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Dysregulation of the input from the prefrontal cortex (PFC) to the nucleus accumbens (NAc) contributes to cue-induced opioid seeking but the heterogeneity in, and regulation of, prelimbic (PL)-PFC to NAc (PL->NAc) neurons that are altered has not been comprehensively explored. Recently, baseline and opiate withdrawal-induced differences in intrinsic excitability of Drd1+(D1+) versus Drd2+(D2+) PFC neurons have been demonstrated. Thus, here we investigated physiological adaptations of PL->NAc D1+versus D2+neurons after heroin abstinence and cue-induced relapse. Drd1-Cre+and Drd2-Cre+transgenic male Long–Evans rats with virally labeled PL->NAc neurons were trained to self-administer heroin followed by 1 week of forced abstinence. Heroin abstinence significantly increased intrinsic excitability in D1+and D2+PL->NAc neurons and increased postsynaptic strength selectively in D1+neurons. These changes were normalized by cue-induced relapse to heroin seeking. Based on protein kinase A (PKA)-dependent changes in the phosphorylation of plasticity-related proteins in the PL cortex during abstinence and cue-induced relapse to cocaine seeking, we assessed whether the electrophysiological changes in D1+and D2+PL->NAc neurons during heroin abstinence were regulated by PKA. In heroin-abstinent PL slices, application of the PKA antagonist (R)-adenosine, cyclic 3′,5′-(hydrogenphosphorothioate) triethylammonium (RP-cAMPs) reversed intrinsic excitability in both D1+and D2+neurons and postsynaptic strength in only D1+neurons. Additionally,in vivobilateral intra-PL infusion of RP-cAMPs after abstinence from heroin inhibited cue-induced relapse to heroin seeking. These data reveal that PKA activity in D1+and D2+PL->NAc neurons is not only required for abstinence-induced physiological adaptations but is also required for cue-induced relapse to heroin seeking.SIGNIFICANCE STATEMENTNeuronal plasticity in the medial prefrontal cortex is thought to underlie relapse to drug seeking, yet the subpopulation of neurons that express this plasticity to functionally guide relapse is unclear. Here we show cell type-specific adaptations in Drd1-expressing versus Drd2-expressing prelimbic pyramidal neurons with efferent projections to nucleus accumbens. These adaptations are bidirectionally regulated during abstinence versus relapse and involve protein kinase A (PKA) activation. Furthermore, we show that disruption of the abstinence-associated adaptations via site-specific PKA inhibition abolishes relapse. These data reveal the promising therapeutic potential of PKA inhibition for preventing relapse to heroin seeking and suggest that cell type-specific pharmacologies that target subpopulations of prefrontal neurons would be ideal for future therapeutic developments.

The full employment interest rate implicit in classical economic theory is 4½%, deduced by including the rate of normal profit in a simple macroeconomic model. By not fixing the interest rate at this optimum, Central Banks endogenously maintain excess productive capacity, cause unemployment, and encourage the exploitation of Labour by Capital.

As the primary agents of skin and soft tissue infections in animals, Staphylococcus spp and Pseudomonas aeruginosa are among the most formidable bacterial pathogens encountered by veterinarians. Staphylococci are commensal inhabitants of the surfaces of healthy skin and mucous membranes, which may gain access to deeper cutaneous tissues by circumventing the stratum corneum’s barrier function. Compromised barrier function occurs in highly prevalent conditions such as atopic dermatitis, endocrinopathies, and skin trauma. P aeruginosa is an environmental saprophyte that constitutively expresses virulence and antimicrobial resistance genes that promote its success as an animal pathogen. For both organisms, infections of the urinary tract, respiratory tract, joints, central nervous system, and body cavities may occur through ascension along epithelial tracts, penetrating injuries, or hematogenous spread. When treating infections caused by these pathogens, veterinarians now face greater therapeutic challenges and more guarded outcomes for our animal patients because of high rates of predisposing factors for infection and the broad dissemination of antimicrobial resistance genes within these bacterial species. This review considers the history of the rise and expansion of multidrug resistance in staphylococci and P aeruginosa and the current state of knowledge regarding the epidemiologic factors that underly the dissemination of these pathogens across companion animal populations. Given the potential for cross-species and zoonotic transmission of pathogenic strains of these bacteria, and the clear role played by environmental reservoirs and fomites, a one-health perspective is emphasized.

Background: Co-curricular (CoC) activity tracking and assessment are required by the Accreditation Council for Pharmacy Education (ACPE) 2016 Standards. The purpose of this manuscript is to evaluate the student-perceived impact of the type of CoC activity chosen. Methods: First-year (P1) through third-year (P3) students in a 4-year Doctor of Pharmacy programme were required to complete two Professional Development Unit (PDUs) activities each semester and two Self-Selected Activities (SSAs) longitudinally through each academic year. PDUs include passive attendance at practitioner presentations, whereas SSAs require more active engagement, such as membership in professional organisations. Students completed surveys for each CoC activity. Survey responses for spring 2020, fall 2020, and spring 2021 were collected through ExamSoft and analysed with PowerBI (2021) and IntellectusStatisticsTM (2019). Results: Students reported positive perceptions for both PDUs and SSAs in the areas of being “different from prior experiences”, “complimenting the curriculum”, “increased my understanding of the profession”, and being of “high quality”. Professional organisation activities were the most commonly selected SSA. Those activities with lower perceived benefit were less clearly aligned with the professional role of a pharmacist, such as intramural sports. Conclusion: Overall, most CoC activities that closely aligned with the profession of pharmacy were perceived to complement the curriculum and enhance students’ understanding of the field. Students reported perceived value in both active and passive CoC activities.

Aims Left bundle branch area pacing (LBBAP) is a promising method for delivering cardiac resynchronization therapy (CRT), but its relative physiological effectiveness compared with His bundle pacing (HBP) is unknown. We conducted a within-patient comparison of HBP, LBBAP, and biventricular pacing (BVP). Methods and results Patients referred for CRT were recruited. We assessed electrical response using non-invasive mapping, and acute haemodynamic response using a high-precision haemodynamic protocol. Nineteen patients were recruited: 14 male, mean LVEF of 30%. Twelve had time for BVP measurements. All three modalities reduced total ventricular activation time (TVAT), (ΔTVATHBP -43 ± 14 ms and ΔTVATLBBAP −35 ± 20 ms vs. ΔTVATBVP −19 ± 30 ms, P = 0.03 and P = 0.1, respectively). HBP produced a significantly greater reduction in TVAT compared with LBBAP in all 19 patients (−46 ± 15 ms, −36 ± 17 ms, P = 0.03). His bundle pacing and LBBAP reduced left ventricular activation time (LVAT) more than BVP (ΔLVATHBP −43 ± 16 ms, P < 0.01 vs. BVP, ΔLVATLBBAP −45 ± 17 ms, P < 0.01 vs. BVP, ΔLVATBVP −13 ± 36 ms), with no difference between HBP and LBBAP (P = 0.65). Acute systolic blood pressure was increased by all three modalities. In the 12 with BVP, greater improvement was seen with HBP and LBBAP (6.4 ± 3.8 mmHg BVP, 8.1 ± 3.8 mmHg HBP, P = 0.02 vs. BVP and 8.4 ± 8.2 mmHg for LBBAP, P = 0.3 vs. BVP), with no difference between HBP and LBBAP (P = 0.8). Conclusion HBP delivered better ventricular resynchronization than LBBAP because right ventricular activation was slower during LBBAP. But LBBAP was not inferior to HBP with respect to LV electrical resynchronization and acute haemodynamic response.

Osmium (Os) based photosensitizers (PSs) are a unique class of nontetrapyrrolic metal-containing PSs that absorb red light. We recently reported a highly potent Os(II) PS, rac-[Os(phen)

PURPOSE: To assess changes in retinopathy of prematurity (ROP) diagnosis in single and serial retinal images. DESIGN: Cohort study. PARTICIPANTS: Cases of ROP recruited from the Imaging and Informatics in Retinopathy of Prematurity (i-ROP) consortium evaluated by 7 graders. METHODS: Seven ophthalmologists reviewed both single and 3 consecutive serial retinal images from 15 cases with ROP, and severity was assigned as plus, preplus, or none. Imaging data were acquired during routine ROP screening from 2011 to 2015, and a reference standard diagnosis was established for each image. A secondary analysis was performed using the i-ROP deep learning system to assign a vascular severity score (VSS) to each image, ranging from 1 to 9, with 9 being the most severe disease. This score has been previously demonstrated to correlate with the International Classification of ROP. Mean plus disease severity was calculated by averaging 14 labels per image in serial and single images to decrease noise. MAIN OUTCOME MEASURES: Grading severity of ROP as defined by plus, preplus, or no ROP. RESULTS: Assessment of serial retinal images changed the grading severity for > 50% of the graders, although there was wide variability. Cohen’s kappa ranged from 0.29 to 1.0, which showed a wide range of agreement from slight to perfect by each grader. Changes in the grading of serial retinal images were noted more commonly in cases of preplus disease. The mean severity in cases with a diagnosis of plus disease and no disease did not change between single and serial images. The ROP VSS demonstrated good correlation with the range of expert classifications of plus disease and overall agreement with the mode class (P = 0.001). The VSS correlated with mean plus disease severity by expert diagnosis (correlation coefficient, 0.89). The more aggressive graders tended to be influenced by serial images to increase the severity of their grading. The VSS also demonstrated agreement with disease progression across serial images, which progressed to preplus and plus disease. CONCLUSIONS: Clinicians demonstrated variability in ROP diagnosis when presented with both single and serial images. The use of deep learning as a quantitative assessment of plus disease has the potential to standardize ROP diagnosis and treatment.

Background: Oral chemotherapy nonadherence is a challenge in clinical oncology. During therapy for acute lymphoblastic leukemia (ALL), poor adherence to 6-mercaptopurine (6MP) increases relapse risk. Clinically significant nonadherence is reported in 30% of children treated for ALL on Children's Oncology Group (COG) trials. Whether nonadherence rates vary across regimens with different treatment schedules and modes of administration is unknown. Methods: We conducted an exploratory, cross-sectional survey study on parents of children (1–18 years) receiving continuation therapy on, or as per Dana-Farber Cancer Institute (DFCI) ALL Consortium Protocol 11-001. Treatment required weekly visits to the clinic and 14 days of oral 6MP every 3 weeks. Survey assessed self-reported sociodemographics, medication-taking, chemotherapy comprehension, and 6MP adherence; adherence survey items were developed from published surveys. Patients were grouped as nonadherent if they endorsed missing one 6MP dose during the last cycle, or more than one dose during prior cycles, for nonmedical reasons. Results: Sixty-two families completed the surveys, all of whom had evaluable adherence data. In total, 25% of patients met the study definition of nonadherence. Twenty-three percent reported that it was “not easy” to follow administration guidelines around the dairy intake and 57% requested more teaching and educational resources. Conclusion: Self-reported nonadherence to oral 6MP in the DFCI ALL Consortium is high, with rates similar to those observed in the COG. This suggests that the additional contact during weekly infusions on the DFCI is insufficient to address barriers affecting oral chemotherapy adherence.

Purpose The purpose of this paper is to develop, apply and validate a mesh-free graph theory–based approach for rapid thermal modeling of the directed energy deposition (DED) additive manufacturing (AM) process. Design/methodology/approach In this study, the authors develop a novel mesh-free graph theory–based approach to predict the thermal history of the DED process. Subsequently, the authors validated the graph theory predicted temperature trends using experimental temperature data for DED of titanium alloy parts (Ti-6Al-4V). Temperature trends were tracked by embedding thermocouples in the substrate. The DED process was simulated using the graph theory approach, and the thermal history predictions were validated based on the data from the thermocouples. Findings The temperature trends predicted by the graph theory approach have mean absolute percentage error of approximately 11% and root mean square error of 23°C when compared to the experimental data. Moreover, the graph theory simulation was obtained within 4 min using desktop computing resources, which is less than the build time of 25 min. By comparison, a finite element–based model required 136 min to converge to similar level of error. Research limitations/implications This study uses data from fixed thermocouples when printing thin-wall DED parts. In the future, the authors will incorporate infrared thermal camera data from large parts. Practical implications The DED process is particularly valuable for near-net shape manufacturing, repair and remanufacturing applications. However, DED parts are often afflicted with flaws, such as cracking and distortion. In DED, flaw formation is largely governed by the intensity and spatial distribution of heat in the part during the process, often referred to as the thermal history. Accordingly, fast and accurate thermal models to predict the thermal history are necessary to understand and preclude flaw formation. Originality/value This paper presents a new mesh-free computational thermal modeling approach based on graph theory (network science) and applies it to DED. The approach eschews the tedious and computationally demanding meshing aspect of finite element modeling and allows rapid simulation of the thermal history in additive manufacturing. Although the graph theory has been applied to thermal modeling of laser powder bed fusion (LPBF), there are distinct phenomenological differences between DED and LPBF that necessitate substantial modifications to the graph theory approach.

Eight weeks after having laboratory-confirmed SARS-CoV-2 breakthrough infections, 2 otherwise healthy, fully immunized adolescent patients in the United States who were experiencing related signs and symptoms were diagnosed with multisystem inflammatory syndrome in children. Our findings indicate that COVID-19 vaccination does not completely protect adolescents against multisystem inflammatory syndrome.

Triple oxygen isotope (δ17O and δ18O) values of high- and low-temperature altered oceanic crust and products of basalt alteration experiments were measured to better constrain ocean isotope compositions in deep time. The data define an array of δ18O and Δ′17O (Δ′17O=δ′17O − λRL × δ′18O + γ) values from mantle values toward 1‰ and −0.01‰, respectively, with a λ of ~0.523. The altered oceanic crust data were used to construct a model for estimating δ18O-Δ′17O values of the ancient oceans if the continental weathering flux (FCW) and/or hydrothermal oceanic crust alteration flux (FHT) changed through time. A maximum lowering of 7‰ and 4‰, respectively, is achieved in the most extreme cases. The δ18O value of the ocean cannot be raised by more than 1.1‰. Eclogites from the Roberts Victor kimberlite (South Africa), with a protolith age of 3.1 Ga, have δ18O-Δ′17O values that precisely overlap with those of the modern altered oceanic crust, suggesting that the Archean oceans had similar isotope values as today. Published triple isotope data for Archean cherts show that all samples have been altered to some degree and suggest an Archean ocean surface temperature of ~70–100 °C. An ocean as light as −2‰ is still consistent with our eclogite data and reduce our temperature estimates by 10 °C.

Objective: The present study aimed to evaluate the effect of baseline frailty status (as measured by modified frailty index-5 [mFI-5]) versus age on postoperative outcomes of patients undergoing surgery for spinal tumors using data from a large national registry.Methods: The National Surgical Quality Improvement Program database was used to collect spinal tumor resection patients’ data from 2015 to 2019 (n = 4,662). Univariate and multivariate analyses for age and mFI-5 were performed for the following outcomes: 30-day mortality, major complications, unplanned reoperation, unplanned readmission, hospital length of stay (LOS), and discharge to a nonhome destination. Receiver operating characteristic (ROC) curve analysis was used to evaluate the discriminative performance of age versus mFI-5.Results: Both univariate and multivariate analyses demonstrated that mFI-5 was a more robust predictor of worse postoperative outcomes as compared to age. Furthermore, based on categorical analysis of frailty tiers, increasing frailty was significantly associated with increased risk of adverse outcomes. ‘Severely frail’ patients were found to have the highest risk, with odds ratio 16.4 (95% confidence interval [CI],11.21–35.44) for 30-day mortality, 3.02 (95% CI, 1.97–4.56) for major complications, and 2.94 (95% CI, 2.32–4.21) for LOS. In ROC curve analysis, mFI-5 score (area under the curve [AUC] = 0.743) achieved superior discrimination compared to age (AUC = 0.594) for mortality.Conclusion: Increasing frailty, as measured by mFI-5, is a more robust predictor as compared to age, for poor postoperative outcomes in spinal tumor surgery patients. The mFI-5 may be clinically used for preoperative risk stratification of spinal tumor patients.

The desire to develop artificial cells to imitate living cells in synthetic vesicle platforms has continuously increased over the past few decades. In particular, heterogeneous synthetic vesicles made from two or more building blocks have attracted attention for artificial cell applications based on their multifunctional modules with asymmetric structures. In addition to the traditional liposomes or polymersomes, polypeptides and proteins have recently been highlighted as potential building blocks to construct artificial cells owing to their specific biological functionalities. Incorporating one or more functionally folded, globular protein into synthetic vesicles enables more cell-like functions mediated by proteins. This Review highlights the recent research about synthetic vesicles toward artificial cell models, from traditional synthetic vesicles to protein-assembled vesicles with asymmetric structures. We aim to provide fundamental and practical insights into applying knowledge on molecular self-assembly to the bottom-up construction of artificial cell platforms with heterogeneous building blocks.

Carbapenems are a critically important class of antimicrobials used to treat infections caused by multi-drug-resistant bacteria. Following an outbreak of a carbapenemase (NDM-5)-producing strain of Escherichia coli at our veterinary institution, we opted to describe the use of carbapenems in our institution and the role that drug contraindications in patients may have played when culture and susceptibility testing identified alternative drug options.Medical record reviews of all cases where a carbapenem was prescribed were performed, and indications for use, timing of prescribing relative to culture and susceptibility reports, and alternative possible antimicrobial treatments were extracted. Contraindications to alternative antimicrobials were also documented.Carbapenems were prescribed infrequently: from 2013 to 2018, they accounted for 0.47% of all antimicrobial prescriptions and were administered to 108 of 56,776 (0.2%) patients seen at our institution. They were prescribed empirically in slightly more than half of the patients (57.6%). Among cases where a carbapenem was prescribed after culture and susceptibility results were available, alternative antimicrobials could have been used in 68.3% of cases.Variability in use of these drugs within an institution highlights the need to develop well-defined use guidelines, including when to use these drugs empirically and how to safely de-escalate or choose alternative drugs guided by culture and susceptibility results.

This paper forensically reconstructs the timings, impacts and processes that drove the sequence of explosive eruptions of La Soufrière, St Vincent in April 2021 using a combination of field-based stratigraphy and textural dissection of the deposit character together with contemporary visual observations. Explosive activity on 9 April and early on 10 April involved destruction of almost all of the 2020/2021 lava dome, c. 60% of the 1979 dome and formation of a 600 m diameter crater by 2pm UTC on 10 April. Following the initial explosion, plumes rose to altitudes of c. 15 km and pyroclastic density currents (PDCs), formed by column collapse, first occurred on 10 April, only after >24 h of explosive activity. Dense PDCs reached the sea only in the Larikai and Roseau valleys, and dilute PDCs were restricted to within 2.5 km of the Summit Crater rim. The tephra fallout deposits are stratified, composed of numerous layers of both lapilli-rich and ash-rich layers, which we have grouped into at least 7 units, based on their common characteristics (Units 1 to 7). Volume estimates, using a range of techniques to constrain uncertainties, indicate that the bulk volume of tephra (fallout and PDC) is 1.19 × 10 8 m 3 ± 20% making this a VEI 4 eruption.

Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): British Heart Foundation Introduction Cardiac resynchronisation therapy (CRT) in the form of His bundle CRT and left bundle area CRT can be more effective than the gold standard, biventricular pacing (BVP). In BVP scar burden is known to predict response whether this is true for these novel modalities is not known. Purpose The purpose of this study was to determine whether left ventricular scar burden assessed using cardiac MRI can be used to predict the electrical and acute haemodynamic response to two novel CRT modalities. Methods Patients with standard CRT indications were recruited. They underwent a pre-procedure cardiac MRI, with late gadolinium enhancement (LGE) to quantify scar. His bundle CRT (His CRT) and left bundle area CRT (LBA CRT) were attempted. The electrical response was measured using high precision non-invasive mapping ECGi (CardioInsight, Medtronic). The haemodynamic response was measured with a high precision protocol. We investigated the impact of scar and baseline electrical characteristic on ECGi and haemodynamic response. Results 26 patients were recruited (85% male, mean age 69 ± 10, with ischaemic cardiomyopathy in 35%). LGE was observed in 96% of cases and the mean (range 1-39%). We found a significant correlation between scar extent and the electrical response with both modalities. There was a significant correlation between a lower scar burden and better electrical response. For His CRT the reduction in left ventricular activation time was better with lower scar burden (R= 0.77, p < 0.01, Picture 1), for LBA CRT for reduction in left ventricular activation was also better with lower scar burden (R = 0.53, p = 0.05, Picture 2). With His CRT there was also a significant correlation between lower scar extent and better acute haemodynamic response ( R = 0.6, p = 0.002) but this was not observed with LBA CRT (R = 0.07, p = 0.77). Conclusion Left ventricular myocardial scar can be used to predict the electrical response to two different conduction system CRT modalities.