of cell–cell junctions are transduced across the cell cortex via the cortical actomyosin cytoskeleton to control the lateral mobility and activity of EGFR, providing novel insight into how cells inhibit mitogenic signaling in response to cell contact

Uncovering treatment burden as a key concept for stroke care: a systematic review of qualitative research

&lt;b&gt;Background&lt;/b&gt; Patients with chronic disease may experience complicated management plans requiring significant personal investment. This has been termed ‘treatment burden’ and has been associated with unfavourable outcomes. The aim of this systematic review is to examine the qualitative literature on treatment burden in stroke from the patient perspective.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Methods and findings&lt;/b&gt; The search strategy centred on: stroke, treatment burden, patient experience, and qualitative methods. We searched: Scopus, CINAHL, Embase, Medline, and PsycINFO. We tracked references, footnotes, and citations. Restrictions included: English language, date of publication January 2000 until February 2013. Two reviewers independently carried out the following: paper screening, data extraction, and data analysis. Data were analysed using framework synthesis, as informed by Normalization Process Theory. Sixty-nine papers were included. Treatment burden includes: (1) making sense of stroke management and planning care, (2) interacting with others, (3) enacting management strategies, and (4) reflecting on management. Health care is fragmented, with poor communication between patient and health care providers. Patients report inadequate information provision. Inpatient care is unsatisfactory, with a perceived lack of empathy from professionals and a shortage of stimulating activities on the ward. Discharge services are poorly coordinated, and accessing health and social care in the community is difficult. The study has potential limitations because it was restricted to studies published in English only and data from low-income countries were scarce.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Conclusions&lt;/b&gt; Stroke management is extremely demanding for patients, and treatment burden is influenced by micro and macro organisation of health services. Knowledge deficits mean patients are ill equipped to organise their care and develop coping strategies, making adherence less likely. There is a need to transform the approach to care provision so that services are configured to prioritise patient needs rather than those of health care systems

Cyclophosphamide augments the efficacy of in situ vaccination in a mouse melanoma model

IntroductionWe have previously shown that an intratumoral (IT) injection of the hu14.18-IL2 immunocytokine (IC), an anti-GD2 antibody linked to interleukin 2, can serve as an in situ vaccine and synergize with local radiotherapy (RT) to induce T cell-mediated antitumor effects. We hypothesized that cyclophosphamide (CY), a chemotherapeutic agent capable of depleting T regulatory cells (Tregs), would augment in situ vaccination. GD2+ B78 mouse melanoma cells were injected intradermally in syngeneic C57BL/6 mice.MethodsTreatments with RT (12Gy) and/or CY (100 mg/kg i.p.) started when tumors reached 100-300 mm3 (day 0 of treatment), followed by five daily injections of IT-IC (25 mcg) on days 5-9. Tumor growth and survival were followed. In addition, tumors were analyzed by flow cytometry.ResultsSimilar to RT, CY enhanced the antitumor effect of IC. The strongest antitumor effect was achieved when CY, RT and IC were combined, as compared to combinations of IC+RT or IC+CY. Flow cytometric analyses showed that the combined treatment with CY, RT and IC decreased Tregs and increased the ratio of CD8+ cells/Tregs within the tumors. Moreover, in mice bearing two separate tumors, the combination of RT and IT-IC delivered to one tumor, together with systemic CY, led to a systemic antitumor effect detected as shrinkage of the tumor not treated directly with RT and IT-IC. Cured mice developed immunological memory as they were able to reject B78 tumor rechallenge.ConclusionTaken together, these preclinical results show that CY can augment the antitumor efficacy of IT- IC, given alone or in combination with local RT, suggesting potential benefit in clinical testing of these combinations

Identify : the investigation and detection of urological neoplasia in patients referred with suspected urinary tract cancer : a multicentre cohort study

Funding Action Bladder Cancer UK, The Rosetree Trust, The Urology Foundation. None had any involvement in the protocol stage of the study.Peer reviewedPublisher PD