Modeling ultrafast anharmonic vibrational coupling in gas-phase fluorobenzene molecules.

In this work, we study the energy flow through anharmonic coupling of vibrational modes after excitation of gas-phase fluorobenzene with a multi-THz pump. We show that to predict the efficiency of anharmonic energy transfer, simple models that only include the anharmonic coupling coefficients and motion of modes at their resonant frequency are not adequate. The full motion of each mode is needed, including the time while the mode is being driven by the pump pulse, because all the frequencies present in the multi-THz pump contribute to the excitation of the non-resonantly excited vibrational modes. Additionally, the model gives us the insight that modes with either A1 or B2 symmetry are more actively involved in anharmonic coupling because these modes have more symmetry-allowed energy transfer pathways.

Dysphagia in primary progressive aphasia: Clinical predictors and neuroanatomical basis.

BACKGROUND AND PURPOSE: Dysphagia is an important feature of neurodegenerative diseases and potentially life-threatening in primary progressive aphasia (PPA) but remains poorly characterized in these syndromes. We hypothesized that dysphagia would be more prevalent in nonfluent/agrammatic variant (nfv)PPA than other PPA syndromes, predicted by accompanying motor features, and associated with atrophy affecting regions implicated in swallowing control. METHODS: In a retrospective case-control study at our tertiary referral centre, we recruited 56 patients with PPA (21 nfvPPA, 22 semantic variant [sv]PPA, 13 logopenic variant [lv]PPA). Using a pro forma based on caregiver surveys and clinical records, we documented dysphagia (present/absent) and associated, potentially predictive clinical, cognitive, and behavioural features. These were used to train a machine learning model. Patients' brain magnetic resonance imaging scans were assessed using voxel-based morphometry and region-of-interest analyses comparing differential atrophy profiles associated with dysphagia presence/absence. RESULTS: Dysphagia was significantly more prevalent in nfvPPA (43% vs. 5% svPPA and no lvPPA). The machine learning model revealed a hierarchy of features predicting dysphagia in the nfvPPA group, with excellent classification accuracy (90.5%, 95% confidence interval = 77.9-100); the strongest predictor was orofacial apraxia, followed by older age, parkinsonism, more severe behavioural disturbance, and more severe cognitive impairment. Significant grey matter atrophy correlates of dysphagia in nfvPPA were identified in left middle frontal, right superior frontal, and right supramarginal gyri and right caudate. CONCLUSIONS: Dysphagia is a common feature of nfvPPA, linked to underlying corticosubcortical network dysfunction. Clinicians should anticipate this symptom particularly in the context of other motor features and more severe disease.

AI Efficacy as a Function of Trainee Interpreter Proficiency: Lessons from a Randomized Controlled Trial.

BACKGROUND AND PURPOSE: Recently, AI tools have been deployed with increasing speed in educational and clinical settings. However, the use of AI by trainees across different levels of experience has not been well studied. This study investigates the impact of AI assistance on diagnostic accuracy for intracranial hemorrhage (ICH) and large vessel occlusion (LVO) by medical students (MS) and resident trainees (RT). MATERIALS AND METHODS: This prospective study was conducted between March 2023 and October 2023. MS and RT were asked to identify ICH and LVO in 100 non-contrast head CTs and 100 head CTAs, respectively. One group received diagnostic aid simulating AI for ICH only (n = 26), the other for LVO only (n = 28). Primary outcomes included accuracy, sensitivity, and specificity for ICH / LVO detection without and with aid. Study interpretation time was a secondary outcome. Individual responses were pooled and analyzed with chi-square; differences in continuous variables were assessed with ANOVA. RESULTS: 48 participants completed the study, generating 10,779 ICH or LVO interpretations. With diagnostic aid, MS accuracy improved 11.0 points (P < .001) and RT accuracy showed no significant change. ICH interpretation time increased with diagnostic aid for both groups (P < .001) while LVO interpretation time decreased for MS (P < .001). Despite worse performance in detection of the smallest vs. the largest hemorrhages at baseline, MS were not more likely to accept a true positive AI result for these more difficult tasks. Both groups were considerably less accurate when disagreeing with the AI or when supplied with an incorrect AI result. CONCLUSIONS: This study demonstrated greater improvement in diagnostic accuracy with AI for MS compared to RT. However, MS were less likely than RT to overrule incorrect AI interpretations and were less accurate, even with diagnostic aid, than the AI was by itself. ABBREVIATIONS: ICH = intracranial hemorrhage; LVO = large vessel occlusion; MS = medical students; RT = resident trainees.

Inhibition of ribonucleotide reductase subunit M2 enhances the radiosensitivity of metastatic pancreatic neuroendocrine tumor.

Ribonucleotide Reductase (RNR) is a rate-limiting enzyme in the production of deoxyribonucleoside triphosphates (dNTPs), which are essential substrates for DNA repair after radiation damage. We explored the radiosensitization property of RNR and investigated a selective RRM2 inhibitor, 3-AP, as a radiosensitizer in the treatment of metastatic pNETs. We investigated the role of RNR subunit, RRM2, in pancreatic neuroendocrine (pNET) cells and responses to radiation in vitro. We also evaluated the selective RRM2 subunit inhibitor, 3-AP, as a radiosensitizer to treat pNET metastases in vivo. Knockdown of RNR subunits demonstrated that RRM1 and RRM2 subunits, but not p53R3, play significant roles in cell proliferation. RRM2 inhibition activated DDR pathways through phosphorylation of ATM and DNA-PK protein kinases but not ATR. RRM2 inhibition also induced Chk1 and Chk2 phosphorylation, resulting in G1/S phase cell cycle arrest. RRM2 inhibition sensitized pNET cells to radiotherapy and induced apoptosis in vitro. In vivo, we utilized pNET subcutaneous and lung metastasis models to examine the rationale for RNR-targeted therapy and 3-AP as a radiosensitizer in treating pNETs. Combination treatment significantly increased apoptosis of BON (human pNET) xenografts and significantly reduced the burden of lung metastases. Together, our results demonstrate that selective RRM2 inhibition induced radiosensitivity of metastatic pNETs both in vitro and in vivo. Therefore, treatment with the selective RRM2 inhibitor, 3-AP, is a promising radiosensitizer in the therapeutic armamentarium for metastatic pNETs.

Widespread Production of Polyunsaturated Aldehydes by Benthic Diatoms of the North Pacific Ocean's Salish Sea.

Diatoms are key primary producers across marine, freshwater, and terrestrial ecosystems. They are responsible for photosynthesis and secondary production that, in part, support complex food webs. Diatoms can produce phytochemicals that have transtrophic ecological effects which increase their competitive fitness. Polyunsaturated aldehydes (PUAs) are one class of diatom-derived phytochemicals that are known to have allelopathic and anti-herbivory properties. The anti-herbivory capability of PUAs results from their negative effect on grazer fecundity. Since their discovery, research has focused on their production by pelagic marine diatoms, and their effects on copepod egg production, hatching success, and juvenile survival and development. Few investigations have explored PUA production by the prolific suite of benthic marine diatoms, despite their importance to coastal trophic systems. In this study, we tested eight species of benthic diatoms for the production of the bioactive PUAs 2,4-heptadienal, 2,4-octadienal, and 2,4-decadienal. Benthic diatom species were isolated from the Salish Sea, an inland sea within the North Pacific ecosystem. All species were found to be producers of at least two PUAs in detectable concentrations, with five species producing all three PUAs in quantifiable concentrations. Our results indicate that production of PUAs from Salish Sea benthic diatoms may be widespread, and thus these compounds may contribute to benthic coastal food web dynamics through heretofore unrecognized pathways. Future studies should expand the geographic scope of investigations into benthic diatom PUA production and explore the effects of benthic diatoms on benthic consumer fecundity.

Characterizing the Stability of Angiotensin II in 0.9% Sodium Chloride Using High Performance Liquid Chromatography and Liquid Chromatography Tandem Mass Spectrometry.

Purpose: The purpose of this study was to evaluate the stability of angiotensin II in 0.9% sodium chloride for up to 5 days. Methods: We prepared angiotensin II dilutions, by aseptically diluting 2.5 mg (1 mL) in 249 mL 0.9% sodium chloride creating a solution of 10 000 ng/mL. Admixtures were stored under refrigeration (5 ± 3°C). Stability of the dilution was assessed by: preservation of clarity, consistency of pH, and retention of concentration. Solutions were sampled at times 0, 24, 48, 72, 96, 120 hours. Solutions were analyzed via High-Performance Liquid Chromatography (HPLC-UV) and Liquid Chromatography Mass Spectrometry (LC-MS/MS). Retention of concentration was set a priori at > 90% of initial concentration. Results: Clarity, color, and pH at all sample time points remained constant. Both methods of analysis confirmed similar results. When stored under refrigeration, the concentration of angiotensin II solution remained above 90% of initial concentration throughout the entire sampling period. Conclusions: Angiotensin II in 0.9% sodium chloride stored in infusion bags under refrigeration (5 ± 3°C) maintained at least 90% of their original concentrations for up to 5 days. Stability was also demonstrated based on turbidity, color, and pH assessment.

Fibroids and unexplained infertility treatment with epigallocatechin gallate: a natural compound in green tea (FRIEND) - protocol for a randomised placebo-controlled US multicentre clinical trial of EGCG to improve fertility in women with uterine fibroids.

INTRODUCTION: Uterine fibroids affect 30%-77% of reproductive-age women and are a significant cause of infertility. Surgical myomectomies can restore fertility, but they often have limited and temporary benefits, with postoperative complications such as adhesions negatively impacting fertility. Existing medical therapies, such as oral contraceptives, gonadotropin hormone-releasing hormone (GnRH) analogues and GnRH antagonists, can manage fibroid symptoms but are not fertility friendly. This study addresses the pressing need for non-hormonal, non-surgical treatment options for women with fibroids desiring pregnancy. Previous preclinical and clinical studies have shown that epigallocatechin gallate (EGCG) effectively reduces uterine fibroid size. We hypothesise that EGCG from green tea extract will shrink fibroids, enhance endometrial quality and increase pregnancy likelihood. To investigate this hypothesis, we initiated a National Institute of Child Health and Human Development Confirm-funded trial to assess EGCG's efficacy in treating women with fibroids and unexplained infertility. METHODS AND ANALYSIS: This multicentre, prospective, interventional, randomised, double-blinded clinical trial aims to enrol 200 participants with fibroids and unexplained infertility undergoing intrauterine insemination (IUI). Participants will be randomly assigned in a 3:1 ratio to two groups: green tea extract (1650 mg daily) or a matched placebo, combined with clomiphene citrate-induced ovarian stimulation and timed IUI for up to four cycles. EGCG constitutes approximately 45% of the green tea extract. The primary outcome is the cumulative live birth rate, with secondary outcomes including conception rate, time to conception, miscarriage rate, change in fibroid volume and symptom severity scores and health-related quality of life questionnaire scores. ETHICS AND DISSEMINATION: The FRIEND trial received approval from the Food and Drug adminstration (FDA) (investigational new drug number 150951), the central Institutional Review Board (IRB) at Johns Hopkins University and FRIEND-collaborative site local IRBs. The data will be disseminated at major conferences, published in peer-reviewed journals and support a large-scale clinical trial. TRIAL REGISTRATION NUMBER: NCT05364008.

Acetogenins from the Stem of Uvaria rufa and Their Cytotoxic Activity.

Four new adjacent bis-tetrahydrofuran acetogenins, bullacin C (7), uvarirufin (9), and uvariasolins III (12) and IV (13), along with 11 known acetogenins, were isolated from the stem of Uvaria rufa. Their structures were elucidated based on spectroscopic data analysis, including 1D and 2D NMR, HRESIMS, and MALDI-MS/MS of the lithium adducts. Absolute configurations were assigned using Mosher ester analysis and ECD measurements. Uvarirufin (9) possesses a unique C-39 skeleton among acetogenins. Most tested acetogenins exhibited cytotoxicity against human cancer cell lines (HCT 116, 22Rv1, MDA-MB-435, OVCAR3). Squamocin (8) and uvarirufin (9) were found to be the most potent, with an IC50 value of 1.2 µM for both in HCT 116 colon cancer cells. Additionally, a new application of Dragendorff's reagent is proposed herein for the TLC detection of acetogenins.

The use and timing of angioembolization in pediatric blunt liver and spleen injury.

BACKGROUND: Nonoperative management (NOM) is the standard of care for the management of blunt liver and spleen injuries (BLSI) in the stable pediatric patient. Angiography with embolization (AE) is used as an adjunctive therapy in the management of adult BLSI patients, but it is rarely used in the pediatric population. In this planned secondary analysis, we describe the current utilization patterns of AE in the management of pediatric BLSI. METHODS: After obtaining IRB approval at each center, cohort data was collected prospectively for children admitted with BLSI confirmed on CT at 10 Level I pediatric trauma centers (PTCs) throughout the United States from April 2013 to January 2016. All patients who underwent angiography with or without embolization for a BLSI were included in this analysis. Data collected included patient demographics, injury details, organ injured and grade of injury, CT finding specifics such as contrast blush, complications, failure of NOM, time to angiography and techniques for embolization. RESULTS: Data were collected for 1004 pediatric patients treated for BLSI over the study period, 30 (3.0%) of which underwent angiography with or without embolization for BLSI. Ten of the patients who underwent angiography for BLSI failed NOM. For patients with embolized splenic injuries, splenic salvage was 100%. Four of the nine patients undergoing embolization of the liver ultimately required an operative intervention, but only one patient required hepatorrhaphy and no patient required hepatectomy after AE. Few angiography studies were obtained early during hospitalization for BLSI, with only one patient undergoing angiography within 1 hour of arrival at the PTC, and 7 within 3 hours. CONCLUSION: Angioembolization is rarely used in the management of BLSI in pediatric trauma patients with blunt abdominal trauma and is generally used in a delayed fashion. However, when implemented, angioembolization is associated with 100% splenic salvage for splenic injuries. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level IV.

Pediatric Traumatic Lumbar Hernias and Associated Injuries: A Case Series.

OBJECTIVE: Traumatic lumbar hernias are a rare entity mostly seen with high-impact, blunt abdominal trauma. This injury occurs when there is disruption of the posterior musculature along with bony structures, allowing for herniation of abdominal contents. There are minimal cases of this entity reported in adults, but even fewer in the pediatric population. METHODS: We describe 3 cases of traumatic lumbar hernia at our institution as well as provide a review of the literature to elucidate the most common mechanisms, severity of injury, and associated injuries. RESULTS: Traumatic lumbar hernia is most commonly seen in restrained passengers involved in motor vehicle collisions. A majority of cases are diagnosed using computed tomography imaging and less frequently during primary surgical exploration. The most common associated injuries were mesenteric and bowel injuries, followed by spinal and chest trauma. Traumatic lumbar hernia often leads to prolonged hospital stays and increased need for posthospital rehabilitation because of associated traumatic comorbidities. CONCLUSIONS: Traumatic lumbar hernia is a rare entity in children, and early suspicion and identification of associated injuries is necessary in the management of these patients.

Binary reversals: a diagnostic sign in primary progressive aphasia.

BACKGROUND: Binary reversals (exemplified by 'yes'/'no' confusions) have been described in patients with primary progressive aphasia (PPA) but their diagnostic value and phenotypic correlates have not been defined. METHODS: We conducted a retrospective cohort study analysing demographic, clinical, neuropsychological, linguistic and behavioural data from patients representing all major PPA syndromes (non-fluent/agrammatic variant, nfvPPA; logopenic variant, lvPPA; semantic variant, svPPA) and behavioural variant frontotemporal dementia (bvFTD). The prevalence of binary reversals and behavioural abnormalities, illness duration, parkinsonian features and neuropsychological test scores were compared between neurodegenerative syndromes, and the diagnostic predictive value of binary reversals was assessed using logistic regression. RESULTS: Data were obtained for 83 patients (21 nfvPPA, 13 lvPPA, 22 svPPA, 27 bvFTD). Binary reversals occurred in all patients with nfvPPA, but significantly less frequently and later in lvPPA (54%), svPPA (9%) and bvFTD (44%). Patients with bvFTD with binary reversals had significantly more severe language (but not general executive or behavioural) deficits than those without reversals. Controlling for potentially confounding variables, binary reversals strongly predicted a diagnosis of nfvPPA over other syndromes. CONCLUSIONS: Binary reversals are a sensitive (though not specific) neurolinguistic feature of nfvPPA, and should suggest this diagnosis if present as a prominent early symptom.

Characterization of organic crystals for second-harmonic generation.

Second-harmonic generation (SHG) is a common technique with many applications. Common inorganic single-crystalline materials used to produce SHG light are effective using short IR/visible wavelengths but generally do not perform well at longer, technologically relevant IR wavelengths such as 1300, 1550, and 2000 nm. Efficient SHG materials possess many of the same key material properties as terahertz (THz) generators, and certain single-crystalline organic THz generation materials have been reported to perform at longer IR wavelengths. Consequently, this work focuses on characterizing three efficient organic THz generators for SHG, namely, DAST (trans-4-[4-(dimethylamino)-N-methylstilbazolium] p-tosylate), DSTMS (4-N,N-dimethylamino-4'-N'-methylstilbazolium 2,4,6-trimethylbenzenesulfonate), and the recently discovered generator PNPA ((E)-4-((4-nitrobenzylidene)amino)-N-phenylaniline). All three of these crystals outperform the beta-barium borate (BBO), an inorganic material commonly used for SHG, using IR pump wavelengths (1200-2000 nm).

Postglacial phylogeography, admixture, and evolution of red spruce (Picea rubens Sarg.) in Eastern North America.

Climate change is a major evolutionary force that can affect the structure of forest ecosystems worldwide. Red spruce (Picea rubens Sarg.) has recently faced a considerable decline in the Southern Appalachians due to rapid environmental change, which includes historical land use, and atmospheric pollution. In the northern part of its range, red spruce is sympatric with closely related black spruce (Picea mariana (Mill.) B.S.P.), where introgressive hybridization commonly occurs. We investigated range-wide population genetic diversity and structure and inferred postglacial migration patterns and evolution of red spruce using nuclear microsatellites. Moderate genetic diversity and differentiation were observed in red spruce. Genetic distance, maximum likelihood and Bayesian analyses identified two distinct population clusters: southern glacial populations, and the evolutionarily younger northern populations. Approximate Bayesian computation suggests that patterns of admixture are the result of divergence of red spruce and black spruce from a common ancestor and then introgressive hybridization during post-glacial migration. Genetic diversity, effective population size (Ne) and genetic differentiation were higher in the northern than in the southern populations. Our results along with previously available fossil data suggest that Picea rubens and Picea mariana occupied separate southern refugia during the last glaciation. After initial expansion in the early Holocene, these two species faced a period of recession and formed a secondary coastal refugium, where introgressive hybridization occurred, and then both species migrated northward. As a result, various levels of black spruce alleles are present in the sympatric red spruce populations. Allopatric populations of P. rubens and P. mariana have many species-specific alleles and much fewer alleles from common ancestry. The pure southern red spruce populations may become critically endangered under projected climate change conditions as their ecological niche may disappear.

Polyoxygenated cyclohexene derivatives and other constituents of Uvaria rufa stem.

Six undescribed compounds, uvarirufols D and E, (+)-uvarigranol B, (-)-uvarigranol E, 6-acetoxy-5-hydroxy-7-methoxyflavanone and cherrevenaphthalene D, along with twelve known compounds, including polyoxygenated cyclohexenes, flavonoids, and lignans, were isolated from the methanol extract of Uvaria rufa stems. Their structures were elucidated by spectroscopic analyses and the absolute configurations were determined using electronic circular dichroism. Several isolates were evaluated for cytotoxic, antitubercular and anti-inflammatory potentials. (-)-6-Acetylzeylenol showed moderate inhibitory activity against Mycobacterium tuberculosis, with MIC value of 47.10 µg/mL. Cherrevenaphthalene D exhibited weak antimycobacterial activity and potent inhibitory effect on lipopolysaccharide-induced nitric oxide (NO) production in RAW 264.7 cells (EC50 = 8.54 µM). 8-Hydroxy-5,7-dimethoxyflavanone displayed moderate level of NO inhibition (EC50 = 43.62 µM) with little cytotoxicity. The polyoxygenated cyclohexenes and lignans were inactive against HCT 116 and 22Rv1 cancer cells (IC50 > 100 µM).

Developing a career versus careering through your professional life.

Vet Jeremy Johnson's career journey went from large animal 'grunt', through a world of pharmaceuticals, to embracing consultancy and then becoming director of new SQP training and registration body Vetpol.

Tirzepatide: A Novel Glucose-Dependent Insulinotropic Polypeptide/Glucagon-Like Peptide 1 Receptor Agonist for the Treatment of Type 2 Diabetes: The First Twincretin.

Tirzepatide is a dual-action glucose-dependent insulinotropic polypeptide/glucagon-like peptide 1 (GLP-1) receptor agonist and the first drug in a new class known as twincretins. It is similar to GLP-1 receptor agonists but provides a synergistic enhancement of the incretin effect to control blood glucose levels and reduce weight. Across the SURPASS research program trials, tirzepatide lowered A1C by 1.7-2.4% from baseline. The proportion of patients using tirzepatide who achieved an A1C <7% ranged from 91 to 97%. Patients in the treatment groups averaged a weight loss of 5.44-11.34 kg (12-25 lb). Across all trials, patients on tirzepatide 15 mg lost 8.8-12.9 kg (19.4-28.44 lb) or 9.17-13.7% body weight. In the SURMOUNT-1 trial, maximum weight loss was 23.6 kg (52 lb) or 22.5% body weight. Tirzepatide is a potent new weapon in the arsenal against diabetes.

Valproate-induced reversible cognitive decline presenting as dementia and associated clinical features: A literature review.

BACKGROUND/AIM: Valproate (VPA) is an effective broad-spectrum anti-seizure medication. Both VPA induced encephalopathy and reversible cognitive decline (VIRCD) have been reported as rare side effects. While the former is well-described in terms of risk factors, mechanism and management, the latter is less recognised and can be easily mistaken for neurodegenerative dementia. In this paper, we present a literature review of VIRCD, describe its clinical features and compare our findings to those in VPA-induced encephalopathy. METHODS: We used PubMed search for valproate induced (dementia OR cognitive impairment OR cognitive decline OR cognitive dysfunction). Patients included were those with normal or well-defined cognitive baseline who presented with dementia after valproate therapy, in whom cognitive decline reversed after VPA dose reduction or discontinuation. Clinical features were compared to published descriptions of VPA-induced encephalopathy. RESULTS: A total of 33 cases in 11 publications were included. Mean age was 51.2 years. Most were being treated for epilepsy on VPA with good seizure control and no encephalopathic features. VPA levels were within the usual quoted range. Mean latency after VPA initiation and symptoms was 6.87 years. Most had parkinsonian features. The most commonly reported cognitive deficits were in short-term memory and processing speed. All recovered fully on VPA discontinuation. CONCLUSION: VIRCD mimics neurodegenerative dementia but is reversible on VPA discontinuation. The absence of encephalopathic features and good seizure control in addition to the prolonged latency make it easy to miss. VIRCD should be considered in relevant patient groups, especially in the presence of extrapyramidal signs.

Non-covalent inhibitors of thioredoxin glutathione reductase with schistosomicidal activity in vivo.

Only praziquantel is available for treating schistosomiasis, a disease affecting more than 200 million people. Praziquantel-resistant worms have been selected for in the lab and low cure rates from mass drug administration programs suggest that resistance is evolving in the field. Thioredoxin glutathione reductase (TGR) is essential for schistosome survival and a validated drug target. TGR inhibitors identified to date are irreversible and/or covalent inhibitors with unacceptable off-target effects. In this work, we identify noncovalent TGR inhibitors with efficacy against schistosome infections in mice, meeting the criteria for lead progression indicated by WHO. Comparisons with previous in vivo studies with praziquantel suggests that these inhibitors outperform the drug of choice for schistosomiasis against juvenile worms.