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Background:The Varicella-zostervirus (VZV) remains dormant in the dorsal root ganglia and can become reactive later in a person's life. Factors such as stress, trauma, chronic disease, systemic illness, immune disorders, and age-related decline in host immunologic responses can potentially incite reactivation. Activation of VZV resulting in shingles following acupuncture has been reported in the literature previously, and some mechanisms have been proposed for this observation.Case:A patient with a history of total thyroidectomy for thyroid cancer presented with chronic neck pain. She was clinically and biochemically in a euthyroid state and on thyroid replacement therapy. She had a history of chickenpox, at age 13, and seasonal allergies. After her first acupuncture session, she received an allergy shot for her seasonal allergies. A day after the procedure, she developed a vesicular rash and was subsequently diagnosed with acute Herpes zoster. Subsequent acupuncture was withheld following this event. She received acyclovir and applied topical Aloe verato the cutaneous lesions, and developed mild scarring, but did not experience postherpetic neuralgia.Conclusions:Acupuncture is a minor trauma that can predispose a patient to reactivation of VZV and shingles in the setting of immune activation with allergen immunotherapy.

The identification of genomic “targets” through next-generation sequencing (NGS) of patient’s NSCLC tumors has resulted in a rapid expansion of targeted treatment options for selected patients. This retrospective study aims to identify the proportion of patients with advanced NSCLC in the Republic of Ireland whose tumors harbor actionable genomic alterations through broad NGS panel testing.

Neurocognitive adverse events (NAEs) have been reported in up to 60% of patients on lorlatinib, a potent central nervous system (CNS)-active ALK-inhibitor.(1) Manifestations may include psychotic, mood, speech and cognitive symptoms. Current guidance recommends permanent discontinuation of lorlatinib in cases of Grade 4 NAEs.

The predicted ambient-temperature crystal structures of organic small molecules are often represented by a single energy-minimized configuration at 0 K. This procedure effectively collapses the ensemble of configurations that would be present at ambient temperature into a single representative structure. This simplification is likely to break down if the crystal structure has multiple different lattice-energy minima within the ambient-temperature ensemble. In this work, we explore the existence of multiple minima within finite-temperature crystal basins by sampling crystals at a range of temperatures followed by rapidly quenching the configurations. We then observe whether each crystal returns to the original minimum or to an ensemble of minima on the lattice-energy landscape. Eight of the twelve compounds examined in this work have at least one polymorph with multi-minima behavior. These multi-minima basins have implications for crystal structure prediction studies, and it is therefore important to understand the factors that lead a crystal structure to have multiple minima. We find that, in general, the existence of multiple minima within a crystal basin is more likely for the compounds that are larger and have more flexibility. We find that the number of minima found tends to increase with the sampling temperature, and the lattice energy of minima found from the same finite-temperature trajectory can vary by >2.0 kJ/mol. Finally, we show that the lattice-energy minima contained within a single ambient-temperature basin can have different space groups and numbers of molecules in the asymmetric unit. Overall, the data suggest that many experimental crystal polymorphs are likely to have multi-minima behavior and are best described by an ensemble of structures encompassing many minima rather than by a single lattice-energy minimum.

Organic photovoltaic (OPV) devices hold a great deal of promise for the emerging solar market. However, to unlock this promise, it is necessary to understand how OPV devices generate free charges. Here, we analyze the energetics and charge delocalization of the interfacial charges in poly(p-phenylenevinylene) (PPV)/[6,6]-phenyl-C61-butyric acid methyl ester (PCBM) and poly(3-hexylthiophene-2,5-diyl) (P3HT)/PCBM devices. We find that, in the PPV system, the interface does not produce molecular disorder, but an interfacial electric field is formed upon the inclusion of environmental polarization that promotes charge separation. In contrast, the P3HT system shows a significant driving force for charge separation due to interfacial disorder confining the hole. However, this feature is overpowered by the polarization of the electronic environment, which generates a field that inhibits charge separation. In the two systems studied herein, electrostatic effects dominate charge separation, overpowering interfacially induced disorder. This suggests that, when balancing polymeric order with electrostratic effects, the latter should take priority.

Molecular crystals cannot be designed in the same manner as macroscopic objects, because they do not assemble according to simple, intuitive rules. Their structures result from the balance of many weak interactions, rather than from the strong and predictable bonding patterns found in metal–organic frameworks and covalent organic frameworks. Hence, design strategies that assume a topology or other structural blueprint will often fail. Here we combine computational crystal structure prediction and property prediction to build energy–structure–function maps that describe the possible structures and properties that are available to a candidate molecule. Using these maps, we identify a highly porous solid, which has the lowest density reported for a molecular crystal so far. Both the structure of the crystal and its physical properties, such as methane storage capacity and guest-molecule selectivity, are predicted using the molecular structure as the only input. More generally, energy–structure–function maps could be used to guide the experimental discovery of materials with any target function that can be calculated from predicted crystal structures, such as electronic structure or mechanical properties.

•The theoretical framework of acceptability (TFA) can a useful adjunct through which to explore the acceptability of cognitive testing in a suspected stroke population•Acceptability of cognitive assessment from the patient perspective encompasses 5 themes: participation motives; trust in health professionals; perceived risks of harm; information provision and burden of testing•These factors influencing acceptability have practical application for clinicians undertaking cognitive assessments of such patients•Patients admitted with suspected stroke expected and willing to participate in cognitive assessments

Organic molecules with charge-transfer (CT) excited states are widely used in industry and are especially attractive as candidates for fabrication of energy efficient OLEDs, as they can harvest energy from nonradiative triplets by means of thermally activated delayed fluorescence (TADF). It is therefore useful to have computational protocols for accurate estimation of their electronic spectra in order to screen candidate molecules for OLED applications. However, it is difficult to predict the photophysical properties of TADF molecules with LR-TDDFT, as semilocal LR-TDDFT is incapable of accurately modeling CT states. Herein, we study absorption energies, emission energies, zero–zero transition energies, and singlet–triplet gaps of TADF molecules using a restricted open-shell Kohn–Sham (ROKS) approach instead and discover that ROKS calculations with semilocal hybrid functionals are in good agreement with experimentsunlike TDDFT, which significantly underestimates energy gaps. We also propose a cheap computational protocol for studying excited states with large CT character that is found to give good agreement with experimental results without having to perform any excited-state geometry optimizations.

The mutational repertoire of cancers creates the neoepitopes that make cancers immunogenic. Here, we introduce two novel tools that identify, with relatively high accuracy, the small proportion of neoepitopes (among the hundreds of potential neoepitopes) that protect the host through an antitumor T cell response. The two tools consist of (a) the numerical difference in NetMHC scores between the mutated sequences and their unmutated counterparts, termed the differential agretopic index, and (b) the conformational stability of the MHC I–peptide interaction. Mechanistically, these tools identify neoepitopes that are mutated to create new anchor residues for MHC binding, and render the overall peptide more rigid. Surprisingly, the protective neoepitopes identified here elicit CD8-dependent immunity, even though their affinity for Kd is orders of magnitude lower than the 500-nM threshold considered reasonable for such interactions. These results greatly expand the universe of target cancer antigens and identify new tools for human cancer immunotherapy.

The package insert, which is jointly authored by the U.S. Food and Drug Administration and the manufacturer of the drug, is a summary of all of the preclinical and clinical data accumulated during the successful development of a new drug. Despite the role of the package insert in the safe practice of medicine, prescribers often minimize, overlook, or misunderstand its importance, suggesting a gap in their training. An anonymous, three-question survey was administered to third year medical students (N=34) from two medical schools to assess how well they had been educated about the evidence-based origin, purpose, and implications of the package insert. The results indicate a deficiency in their medical education, and the authors contrast the student responses with the facts. These results underscore the need to revise medical school curricula to provide future prescribers with more education about the importance of the package insert and the relationship between pharmaceutical companies, the U.S. Food and Drug Administration, and prescribers. (Journal of Psychiatric Practice2014;20:284–290)

A methodology to link an atomistic description of a polymeric semiconductor with the experimental electrical characteristics of real devices is proposed. Microscopic models of poly(3-hexylthiophene) (P3HT) of different regioregularity are generated using molecular dynamics and their electronic structure determined via an approximate quantum chemistry scheme. The resulting density of trap states and distribution of localized and delocalized states is then compared with that obtained from thin film transistor measurements of P3HT at different regioregularities. The two complementary methodologies provide a converging description of the electron transport in semicrystalline P3HT and the role of regioregularity. States at the valence band edge are localized, but delocalized “band-like” states are thermally accessible and quantitatively characterized. Both theory and experiment agree that contrary to a commonly held belief the trap density and the DOS shape are little affected by the presence of regioregularity defects.

•The APPLE study is a post stroke cohort study with inclusive recruitment and follow up at 1,6,12 and 18 months.•Data include assessment of pre-stroke cognition, prospective neuropsychological assessment, baseline imaging and a biobank.•The APPLE materials (data, biobank, imaging) can be made available as a resource to other researchers.

The direct perforant path (PP) projection to CA3 is a major source of cortical input to the hippocampal region, yet relatively little is known about the basic properties of physiology and plasticity in this pathway. We tested whether PP long-term potentiation (LTP) in CA3 possesses the Hebbian property of associativity; i.e., whether the firing of fibers of different orders can induce PP LTP. We stimulated PP with weak trains of high-frequency stimulation (HFS), which by itself was below the threshold for LTP induction. The identical HFS was effective in inducing LTP when the mossy fiber pathway (MF) was activated simultaneously, thus demonstrating associative plasticity between the two pathways. We also demonstrated associative LTP between PP and recurrent collateral fibers (RC). PP LTP was blocked by theN-methyl-d-aspartate receptor (NMDAR) antagonist 2-amino-5-phosphonovaleric acid in both the associative and homosynaptic induction conditions. Neither MF nor RC fiber HFS alone resulted in permanent changes in PP field excitatory postsynaptic potential (fEPSP) amplitude. However, HFS delivered to either MF or RC alone led to transient heterosynaptic depression of the PP fEPSP. Our results support the conceptual framework that regards CA3 as an autoassociative memory network in which efficient retrieval of previously stored activity patterns is mediated by associative plasticity of the PP synapse.

The mechanisms generating giant miniature excitatory postsynaptic currents (mEPSCs) were investigated at the hippocampal mossy fiber (MF) to CA3 pyramidal cell synapse in vitro. These giant mEPSCs have peak amplitudes as large as 1,700 pA (13.6 nS) with a mean maximal mEPSC amplitude of 366 ± 20 pA (mean ± SD; 5 nS; n= 25 cells). This is compared with maximal mEPSC amplitudes of <100 pA typically observed at other cortical synapses. We tested the hypothesis that giant mEPSCs are due to synchronized release of multiple vesicles across the release sites of single MF boutons by directly inducing vesicular release using secretagogues. If giant mEPSCs result from simultaneous multivesicular release, then secretagogues should increase the frequency of small mEPSCs selectively. We found that hypertonic sucrose and spermine increased the frequency of both small and giant mEPSCs. The peptide toxin secretagogues alpha-latrotoxin and pardaxin failed to increase the frequency of giant mEPSCs, but the possible lack of tissue penetration of the toxins make these results equivocal. Because a multiquantal release mechanism is likely to be mediated by a spontaneous increase in presynaptic calcium concentration, a monoquantal mechanism is further supported by results that giant mEPSCs were not affected by manipulations of extracellular or intracellular calcium concentrations. In addition, reducing the temperature of the bath to 15°C failed to desynchronize the rising phases of giant mEPSCs. Together these data suggest that the giant mEPSCs are generated via a monovesicular mechanism. Three-dimensional analysis through serial electron microscopy of the MF boutons revealed large clear vesicles (50 to 160 nm diam) docked presynaptically at the MF synapse in sufficient numbers to account for the amplitude and frequency of giant mEPSCs recorded electrophysiologically. It is concluded that release of the contents of a single large clear vesicle generates giant mEPSCs at the MF to CA3 pyramidal cell synapse.

Abstract: There have been very few investigations of the spatial properties of taste stimuli localized to specific areas of the oral cavity. This is surprising, since the spatial localization of taste sensations may contribute to the overall taste percept, much as do quality, intensity, and the temporal characteristics of tastes. The difficulty in elirrdnating the confounding factor of a tactile sensation may partially account for the paucity of such studies, since a gustatory stimulus cannot be presented as a liquid without a tactile component. As a step toward understanding the localizability of gustatory sensations, we designed a yoked stimulator and an experimental procedure to control for tactile cues. Lateral discrimination was evaluated at the tip of the tongue with four taste stimuli (sodium saccharin, sodium chloride, citric acid, and quinine hydrochloride) by presenting a taste and a blank solution simultaneously at two locations on the tongue. We found that subjects could lateralize all four taste stimuli in the absence of any discriminative tactile cues. Subjects’ ability to lateralize varied as a psychometric function of the stimulus concentration. Detection thresholds, measured in a forced-choice two-interval staircase procedure with the same yoked stimulator that was used in the lateralization task, were always lower than lateralization thresholds, and both lateralization and detection thresholds were correlated within subjects. Subjects were unable to lateralize taste cues on a nongustatory surface under the upper lip at the highest tested concentrations, at which performance was 100% on a gustatory surface (dorsal anterior tongue). These results show that (1) taste compounds can be lateralized in the absence of any discriminative mechanical cue (but only on the gustatory epithelium) and (2) although the localization of a compound does not logically require conscious detection of the taste (cf.blind sight), subjects always detected a taste when they were able to lateralize.

The Turin papyrus map is over 3000 years old. More than 100 years of study mainly by egyptologists and by some geologists demonstrate that it shows workings in a known ancient mining and quarrying district of Upper Egypt (the Wadi Hammamat). It seems to have been made in connection with the transportation (and damage?) of a statue from the quarries. The map is significant because of its antiquity and because it shows substantial geological information which underlies the mining and quarrying knowledge which it contains.

Two letters to the editor are presented in response to the letter of Roy Sablosky on atheism in the January 13, 2007 issue.

To the Editor:—A 21-year-old man entered the hospital because abdominal pain, which had been present intermittently for two weeks, was located in the epigastrium, and usually occurred after meals. There was accompanying nausea and mild vomiting on two occasions. There had been no weight loss or melena.Two years previously an uppergastrointestinal tract x-ray series reportedly had demonstrated an active duodenal ulcer. The patient responded promptly to conservative ulcer therapy.Physical examination, routine laboratory and chest x-ray studies revealed nothing abnormal. An uppergastrointestinal tract x-ray series showed partial obstruction of the second portion of the duodenum with dilatation of the proximal part (Fig 1). An ulcer crater was not identified.At exploratory laparotomy an annular pancreas was identified which completely encircled the second portion of the duodenum (Fig 2). A side-to-side duodenoduodenostomy was performed. There was no evidence of duodenal ulcer. Two months postoperatively the patient was asymptomatic. Postoperative