Vibronic Coupling Drives the Ultrafast Internal Conversion in a Functionalized Free-Base Porphyrin.

Internal conversion (IC) is a common radiationless transition in polyatomic molecules. Theory predicts that molecular vibrations assist IC between excited states, and ultrafast experiments can provide insight into their structure-function relationship. Here we elucidate the dynamics of the vibrational modes driving the IC process within the Q band of a functionalized porphyrin molecule. Through a combination of ultrafast multidimensional spectroscopies and theoretical modeling, we observe a 60 fs Qy-Qx IC and demonstrate that it is driven by the interplay among multiple high-frequency modes. Notably, we identify 1510 cm-1 as the leading tuning mode that brings the porphyrin to an optimal geometry for energy surface crossing. By employing coherent wave packet analysis, we highlight a set of short-lived vibrations (1200-1400 cm-1), promoting the IC within ≈60 fs. Furthermore, we identify one coupling mode (1350 cm-1) that is responsible for vibronic mixing within the Q states. Our findings indicate that porphyrin-core functionalization modulates IC effectively, offering new opportunities in photocatalysis and optoelectronics.

Incidence and Risk Factors of Heterotopic Ossification in the Knee After Reamed Tibial Nailing.

INTRODUCTION: Heterotopic ossification (HO) in the knee after tibial intramedullary nailing (IMN) has yet to be thoroughly investigated. Our aim was to assess frequency and associated factors for HO in the knee after tibial IMN. METHODS: This is a retrospective review at a single level 1 urban trauma center of 213 patients who underwent reamed tibial IMN. Plain radiographs were reviewed postoperatively and on final follow-up (≥6 weeks). Chart review was performed for surgical approach (suprapatellar versus infrapatellar), demographics, injury characteristics, and clinical follow-up. The primary outcome was frequency of HO. RESULTS: HO on final follow-up (mean: 41.43 weeks) was recorded in 15% cases. Postsurgical retroinfrapatellar reaming debris (odds ratio [OR], 4.73), Injury Severity Score (OR, 1.05), intensive care unit admission (OR, 2.89), chest injury (OR, 3.4), and ipsilateral retrograde femoral IMN (OR, 5.08) showed a notable association with HO development. No association was observed in HO formation between surgical approach, knee pain, or range-of-motion deficits. DISCUSSION: Radiographic evidence of HO in the knee after reamed tibial IMN is not uncommon and is associated with retained reaming debris, Injury Severity Score, chest injury, intensive care unit admission, and ipsilateral retrograde femoral nailing. No differences were noted in HO formation between approaches. HO was not associated with knee pain or range-of-motion deficits.

Transcriptomic signatures of individual cell types in cerebral cavernous malformation.

Cerebral cavernous malformation (CCM) is a hemorrhagic neurovascular disease with no currently available therapeutics. Prior evidence suggests that different cell types may play a role in CCM pathogenesis. The contribution of each cell type to the dysfunctional cellular crosstalk remains unclear. Herein, RNA-seq was performed on fluorescence-activated cell sorted endothelial cells (ECs), pericytes, and neuroglia from CCM lesions and non-lesional brain tissue controls. Differentially Expressed Gene (DEG), pathway and Ligand-Receptor (LR) analyses were performed to characterize the dysfunctional genes of respective cell types within CCMs. Common DEGs among all three cell types were related to inflammation and endothelial-to-mesenchymal transition (EndMT). DEG and pathway analyses supported a role of lesional ECs in dysregulated angiogenesis and increased permeability. VEGFA was particularly upregulated in pericytes. Further pathway and LR analyses identified vascular endothelial growth factor A/ vascular endothelial growth factor receptor 2 signaling in lesional ECs and pericytes that would result in increased angiogenesis. Moreover, lesional pericytes and neuroglia predominantly showed DEGs and pathways mediating the immune response. Further analyses of cell specific gene alterations in CCM endorsed potential contribution to EndMT, coagulation, and a hypoxic microenvironment. Taken together, these findings motivate mechanistic hypotheses regarding non-endothelial contributions to lesion pathobiology and may lead to novel therapeutic targets. Video Abstract.

Young Collision Athletes Have High Rate of Return to Play and Good Clinical Outcomes Following Open Latarjet Procedure.

PURPOSE: To evaluate return to play (RTP), clinical outcomes, and recurrence rates in collision athletes 20 years of age and younger who underwent open Latarjet for anterior shoulder instability. METHODS: A retrospective review of collision athletes 20 years of age and younger, who underwent an open Latarjet procedure by a single surgeon between the years of 2010-2020 was carried out. Inclusion criteria were 1) collision athlete, 2) underwent open Latarjet procedure, 3) 16-20 years old, and 4) minimum 24-month follow-up. Exclusion criteria were 1) other pathology of the ipsilateral shoulder and 2) noncollision athlete. Rate of RTP, time to RTP, rate of return to preinjury level, the Shoulder Instability Return to Sport after Injury score (SIRSI) score, Subjective Shoulder Value (SSV), visual analogue scale (VAS) scores, and recurrence events were recorded. Quantitative statistical analysis was carried out. RESULTS: The study included 105 male collision athletes with a mean age of 18.6 ± 1.0 years (range: 17-20). The mean follow-up for patients was 36 ± 26.2 months. A total of 93 (88.6%) RTP at a mean time of 6.3 ± 2.2 months, with 73 (69.5%) returning to their preinjury level of participation. The mean SIRSI score was 69.2 ± 21.8, the mean VAS score was 2.3 ± 2.1, and the mean SSV score was 84.1 ± 16.8. Five patients (4.8%) redislocated their shoulder, with 4 of these requiring a further surgery (3.8%). Two patients (1.9%) reported incidents of subluxation. CONCLUSIONS: The open Latarjet procedure in young collision athletes results in high rates of RTP, excellent functional outcomes and low recurrence rates at mid-term follow-up. Additionally, complication rates are low in this cohort. LEVEL OF EVIDENCE: Level IV, case series.

Improving effective depression care in an outpatient psychiatric clinic.

BACKGROUND: With more than 20 million adults experiencing a major depressive episode in 2020, depression is one of the most widespread and costly illnesses in the United States. LOCAL PROBLEM: An audit of medical records at an outpatient psychiatric clinic revealed that none of the patients (0/56) were receiving standardized depression screening at follow-up appointments. METHODS: An 8-week rapid cycle Plan-Do-Study-Act model for change was used to spearhead a quality improvement (QI) project for effective depression care. The QI project comprised ongoing data collection through chart audit every 3 days, which drove tests of change (TOC). Team engagement surveys were also assessed for change in team engagement scores. INTERVENTIONS: The Patient Health Questionnaire-9 (PHQ-9) was used to assess depression, and an effective care log (ECL) measured effective depression care. Every 2 weeks, a TOC was implemented, which guided further iterative changes throughout the project. RESULTS: Effective depression care increased to 74% over the course of the project, surpassing the initial aim of 50%. Completion rates of the PHQ-9 (76%) and ECL (91%) increased. Team engagement (27.1) also increased over the course of the project. CONCLUSIONS: This project improved effective depression care. The success was largely due to the iterative TOCs, ECL, and team engagement.

A gated-time-of-flight top-hat electrostatic analyzer for low energy ion measurements.

When incorporated into a top-hat electrostatic analyzer, a gate electrode enables the separation of ions by their mass-per-charge with modest mass resolution (M/∆M ∼ 10). Gated-time-of-flight (TOF) instruments avoid the energy straggling and angular scattering effects prevalent in foil-based detection systems, providing more pristine measurements of three-dimensional distribution functions of incident ions. Gated-TOF implementations are ideal for measuring the properties of low-energy (i.e., <100 eV) thermal ions in various space environments. We present an instrument prototype capable of separating H+, He+, O+, and O2+ in Earth's ionosphere and demonstrate that in addition to providing species determination, precise operation of the gate electrode provides an electronically adjustable geometric factor that can extend a single instrument's dynamic range by several orders of magnitude.

False or Misleading Claims in Online Direct-to-Consumer Ketamine Advertising in Maryland.

This cross-sectional study evaluates the prevalence of false or misleading information in online direct-to-consumer advertising for off-label and unapproved ketamine in Maryland.

Nanomedicines to treat rare neurological disorders: The case of Krabbe disease.

The brain remains one of the most challenging therapeutic targets due to the low and selective permeability of the blood-brain barrier and complex architecture of the brain tissue. Nanomedicines, despite their relatively large size compared to small molecules and nucleic acids, are being heavily investigated as vehicles to delivery therapeutics into the brain. Here we elaborate on how nanomedicines may be used to treat rare neurodevelopmental disorders, using Krabbe disease (globoid cell leukodystrophy) to frame the discussion. As a monogenetic disorder and lysosomal storage disease affecting the nervous system, the lessons learned from examining nanoparticle delivery to the brain in the context of Krabbe disease can have a broader impact on the treatment of various other neurodevelopmental and neurodegenerative disorders. In this review, we introduce the epidemiology and genetic basis of Krabbe disease, discuss current in vitro and in vivo models of the disease, as well as current therapeutic approaches either approved or at different stage of clinical developments. We then elaborate on challenges in particle delivery to the brain, with a specific emphasis on methods to transport nanomedicines across the blood-brain barrier. We highlight nanoparticles for delivering therapeutics for the treatment of lysosomal storage diseases, classified by the therapeutic payload, including gene therapy, enzyme replacement therapy, and small molecule delivery. Finally, we provide some useful hints on the design of nanomedicines for the treatment of rare neurological disorders.

Minutes-duration optical flares with supernova luminosities.

In recent years, certain luminous extragalactic optical transients have been observed to last only a few days1. Their short observed duration implies a different powering mechanism from the most common luminous extragalactic transients (supernovae), whose timescale is weeks2. Some short-duration transients, most notably AT2018cow (ref. 3), show blue optical colours and bright radio and X-ray emission4. Several AT2018cow-like transients have shown hints of a long-lived embedded energy source5, such as X-ray variability6,7, prolonged ultraviolet emission8, a tentative X-ray quasiperiodic oscillation9,10 and large energies coupled to fast (but subrelativistic) radio-emitting ejecta11,12. Here we report observations of minutes-duration optical flares in the aftermath of an AT2018cow-like transient, AT2022tsd (the 'Tasmanian Devil'). The flares occur over a period of months, are highly energetic and are probably nonthermal, implying that they arise from a near-relativistic outflow or jet. Our observations confirm that, in some AT2018cow-like transients, the embedded energy source is a compact object, either a magnetar or an accreting black hole.

mTORC1 Inhibitor Rapamycin Inhibits Growth of Cerebral Cavernous Malformation in Adult Mice.

BACKGROUND: Cerebral cavernous malformations (CCMs) are vascular malformations that frequently cause stroke. CCMs arise due to loss of function in one of the genes that encode the CCM complex, a negative regulator of MEKK3-KLF2/4 signaling in vascular endothelial cells. Gain-of-function mutations in PIK3CA (encoding the enzymatic subunit of the PI3K (phosphoinositide 3-kinase) pathway associated with cell growth) synergize with CCM gene loss-of-function to generate rapidly growing lesions. METHODS: We recently developed a model of CCM formation that closely reproduces key events in human CCM formation through inducible CCM loss-of-function and PIK3CA gain-of-function in mature mice. In the present study, we use this model to test the ability of rapamycin, a clinically approved inhibitor of the PI3K effector mTORC1, to treat rapidly growing CCMs. RESULTS: We show that both intraperitoneal and oral administration of rapamycin arrests CCM growth, reduces perilesional iron deposition, and improves vascular perfusion within CCMs. CONCLUSIONS: Our findings further establish this adult CCM model as a valuable preclinical model and support clinical testing of rapamycin to treat rapidly growing human CCMs.

Posterior Shoulder Instability but Not Anterior Shoulder Instability Is Related to Glenoid Version.

Purpose: To assess and compare glenoid version in patients with anterior shoulder instability (ASI), posterior shoulder instability (PSI), and a control group. Methods: The operative notes of all patients that had undergone arthroscopic shoulder instability repair between January 2017 and May 2022 were retrospectively reviewed. Magnetic resonance imaging scans were then analyzed, and glenoid version was measured by a single blinded observer. A P value <.05 was considered statistically significant. Results: There were 100 patients included in the ASI group, 65 in PSI group, and 100 in the control group. The mean glenoid versions for the ASI group were -16°, -9.1°, and -9.2° for the vault version, simplified vault version, and chondrolabral version, respectively. The mean glenoid versions for the PSI group were -21°, -13.4°, and -16.6° for the vault version, simplified vault version, and chondrolabral version, respectively. The mean versions for the control group were -17.8°, -9.5°, and -9.8° for the vault version, simplified vault version and chondrolabral version, respectively. ANOVA testing and post hoc comparisons revealed the PSI group to be significantly more retroverted than both other groups P < .001. The ASI group's degree of glenoid version was not significantly different to that of the control P = .009. Conclusion: Patients with PSI have a higher degree of retroversion in comparison to those with ASI and control. There is no significant difference in glenoid version among patients with ASI when compared with control. Level of Evidence: Level III, retrospective comparative study.

Machine learning instructed microfluidic synthesis of curcumin-loaded liposomes.

The association of machine learning (ML) tools with the synthesis of nanoparticles has the potential to streamline the development of more efficient and effective nanomedicines. The continuous-flow synthesis of nanoparticles via microfluidics represents an ideal playground for ML tools, where multiple engineering parameters - flow rates and mixing configurations, type and concentrations of the reagents - contribute in a non-trivial fashion to determine the resultant morphological and pharmacological attributes of nanomedicines. Here we present the application of ML models towards the microfluidic-based synthesis of liposomes loaded with a model hydrophobic therapeutic agent, curcumin. After generating over 200 different liposome configurations by systematically modulating flow rates, lipid concentrations, organic:water mixing volume ratios, support-vector machine models and feed-forward artificial neural networks were trained to predict, respectively, the liposome dispersity/stability and size. This work presents an initial step towards the application and cultivation of ML models to instruct the microfluidic formulation of nanoparticles.

Leadership Coaching in Surgical Residency: Reasons for Referral and Topics Addressed to Improve Nontechnical Skill.

PURPOSE: Professional coaching has been utilized in the military and private sector with a long track record of optimizing efficiency, improving high-functioning team performance, and creating greater satisfaction among the workforce. Recent studies in physician populations have suggested that coaching may protect healthcare providers from burnout and improve quality of life and resilience. The aims of the current study were to describe our single-institution experience with the introduction of a leadership coaching program among surgical residents and to characterize the nature of the common reasons for referral for coaching. METHODS: Upon identification by program faculty that a resident would benefit from coaching, an email was sent from the program director to the coach to establish contact between the coach and resident, with a brief synopsis of the factors that lead to the resident being referred for coaching. The study team obtained deidentified, simplified synopses of the initial email correspondences from program leadership reaching out to residents to refer them to coaching. Common recurring themes were quantified. Later, coaches reviewed their notes kept during coaching sessions and, in a similar fashion, identified topics discussed and skills developed in coaching sessions for each resident. Topics were summarized for each resident, and a deidentified list of residents and the themes reviewed in coaching were provided to the study team, who quantified these topics. Baseline demographic information on the resident cohort, including training level, gender, and number of repeat referrals were summarized to delineate differences in patterns of repeat referral and attrition. RESULTS: This study was conducted within the general surgery residency program at a single academic medical center, composed of 43 categorical and 8 preliminary residents. Over a 2.5-year period, 21 residents were referred: 5 chief, 8 senior, 5 midlevel, and 3 junior (1 preliminary) residents. Male residents represented 2/3 and female residents 1/3 of the total number of referrals. There were 3 repeat referrals, 2 male and 1 female. We identified 2 overarching reasons for which residents were referred for coaching: request for structured leadership training and request for communication training. Six themes were identified upon review of referrals for coaching. Among these were the need for improved communication, methods to improve team integration, tools to balance professional and personal responsibilities, and practices to improve confidence and assertiveness. Through the coaching relationship, residents reviewed deficits and received an individualized plan to address newly identified problem areas. Upon initiation of coaching, new themes like anxiety management, emotional intelligence, and cultural acclimatization were identified. During each coaching session, residents participate in exercises designed to build habits of effective listening, communication, and conflict resolution. CONCLUSIONS: Coaching in surgical residency provides a structured program for residents to develop skills in planning and orchestrating team operations, listening and communicating effectively, mitigating conflict, and managing professional and personal responsibilities. Follow-up studies will focus on the long-term effects of professional coaching, evaluating survey data from self-assessments and professional evaluations.

An Overview of Selected Bacterial Infections in Cancer, Their Virulence Factors, and Some Aspects of Infection Management.

In cancer development and its clinical course, bacteria can be involved in etiology and secondary infection. Regarding etiology, various epidemiological studies have revealed that Helicobacter pylori can directly impact gastric carcinogenesis. The Helicobacter pylori-associated virulence factor cytotoxin-associated gene A perhaps plays an important role through different mechanisms such as aberrant DNA methylation, activation of nuclear factor kappa B, and modulation of the Wnt/ß-catenin signaling pathway. Many other bacteria, including Salmonella and Pseudomonas, can also affect Wnt/ß-catenin signaling. Although Helicobacter pylori is involved in both gastric adenocarcinoma and mucosa-associated lymphoid tissue lymphoma, its role in the latter disease is more complicated. Among other bacterial species, Chlamydia is linked with a diverse range of diseases including cancers of different sites. The cellular organizations of Chlamydia are highly complex. Interestingly, Escherichia coli is believed to be associated with colon cancer development. Microorganisms such as Escherichia coli and Pseudomonas aeruginosa are frequently isolated from secondary infections in cancer patients. In these patients, the common sites of infection are the respiratory, gastrointestinal, and urinary tracts. There is an alarming rise in infections with multidrug-resistant bacteria and the scarcity of suitable antimicrobial agents adversely influences prognosis. Therefore, effective implementation of antimicrobial stewardship strategies is important in cancer patients.

The behavior of standing waves near the end of an open pipe with low mean flow.

The acoustic standing wave near the end of an open pipe is investigated using spectrally analyzed high-speed transmission electronic speckle pattern interferometry. It is shown that the standing wave extends beyond the open end of the pipe and the amplitude decays exponentially with distance from the end. Additionally, a pressure node is observed near the end of the pipe in a position that is not spatially periodic with the other nodes in the standing wave. A sinusoidal fit to the amplitude of the standing wave inside the pipe indicates that the end correction is well predicted by current theory.

Assessing Differential Particle Deformability under Microfluidic Flow Conditions.

Assessing the mechanical behavior of nano- and micron-scale particles with complex shapes is fundamental in drug delivery. Although different techniques are available to quantify the bulk stiffness in static conditions, there is still uncertainty in assessing particle deformability in dynamic conditions. Here, a microfluidic chip is designed, engineered, and validated as a platform to assess the mechanical behavior of fluid-borne particles. Specifically, potassium hydroxide (KOH) wet etching was used to realize a channel incorporating a series of micropillars (filtering modules) with different geometries and openings, acting as microfilters in the direction of the flow. These filtering modules were designed with progressively decreasing openings, ranging in size from about 5 down to 1 µm. Discoidal polymeric nanoconstructs (DPNs), with a diameter of 5.5 µm and a height of 400 nm, were realized with different poly(lactic-co-glycolic acid) (PLGA) and poly(ethylene glycol) (PEG) ratios (PLGA/PEG), namely, 5:1 and 1:0, resulting in soft and rigid particles, respectively. Given the peculiar geometry of DPNs, the channel height was kept to 5 µm to limit particle tumbling or flipping along the flow. After thorough physicochemical and morphological characterization, DPNs were tested within the microfluidic chip to investigate their behavior under flow. As expected, most rigid DPNs were trapped in the first series of pillars, whereas soft DPNs were observed to cross multiple filtering modules and reach the micropillars with the smallest opening (1 µm). This experimental evidence was also supported by computational tools, where DPNs were modeled as a network of springs and beads immersed in a Newtonian fluid using the smoothed particle hydrodynamics (SPH) method. This preliminary study presents a combined experimental-computational framework to quantify, compare, and analyze the characteristics of particles having complex geometrical and mechanical attributes under flow conditions.

Medical use and combination drug therapy among US adult users of central nervous system stimulants: a cross-sectional analysis.

OBJECTIVE: Examine patterns of adult medical use of amphetamine and methylphenidate stimulant drugs, classified in the USA as Schedule II controlled substances with a high potential for psychological or physical dependence. DESIGN: Cross-sectional study. SETTING AND PARTICIPANTS: Prescription drug claims for US adults, age 19-64 years, included in a commercial insurance claims database with 9.1 million continuously enrolled adults from 1 October 2019, through 31 December 2020. Stimulant use was defined as adults filling one or more stimulant prescriptions during calendar 2020. OUTCOME MEASURES: The primary outcome was an outpatient prescription claim, service date and days' supply for central nervous system (CNS)-active drugs. Combination-2 was defined as 60 days or more of combination treatment with a Schedule II stimulant and one or more additional CNS-active drugs. Combination-3 therapy was defined as the addition of 2 or more additional CNS-active drugs. Using service date and days' supply, we examined the number of stimulant and other CNS-active drugs for each of the 366 days of 2020. RESULTS: Among 9 141 877 continuously enrolled adults, the study identified 276 223 individuals (3.0%) using Schedule II stimulants during 2020. They filled a median of 8 (IQR, 4-11) prescriptions for these stimulant drugs that provided 227 (IQR, 110-322) treatment days of exposure. Among this group, 125 781 (45.5%) combined use of one or more additional CNS active drugs for a median of 213 (IQR, 126-301) treatment days. Also, 66 996 (24.3%) stimulant users used two or more additional CNS-active drugs for a median of 182 (IQR, 108-276) days. Among stimulants users, 131 485 (47.6%) were exposed to an antidepressant, 85 166 (30.8%) filled prescriptions for anxiety/sedative/hypnotic medications and 54 035 (19.6%) received opioid prescriptions. CONCLUSION: A large proportion of adults using Schedule II stimulants are simultaneously exposed to one or more other CNS-active drugs, many with tolerance, withdrawal effects or potential for non-medical use. There are no approved indications and limited clinical trial testing of these multi-drug combinations, and discontinuation may be challenging.