Elusive Seed Formation via Electrical Confinement: Control of a Novel Cocrystal in Cooling Crystallization

Pharmaceutical cocrystals are multicomponent materials formed to enhance the properties of active pharmaceutical ingredients (APIs) and are commercially used to increase the number of drug candidates that successfully make it through the drug discovery pipeline. Nevertheless, the industrial production of cocrystals and other elusive solid forms remains a challenge. The main limitations are due to challenges related to the scale-up, solid-form control, and undesirable parameters needed for the preparation method. This study leverages the features of electrospray crystallization to generate elusive cocrystal forms that contain the API acetaminophen (paracetamol) and its regioisomer metacetamol. We report the formation of a new cocrystal, which is held together by van der Waals interactions, and the use of the newly electrosprayed cocrystals as seeds to tune the performance of cooling crystallization, allowing this commonly used crystallization method to produce the elusive cocrystal. The electrosprayed cocrystal displays a previously unseen sponge-like surface topology and a fourfold solubility enhancement over those found for single-component APIs. This new technology expands the accessibility to new solid forms that were previously inaccessible by other crystallization methods.</p

Validation of AD8-Philippines (AD8-P): A brief informant-based questionnaire for dementia screening in the Philippines

Aim: This study was aimed at validating the Filipino version of AD8 (AD8-P). Methods: Community-dwelling Filipino older persons aged ≥60 years, together with their informants, participated in this study. Psychologists independently interviewed the informants with AD8-P and administered the Filipino-validated Mini-Mental State Examination (MMSE-P) and Montreal Cognitive Assessment (MoCA-P) to the older persons. Neurologists and geriatrician conducted physical and neurological examination and Clinical Dementia Rating™ (CDR™) to determine cognitive diagnosis and were blinded with the results of AD8-P. Dementia was diagnosed based on DSM-IV-TR criteria. AD8-P discriminatory ability to screen for dementia was evaluated according to DSM-IV-TR diagnostic criteria for dementia. Results: A total of 366 community-dwelling Filipino older persons aged ≥60 years, 213 with normal cognition and 153 with dementia, and their informants were included in this study. Majority (90%) were at the mildest stage of dementia. Area under the receiver-operating-characteristic curve (AUROC) for AD8-P was 0.94 (95% CI 0.92 to 0.96), demonstrating excellent overall predictive power to screen for dementia. The optimal AD8-P cut-off score with best balance sensitivity (91.5%) and specificity (77.9%) was ≥3. Conclusion: AD8-P demonstrated good psychometric properties to screen for dementia, even at the earliest stage of cognitive decline

Form factors for B−−>πlνB-->\pi l\nu decay in a model constrained by chiral symmetry and quark model

The form factors for the $B-->\pi$ transition are evaluated in the entire momentum transfer range by using the constraints obtained in the framework combining the heavy quark expansion and chiral symmetry for light quarks and the quark model. In particular, we calculate the valence quark contributions and show that it together with the equal time commutator contribution simulate a B-meson pole q^2-dependence of form factors in addition to the usual vector meson B^{*}-pole diagram for $B --> \pi l\nu$ in the above framework. We discuss the predictions in our model, which provide an estimate of |V_{ub}|^2.Comment: 7 pages, Revtex, 5 figure, fig 3 is replaced and some text is adde

Treatment challenges associated with bone echinococcosis

Objectives In this literature review, we concentrate on epidemiology and therapy of osseous echinococcosis, with an emphasis on the recurrence risk. Methods Literature review 1930-2012. Results We retrieved 200 publications based upon single case reports or case series, mostly from resource-poor settings. Among the 721 rural patients (22% females; median age 37 years), 60% of all reported cases were from the Mediterranean region and almost all patients were immune competent. Echinococcus granulosus was identified as the most frequent species. Most infections involved a single bone (602/721; 83%) and often the spine (321 cases; 45%). In eight cases (8/702; 1%), a secondary bacterial surgical site infection was reported. Surgical intervention was performed in 702 cases (97%), with single intervention in 687 episodes (95%). Complete excision of the lesion was possible in only 117 episodes (16%). Albendazole was by far the most frequently used agent in monotherapy with various dosages, while mebendazole in monotherapy was less frequent (32 cases). The median duration of antihelminthic therapy was 6 months (range 0.7-144 months). There were 124 recurrences (17%) after a median delay of 2 years (range 0.4-17 years). In multivariate analysis, the presence of visceral organ involvement increased the odds of recurrence by 5.4 (95% CI 3.1-9.4), whereas the number of surgical interventions, the duration of antihelminthic therapy or the use of hypertonic saline did not influence recurrence. Conclusions Bone echinococcosis is a rare parasitic disease. While treatment modalities vary considerably, combined surgical and medical approaches are the standard of care with a 17% risk of recurrenc

Deep Learning for Cardiologist-level Myocardial Infarction Detection in Electrocardiograms

Myocardial infarction is the leading cause of death worldwide. In this paper, we design domain-inspired neural network models to detect myocardial infarction. First, we study the contribution of various leads. This systematic analysis, first of its kind in the literature, indicates that out of 15 ECG leads, data from the v6, vz, and ii leads are critical to correctly identify myocardial infarction. Second, we use this finding and adapt the ConvNetQuake neural network model--originally designed to identify earthquakes--to attain state-of-the-art classification results for myocardial infarction, achieving $99.43\%$ classification accuracy on a record-wise split, and $97.83\%$ classification accuracy on a patient-wise split. These two results represent cardiologist-level performance level for myocardial infarction detection after feeding only 10 seconds of raw ECG data into our model. Third, we show that our multi-ECG-channel neural network achieves cardiologist-level performance without the need of any kind of manual feature extraction or data pre-processing.Comment: Accepted to the European Medical and Biological Engineering Conference (EMBEC) 202

Intermediate distance correlators in hot Yang-Mills theory

Lattice measurements of spatial correlation functions of the operators FF and FF-dual in thermal SU(3) gauge theory have revealed a clear difference between the two channels at "intermediate" distances, x ~ 1/(pi T). This is at odds with the AdS/CFT limit which predicts the results to coincide. On the other hand, an OPE analysis at short distances (x << 1/(pi T)) as well as effective theory methods at long distances (x >> 1/(pi T)) suggest differences. Here we study the situation at intermediate distances by determining the time-averaged spatial correlators through a 2-loop computation. We do find unequal results, however the numerical disparity is small. Apart from theoretical issues, a future comparison of our results with time-averaged lattice measurements might also be of phenomenological interest in that understanding the convergence of the weak-coupling series at intermediate distances may bear on studies of the thermal broadening of heavy quarkonium resonances.Comment: 31 page

Lower Limb Muscle Strength and Muscle Mass Are Associated With Incident Symptomatic Knee Osteoarthritis: A Longitudinal Cohort Study

Recent literature suggests that sarcopenia, often represented by low lower limbs muscle mass and strength, can be considered a potential risk factor for knee osteoarthritis (OA), but the available literature is still limited. We therefore aimed to investigate whether sarcopenia is associated with a higher risk of radiographic (ROA) and symptomatic knee OA (SxOA) in a large cohort of North American people in the context of the OA initiative. Sarcopenia at baseline was diagnosed in case of low skeletal muscle mass (i.e., lower skeletal mass index) and poor performance in the chair stands test. The outcomes of interest for this study included ROA (radiographical osteoarthritis) if a knee developed a Kellgren and Lawrence (KL) grade ≥2 at follow-up, and SxOA (symptomatic osteoarthritis) defined as new onset of a combination of painful knee OA. Altogether, 2,492 older participants (mean age: 68.4 years, 61.4% females) were included. At baseline, sarcopenia was present in 6.1% of the population. No significant difference in ROA prevalence was observed between those with and without sarcopenia (p=0.76), whilst people with sarcopenia reported a significant higher prevalence of SxOA (p&lt;0.0001). Using a logistic regression analysis, adjusting for potential confounders at baseline and the diagnosis of sarcopenia during follow-up, sarcopenia was associated with a higher incidence of knee SxOA (odds ratio, OR=2.29; 95%CI [confidence interval]: 1.42-3.71; p=0.001), but not knee ROA (OR=1.48; 95%CI: 0.53-4.10; p=0.45). In conclusion, sarcopenia could be associated with a higher risk of negative knee OA outcomes, in particular symptomatic forms

Recommendations from the United European Gastroenterology evidence-based guidelines for the diagnosis and therapy of chronic pancreatitis

In collaboration with United European Gastroenterology, the working group on 'Harmonizing diagnosis and treatment of chronic pancreatitis across Europe' (HaPanEU) developed European guidelines for the management of chronic pancreatitis using an evidence-based approach.Recommendations of multidisciplinary review groups based on systematic literature reviews to answer predefined clinical questions are summarised. Recommendations are graded using the Grading of Recommendations Assessment, Development and Evaluation system.Recommendations covered topics related to the clinical management of chronic pancreatitis: aetiology, diagnosis of chronic pancreatitis with imaging, diagnosis of pancreatic exocrine insufficiency, surgical therapy, medical therapy, endoscopic therapy, treatment of pancreatic pseudocysts, pancreatic pain, nutrition and malnutrition, diabetes mellitus and the natural course of the disease and quality of life.The HaPanEU/United European Gastroenterology guidelines provide evidence-based recommendations concerning key aspects of the medical and surgical management of chronic pancreatitis based on current available evidence. These recommendations should serve as a reference standard for existing management of the disease and as a guide for future clinical research. This article summarises the HaPanEU recommendations and statements

Ward Identities, B-> \rho Form Factors and |V_ub|

The exclusive FCNC beauty semileptonic decay B-> \rho is studied using Ward identities in a general vector meson dominance framework, predicting vector meson couplings involved. The long distance contributions are discussed which results to obtain form factors and |V_ub|. A detailed comparison is given with other approaches.Comment: 30 pages+four postscript figures, an Appendix adde

Isospin Breaking in the Pion-Nucleon Coupling from QCD Sum Rules

We use QCD sum rules for the three point function of a pseudoscalar and two nucleonic currents in order to estimate the charge dependence of the pion nucleon coupling constant $g_{NN\pi}$ coming from isospin violation in the strong interaction. The effect can be attributed primarily to the difference of the quark condensates $$and$$. For the splitting $(g_{pp\pi_0} - g_{nn\pi_0}) / g_{NN\pi}$ we obtain an interval of $1.2 * 10^{-2}$ to $3.7 * 10^{-2}$, the uncertainties coming mainly from the input parameters. The charged pion nucleon coupling is found to be the average of $g_{pp\pi_0}$ and $g_{nn\pi_0}$. Electromagnetic effects are not included.Comment: 18 pages (REVTeX) + 2 figures (as PostScript), to be published in PRC, replaced with final version: inclusion of pi-eta mixing and N -> N* transition