Preparation of ß-Hydroxyketones (Aldols) from the Alkylation of O-Silyl Aryl Cyanohydrins with Epoxides.

ß-Hydroxyketones (aldols) are prepared from the alkylation-deprotection of O-silylated aryl cyanohydrins with epoxides. Key to the success of the method was the suppression of an in situ cyclic imidate formation that occurs upon initial opening of the epoxide ring.

Transition from in-person to telehealth standardized patient encounters: A retrospective analysis of 18 cases.

INTRODUCTION: Due to the COVID-19 pandemic, many pedagogical activities shifted from in-person to virtual modalities, including standardized patient (SP) encounters. While many academic institutions may not have previously been conducting SP encounters virtually, this change provided student pharmacists with new opportunities to learn and practice telehealth techniques, which are important with the continuously evolving healthcare landscape. METHODS: This retrospective study analyzed pharmacy student performance on and perceptions of SP cases in fall 2019 (in-person) and fall 2020 (telehealth) semesters. The primary objective was to compare average total scores on SP cases from fall 2019 (in-person) and fall 2020 (telehealth) for first-, second-, and third-year pharmacy students (P1, P2, and P3, respectively). Secondary objectives were to compare average scores from case-specific and relationship and communication (R&C) checklists, as well as to describe student perceptions of the pedagogy. RESULTS: Total scores on SP cases decreased from in-person to telehealth for the average of all P1 SP cases, but not for P2 or P3 cases. Case-specific scores did not change, but R&C scores decreased significantly across all three years. Student survey data revealed difficulty with communicating effectively and building rapport via telehealth. CONCLUSIONS: Overall, student performance on in-person vs. telehealth SP encounters was similar, though P1 students performed more poorly on SP cases conducted via telehealth compared to P2 or P3 students. Thus, faculty could consider focusing on in-person encounters for early learners before introducing virtual encounters. This study also highlights the difficulty in establishing rapport when communicating with patients via telehealth.

Identification of Penicillin Binding Protein 4 (PBP4) as a critical factor for Staphylococcus aureus bone invasion during osteomyelitis in mice.

Staphylococcus aureus infection of bone is challenging to treat because it colonizes the osteocyte lacuno-canalicular network (OLCN) of cortical bone. To elucidate factors involved in OLCN invasion and identify novel drug targets, we completed a hypothesis-driven screen of 24 S. aureus transposon insertion mutant strains for their ability to propagate through 0.5 µm-sized pores in the Microfluidic Silicon Membrane Canalicular Arrays (µSiM-CA), developed to model S. aureus invasion of the OLCN. This screen identified the uncanonical S. aureus transpeptidase, penicillin binding protein 4 (PBP4), as a necessary gene for S. aureus deformation and propagation through nanopores. In vivo studies revealed that Δpbp4 infected tibiae treated with vancomycin showed a significant 12-fold reduction in bacterial load compared to WT infected tibiae treated with vancomycin (p<0.05). Additionally, Δpbp4 infected tibiae displayed a remarkable decrease in pathogenic bone-loss at the implant site with and without vancomycin therapy. Most importantly, Δpbp4 S. aureus failed to invade and colonize the OLCN despite high bacterial loads on the implant and in adjacent tissues. Together, these results demonstrate that PBP4 is required for S. aureus colonization of the OLCN and suggest that inhibitors may be synergistic with standard of care antibiotics ineffective against bacteria within the OLCN.

A Systematic Review of Entrepreneurship in Pharmacy Practice and Education.

Objective. To review literature pertaining to entrepreneurship in pharmacy practice, education, and the knowledge, skills, and attitudes (KSAs) identified for pharmacist entrepreneurs. Findings. In terms of pharmacy practice, entrepreneurship was most frequently identified with innovation and creativity to develop new opportunities for pharmacists. The most frequent role for entrepreneurship in pharmacy education was related to schools putting a greater emphasis on innovation, creativity, or divergent thinking. Risk-taking and creativity/innovation were the most frequently identified KSAs, with 17 (63.0%) manuscripts mentioning these as important for a pharmacist entrepreneur. Other KSAs pertaining to pharmacy entrepreneurship that were mentioned in the articles included self-starter, management, proactivity, communication, strategic planning, positivity, decision-making, teamwork, versatility, marketing, critical thinking, competitiveness, proposal development, numeracy, technology, self-reflection, persistence, social responsibility, and cultural competence. Summary. No consensus for entrepreneurship in pharmacy practice or education currently exists. In order to improve instructional design and assessment for pharmacy entrepreneurship education, a core set of KSAs for a pharmacist entrepreneur construct must be identified. The most commonly cited KSAs in related literature that are not already part of the Accreditation Council for Pharmacy Education standards include risk-taking, strategic planning, marketing, competitiveness, and social responsibility. These may serve as a starting point for enhancing pharmacy curricula to embrace pharmacist entrepreneurship.

Acute and chronic toxicity of copper to the euryhaline rotifer, Brachionus plicatilis ("L" strain).

This article presents data from original research, intended for the use in the development of copper (Cu) criteria for the protection of estuarine and marine organisms and their uses in the United States. Two 48-h static-acute toxicity tests-one with and one without added food-and a 96-h static multigeneration life-cycle test (P1-F2 generations) were performed concurrently using the euryhaline rotifer Brachionus plicatilis ("L" strain) to develop a Cu acute-to-chronic ratio (ACR) for this species. Tests were performed at 15 g/L salinity, at 25°C, and the exposure concentrations of dissolved Cu were verified. Supplemental chemical analyses were performed and reported for the development of a Cu-saltwater biotic ligand model (BLM). Supplemental analyses included alkalinity, calcium, chloride, dissolved organic carbon (DOC), hardness, magnesium, potassium, sodium, and temperature. The acute toxicity test measurement end points were the dissolved Cu median lethal concentration (LC50) values based on rotifer survival. The chronic measurement end points were the dissolved Cu no-observed-effect concentration (NOEC), lowest-observed-effect concentration (LOEC), EC25, EC20, and EC10 based on the intrinsic rate of rotifer population increase (r). The 48-h LC50(Fed), 48-h LC50(Unfed), 96-h NOEC, 96-h LOEC, EC25, EC20, and EC10 were 20.8, 13.4, 6.1, 10.3, 11.7, 10.9, and 8.8 µg Cu/L, respectively. The ACRs were calculated as ratios of each 48-h LC50 value [fed and unfed) and each of the 96-h chronic values (ChV; geometric mean of NOEC and LOEC)], EC10, EC20, and EC25. The ACRs ranged from 1.15 to 2.63.

The effects of salinity, pH, and dissolved organic matter on acute copper toxicity to the rotifer, Brachionus plicatilis ("L" strain).

This paper presents data from original research for use in the development of a marine biotic ligand model and, ultimately, copper criteria for the protection of estuarine and marine organisms and their uses. Ten 48-h static acute (unfed) copper toxicity tests using the euryhaline rotifer Brachionus plicatilis ("L" strain) were performed to assess the effects of salinity, pH, and dissolved organic matter (measured as dissolved organic carbon; DOC) on median lethal dissolved copper concentrations (LC50). Reconstituted and natural saltwater samples were tested at seven salinities (6, 11, 13, 15, 20, 24, and 29 g/L), over a pH range of 6.8-8.6 and a range of dissolved organic carbon of <0.5-4.1 mg C/L. Water chemistry analyses (alkalinity, calcium, chloride, DOC, hardness, magnesium, potassium, sodium, salinity, and temperature) are presented for input parameters to the biotic ligand model. In stepwise multiple regression analysis of experimental results where salinity, pH, and DOC concentrations varied, copper toxicity was significantly related only to the dissolved organic matter content (pH and salinity not statistically retained; alpha=0.05). The relationship of the 48-h dissolved copper LC50 values and dissolved organic carbon concentrations was LC50 (microg Cu/L)=27.1xDOC (mg C/L)1.25; r2=0.94.

Clinical trial: benefits and risks of immunomodulators and maintenance infliximab for IBD-subgroup analyses across four randomized trials.

BACKGROUND: Benefits and risks of concomitant immunomodulators and maintenance infliximab in inflammatory bowel disease (IBD) patients have not been adequately evaluated. AIM: To assess the effect of concomitant immunomodulator and infliximab maintenance therapy using data from four prospective, randomized Phase 3 trials in IBD patients. METHODS: Overall, 1383 patients from ACCENT I and ACCENT II [luminal and fistulizing Crohn's disease trials] and ACT 1 and ACT 2 [ulcerative colitis trials] were analysed. Patients were treated with placebo or infliximab 5 or 10 mg/kg at weeks 0, 2 and 6 followed by every-8-week maintenance therapy. Clinical response, clinical remission, fistula response, complete fistula response, infection and infusion reaction rates; serum infliximab concentrations and immunogenicity were summarized by baseline concomitant immunomodulator subgroup (use or non-use). RESULTS: Overall, almost 40% of evaluated IBD patients received concomitant immunomodulators. Efficacy, infection, and serious infection rates were generally similar in patients who received maintenance therapy with or without concomitant immunomodulators. There were no consistent differences in serum infliximab concentrations with or without immunomodulators in patients who received scheduled maintenance therapy. Concomitant immunomodulators reduced infusion reactions and immunogenicity. CONCLUSION: Concomitant immunomodulators did not improve efficacy or pharmacokinetics in IBD patients who received maintenance infliximab.

Maintenance infliximab does not result in increased abscess development in fistulizing Crohn's disease: results from the ACCENT II study.

BACKGROUND: Rapid fistula healing may predispose Crohn's disease patients to abscess development. AIM: Data from ACCENT II were analysed to determine whether fistula-related abscess development is affected by infliximab exposure. METHODS: Following infliximab 5 mg/kg infusions at weeks 0, 2 and 6, patients were evaluated for fistula response for two consecutive visits at least 4 weeks apart. Patients (N = 282) were randomized at week 14 to either placebo or infliximab 5 mg/kg every 8 weeks through week 46. If response was lost at or after week 22, patients could crossover to a 5 mg/kg higher infliximab dose. Fistula-related abscesses were diagnosed by physical examination or by imaging procedures according to usual practice. RESULTS: Infliximab exposure was approximately twofold higher for the infliximab maintenance group. Twenty-one (15%) patients in the infliximab maintenance group had at least one newly developed fistula-related abscess compared with 27 (19%) in the placebo maintenance group (P = 0.526). The proportion of patients with a new fistula-related abscess was similar regardless of whether or not patients crossed over to a 5 mg/kg higher infliximab dose. The number of fistula-related abscesses diagnosed over time did not differ between groups. CONCLUSION: Abscess development in patients with fistulizing Crohn's disease is not dependent on cumulative infliximab exposure.

Order-to-chaos transition in rotational nuclei.

We have developed a new method to study the order-to-chaos transition in rotational nuclei. Correlations between successive gamma rays are used to determine the average complexity of the intermediate levels and thereby the ratio of the interaction potential between levels to the level spacing. The measured ratios, 0.15 to 1.5, span the range from nearly fully ordered to nearly fully chaotic.

Evidence for a new type of shears mechanism in 106Cd.

Lifetimes of states in the lowest lying positive parity band in 106Cd have been measured using the Doppler shift attenuation method. The deduced B(E2) transition rates show a marked decrease with increasing spin. Cranking and semiclassical model calculations suggest that the structure has the character of a shears-type band resulting from the coupling of g(9/2) proton holes to aligned pairs of h(11/2) and g(7/2) neutron particles. This is the first clear evidence for the phenomenon of "antimagnetic" rotation in nuclei.

Rotational damping in ytterbium nuclei.

We have made the first clear measurements of rotational damping widths in nuclei. In a mixture of three Yb nuclei, these widths are 300 +/- 60 keV between 1.2 and 1.5 MeV gamma-ray energy [approximately (37-57)Planck's constant]. Compound damping and motional narrowing are discussed in connection with these results.

Very extended shapes in the A--110 region.

High-angular-momentum states in 108Cd were populated via the (64)Ni((48)Ca,4n) reaction at a beam energy of 207 MeV. Gamma rays were detected using the Gammasphere array. A rotational band has been observed with a dynamic moment of inertia and deduced lower limit of the quadrupole moment suggesting a major-to-minor axis ratio larger than 1.8:1, placing it among the most deformed structures identified in any nucleus, to date.

Primary care physicians' experience with mental health consultation.

A total of 684 primary care physicians in Wisconsin participated in a survey designed to explore their experiences of consulting with and referring patients to mental health care professionals. The respondents indicated that they had only moderate access to mental health care professionals, and even less access when a patient was covered by Medicare or Medicaid or had no insurance. Physicians in group practices that included at least one mental health professional reported having better access to care than those in practices that did not include mental health services. Perceived access to mental health care services was not related to community size or to a managed care setting.

ATF-7, a novel bZIP protein, interacts with the PRL-1 protein-tyrosine phosphatase.

We have identified a novel basic leucine zipper (bZIP) protein, designated ATF-7, that physically interacts with the PRL-1 protein-tyrosine phosphatase (PTPase). PRL-1 is a predominantly nuclear, farnesylated PTPase that has been linked to the control of cellular growth and differentiation. This interaction was initially found using the yeast two-hybrid system. ATF-7 is most closely related to members of the ATF/CREB family of bZIP proteins, with highest homology to ATF-4. ATF-7 homodimers can bind specifically to CRE elements. ATF-7 is expressed in a number of different tissues and is expressed in association with differentiation in the Caco-2 cell model of intestinal differentiation. We have confirmed the PRL-1.ATF-7 interaction and mapped the regions of ATF-7 and PRL-1 important for interaction to ATF-7's bZIP region and PRL-1's phosphatase domain. Finally, we have determined that PRL-1 is able to dephosphorylate ATF-7 in vitro. Further insight into ATF-7's precise cellular roles, transcriptional function, and downstream targets are likely be of importance in understanding the mechanisms underlying the complex processes of maintenance, differentiation, and turnover of epithelial tissues.

Video-capture teleradiology for the after-hours reading of computerized tomography scans.

We evaluated the after-hours support that radiologists could provide from their homes to an urban hospital for reading emergency computerized tomography (CT) scans. During a six-month study period, 36 CT scans were acquired using a video-capture card in a PC and transmitted via an ordinary telephone line. The teleradiology interpretation and the formal report (from the hard copy) were compared with a reference or gold standard interpretation made by a radiologist and an emergency physician for 31 of the 36 cases. In comparison with the gold standard, there were 26 correct diagnoses by teleradiology (84%) and five incorrect (16%). Head CT scans accounted for 74% of the transmitted scans and all five of the cases with discrepant diagnoses. The cause of the single clinically relevant discrepancy was found to be unrelated to the use of teleradiology. In comparison with the formal report, the accuracy of the teleradiologist was not significantly different for all categories combined or for head CT scans alone. Video-capture technology provided a reliable means of transmitting CT scans for after-hours interpretation in emergency cases.

PRL-1 PTPase expression is developmentally regulated with tissue-specific patterns in epithelial tissues.

The mechanisms controlling tyrosine phosphorylation of cellular proteins are important in the regulation of many cellular processes, including development and differentiation. Protein tyrosine phosphatases (PTPases) may be as important as protein tyrosine kinases (PTKs) in these processes. PRL-1 is a distinct PTPase originally identified as an immediate-early gene in liver regeneration whose expression is associated with growth in some tissues but with differentiation in others. We now demonstrate that the PRL-1 protein is expressed during development in a number of digestive epithelial tissues. It is expressed at variable time points in the developing intestine, but its expression is limited to the developing villus enterocytes. In the gastric epithelium, PRL-1 expression in the adult is restricted to zymogen cells. PRL-1 is also expressed in the developing liver and esophagus and in the epithelia of the kidney and lung. In each of these contexts, the expression of PRL-1 is associated with terminal differentiation, suggesting that it may play a role in this important developmental process.

Quantitation of T-cell receptor frequencies by competitive polymerase chain reaction: dynamics of T-cell clonotype frequencies in an expanding tumor-infiltrating lymphocyte culture.

The use of T-cell receptor (TCR) genes as markers for antigen-reactive T cells is dependent on the ability of the TCR genes to rapidly identify antigen-reactive T-cell clonotypes in patient samples. We recently reported a competitive reverse-transcriptase polymerase chain reaction (cRT-PCR) method that can measure the frequency of individual TCRBV subfamilies and clonotypes in mixed lymphocyte populations more accurately than other semiquantitative PCR assays. However, it is impractical to measure changes in the absolute frequency of each TCRBV subfamily to identify those T cells with increasing frequency after antigen stimulation in vivo or in vitro. Therefore, we have modified our cRT-PCR method to more rapidly identify expanding T-cell populations by combining all of the TCRBV subfamily-specific competitors into a single sample to determine the relative abundance of each TCRBV subfamily. Using an expanding TIL 620 culture, we identified four TCRBV (BV2, BV12, BV17, and BV23) subfamilies that expanded over a 23-day period. These subfamilies accounted for 23% of the T cells in the day 35 culture and increased to 57%, 92%, and 80% of the days 44, 51, and 58 cultures respectively. Analysis of DNA sequences demonstrated that the observed expansion was caused primarily by a single clonotype within each subfamily. T cells expressing BV17 and BV23 recognized gp100 and MART-1 respectively. Therefore, this cRT-PCR method can detect expanding T-cell populations based solely on their TCRBV subfamily expression. Furthermore, T-cell expansion in a mixed TIL population was a good predictor of antigen reactivity.