Dysbiosis not observed in Canadian horse with free fecal liquid (FFL) using 16S rRNA sequencing.

Free Fecal Liquid (FFL), also termed Fecal Water Syndrome (FWS), is an ailment in horses characterized by variable solid and liquid (water) phases at defecation. The liquid phase can be excreted before, during, or after the solid defecation phase. While the underlying causes of FFL are unknown, hindgut dysbiosis is suggested to be associated with FFL. Three European studies investigated dysbiosis in horses with FFL using 16S rRNA sequencing and reported results that conflicted between each other. In the present study, we also used 16S rRNA sequencing to study the fecal microbial composition in 14 Canadian horses with FFL, and 11 healthy stable mate controls. We found no significant difference in fecal microbial composition between FFL and healthy horses, which further supports that dysbiosis is not associated with FFL.

Characterization of a novel pulse normalization technology for beam scanning of small fields without a reference chamber.

PURPOSE: A novel pulse normalization technology enabling the acquisition of low noise beam data without the use of a physical reference chamber has recently been commercially released. The purpose of this study was to characterize the use of this technology for beam scanning of small fields required in the commissioning of a stereotactic radiotherapy program. METHODS: Three detectors (Edge diode, microDiamond, PinPoint) were used to acquire beam data under three conditions: with a reference chamber, with pulse normalization and no reference chamber (PN), and without pulse normalization and no reference chamber (nPN). Percent depth dose (PDD) scans were acquired for 0.5, 1.0, 2.0, and 3.0 cm2 field sizes and profiles were acquired at 1.4, 10, and 30 cm depths using continuous scanning. The coefficient of variation (CoV) was calculated for all beam data to compare signal-to-noise and gamma comparisons (1%, 1 mm) were calculated of the PN and nPN scans compared to the reference data. RESULTS: Average 95th percentile CoV values were similar for all detectors across conditions, with PN data being comparable to reference data and minor increases observed for nPN data. Mean gamma pass rates for PN PDD scans exceeded 98% for all detectors. Profile gamma pass rates were 100% for all detectors at 1.4 and 10 cm depth. At 30 cm depth, profiles acquired with the PinPoint and microDiamond detectors had lower mean gamma pass rates than the Edge, at 95% and 95.7%, respectively. CONCLUSIONS: A novel pulse normalization technology was demonstrated to be effective for acquiring beam profiles and PDDs for small fields without the use of a physical reference chamber. Limitations in how the method is implemented led to some errors in data acquired using lower sensitivity detectors. When used with a diode, pulse normalization produced equivalent scans to those acquired with a reference chamber.

Structure of the five-coordinate CoII complex (1H-imidazole){tris-[(1-benzyl-triazol-4-yl-κN3)meth-yl]amine-κN}cobalt(II) bis-(tetra-fluoro-borate).

The title compound, [Co(C3H4N2)(C30H30N10)](BF4)2, is a five-coordinate CoII complex based on the neutral ligands tris-[(1-benzyl-triazol-4-yl)meth-yl]amine (tbta) and imidazole. It exhibits a distorted trigonal bipyramidal geometry in which the equatorial positions are occupied by the three N-atom donors from the triazole rings of the tripodal tbta ligand. The apical amine N-atom donor of tbta and the N-atom donor of the imidazole ligand occupy the axial positions of the coordination sphere. Two tetra-fluoro-borate anions provide charge balance in the crystal.

Frenotomy Provides Improved Direct Laryngoscopy Exposure in Select Adult Patients With Ankyloglossia.

Objective: To analyze the effects of lingual frenotomy on adults with restrictive ankyloglossia and difficult direct laryngoscopy exposure. Methods: A case series study was conducted. Restriction of tongue protrusion due to ankyloglossia was identified in 2 patients who had a history of suboptimal true vocal fold (TVF) exposure on direct laryngoscopy for phonomicrosurgery. Inadequate exposure of the vocal folds was achieved on direct laryngoscopy attempts with manual tongue protrusion. Mandibular tori were not present in these patients. An intraoperative lingual frenotomy was performed in both patients. Results: After frenotomy and with manual tongue protrusion, direct laryngoscopy exposure was substantially improved allowing for considerably more visualization of the anterior TVFs. Conclusion: Lingual frenulum procedures with manual tongue protrusion should be considered in select adult patients with restrictive ankyloglossia affecting optimal direct laryngoscopy exposure.

Clinical Utility of Laser Speckle Contrast Imaging and Real-Time Quantification of Bowel Perfusion in Minimally Invasive Left-Sided Colorectal Resections.

BACKGROUND: Left-sided colorectal surgery demonstrates high anastomotic leak rates, with tissue ischemia thought to influence outcomes. Indocyanine green is commonly used for perfusion assessment, but evidence remains mixed for whether it reduces colorectal anastomotic leaks. Laser speckle contrast imaging provides dye-free perfusion assessment in real-time through perfusion heat maps and quantification. OBJECTIVE: This study investigates the efficacy of advanced visualization (indocyanine green versus laser speckle contrast imaging), perfusion assessment, and utility of laser speckle perfusion quantification in determining ischemic margins. DESIGN: Prospective intervention group using advanced visualization with case-matched, retrospective control group. SETTINGS: Single academic medical center. PATIENTS: Forty adult patients undergoing elective, minimally invasive, left-sided colorectal surgery. INTERVENTIONS: Intraoperative perfusion assessment using white light imaging and advanced visualization at 3 time points: T1-proximal colon after devascularization, before transection, T2-proximal/distal colon before anastomosis, and T3-completed anastomosis. MAIN OUTCOME MEASURES: Intraoperative indication of ischemic line of demarcation before resection under each visualization method, surgical decision change using advanced visualization, post hoc laser speckle perfusion quantification of colorectal tissue, and 30-day postoperative outcomes. RESULTS: Advanced visualization changed surgical decision-making in 17.5% of cases. For cases in which surgeons changed a decision, the average discordance between the line of demarcation in white light imaging and advanced visualization was 3.7 cm, compared to 0.41 cm ( p = 0.01) for cases without decision changes. There was no statistical difference between the line of ischemic demarcation using laser speckle versus indocyanine green ( p = 0.16). Laser speckle quantified lower perfusion values for tissues beyond the line of ischemic demarcation while suggesting an additional 1 cm of perfused tissue beyond this line. One (2.5%) anastomotic leak occurred in the intervention group. LIMITATIONS: This study was not powered to detect differences in anastomotic leak rates. CONCLUSIONS: Advanced visualization using laser speckle and indocyanine green provides valuable perfusion information that impacts surgical decision-making in minimally invasive left-sided colorectal surgeries. See Video Abstract . UTILIDAD CLNICA DE LAS IMGENES DE CONTRASTE MOTEADO CON LSER Y LA CUANTIFICACIN EN TIEMPO REAL DE LA PERFUSIN INTESTINAL EN RESECCIONES COLORRECTALES DEL LADO IZQUIERDO MNIMAMENTE INVASIVAS: ANTECEDENTES:La cirugía colorrectal del lado izquierdo demuestra altas tasas de fuga anastomótica, y se cree que la isquemia tisular influye en los resultados. El verde de indocianina se utiliza habitualmente para evaluar la perfusión, pero la evidencia sobre si reduce las fugas anastomóticas colorrectales sigue siendo contradictoria. Las imágenes de contraste moteado con láser proporcionan una evaluación de la perfusión sin colorantes en tiempo real a través de mapas de calor de perfusión y cuantificación.OBJETIVO:Este estudio investiga la eficacia de la evaluación de la perfusión mediante visualización avanzada (verde de indocianina versus imágenes de contraste moteado con láser) y la utilidad de la cuantificación de la perfusión con moteado láser para determinar los márgenes isquémicos.DISEÑO:Grupo de intervención prospectivo que utiliza visualización avanzada con un grupo de control retrospectivo de casos emparejados.LUGARES:Centro médico académico único.PACIENTES:Cuarenta pacientes adultos sometidos a cirugía colorrectal electiva, mínimamente invasiva, del lado izquierdo.INTERVENCIONES:Evaluación de la perfusión intraoperatoria mediante imágenes con luz blanca y visualización avanzada en tres puntos temporales: T1-colon proximal después de la devascularización, antes de la transección; T2-colon proximal/distal antes de la anastomosis; y T3-anastomosis completa.PRINCIPALES MEDIDAS DE VALORACIÓN:Indicación intraoperatoria de la línea de demarcación isquémica antes de la resección bajo cada método de visualización, cambio de decisión quirúrgica mediante visualización avanzada, cuantificación post-hoc de la perfusión con láser moteado del tejido colorrectal y resultados posoperatorios a los 30 días.RESULTADOS:La visualización avanzada cambió la toma de decisiones quirúrgicas en el 17,5% de los casos. Para los casos en los que los cirujanos cambiaron una decisión, la discordancia promedio entre la línea de demarcación en las imágenes con luz blanca y la visualización avanzada fue de 3,7 cm, en comparación con 0,41 cm (p = 0,01) para los casos sin cambios de decisión. No hubo diferencias estadísticas entre la línea de demarcación isquémica utilizando láser moteado versus verde de indocianina (p = 0,16). El moteado con láser cuantificó valores de perfusión más bajos para los tejidos más allá de la línea de demarcación isquémica y al mismo tiempo sugirió 1 cm adicional de tejido perfundido más allá de esta línea. Se produjo una fuga anastomótica (2,5%) en el grupo de intervención.LIMITACIONES:Este estudio no tuvo el poder estadístico suficiente para detectar diferencias en las tasas de fuga anastomótica.CONCLUSIONES:La visualización avanzada utilizando moteado láser y verde de indocianina proporciona información valiosa sobre la perfusión que impacta la toma de decisiones quirúrgicas en cirugías colorrectales mínimamente invasivas del lado izquierdo. (Traducción-Dr. Ingrid Melo).

Flagella are required to coordinately activate competition and host colonization factors in response to a mechanical signal.

Bacteria employ antagonistic strategies to eliminate competitors of an ecological niche. Contact-dependent mechanisms, such as the type VI secretion system (T6SS), are prevalent in host-associated bacteria, yet we know relatively little about how T6SS+ strains make contact with competitors in highly viscous environments, such as host mucus. To better understand how cells respond to and contact one another in such environments, we performed a genome-wide transposon mutant screen of the T6SS-wielding beneficial bacterial symbiont, Vibrio fischeri, and identified two sets of genes that are conditionally required for killing. LPS/capsule and flagellar-associated genes do not affect T6SS directly and are therefore not required for interbacterial killing when cell contact is forced yet are necessary for killing in high-viscosity liquid (hydrogel) where cell-cell contact must be biologically mediated. Quantitative transcriptomics revealed that V. fischeri significantly increases expression of both T6SS genes and cell surface modification factors upon transition from low- to high-viscosity media. Consistent with coincubation and fluorescence microscopy data, flagella are not required for T6SS expression in hydrogel. However, flagella play a key role in responding to the physical environment by promoting expression of the surface modification genes identified in our screen, as well as additional functional pathways important for host colonization including uptake of host-relevant iron and carbon sources, and nitric oxide detoxification enzymes. Our findings suggest that flagella may act as a mechanosensor for V. fischeri to coordinately activate competitive strategies and host colonization factors, underscoring the significance of the physical environment in directing complex bacterial behaviors.

Technical note: Commissioning of a low-cost system for directly 3D printed flexible bolus.

PURPOSE: To present the commissioning process of a low-cost solution for directly 3D printed flexible patient specific bolus. METHODS: The 3D printing solution used in this study consisted of a resin stereolithography 3D printer and a flexible curing resin. To test the dimensional accuracy of the 3D printer, rectangular cuboids with varying dimensions were 3D printed and their measured dimensions were compared to the designed dimensions. Percent Depth Dose (PDD) profiles were measured by irradiating film embedded in a 3D printed phantom made of the flexible material. A CT of the phantom was acquired and used to replicate the irradiation setup in the treatment planning system. PDDs were calculated for both the native HU of the phantom, and with the phantom HU overridden to 300 HU to match its physical density. Dosimetric agreement was characterized by comparing calculated to measured depths of R90, R80, and R50. Upon completion of the commissioning process, a bolus was 3D printed for a clinical case study for treatment of the nose. RESULTS: Dimensional accuracy of the printer and material combination was found to be good, with all measured dimensions of test cuboids within 0.5 mm of designed. PDD measurements demonstrated the best dosimetric agreement when the material was overridden to 300 HU, corresponding to the measured physical density of the material of 1.18 g/cc. Calculated and measured depths of R90, R80, and R50 all agreed within 1 mm. The bolus printed for the clinical case was free from defects, highly conformal, and led to a clinically acceptable plan. CONCLUSION: The results of the commissioning measurements performed indicate that the 3D printer and material solution are suitable for clinical use. The 3D printer and material combination can provide a low-cost solution a clinic can implement in-house to directly 3D print flexible bolus.

Prostaglandins limit nuclear actin to control nucleolar function during oogenesis.

Prostaglandins (PGs), locally acting lipid signals, regulate female reproduction, including oocyte development. However, the cellular mechanisms of PG action remain largely unknown. One cellular target of PG signaling is the nucleolus. Indeed, across organisms, loss of PGs results in misshapen nucleoli, and changes in nucleolar morphology are indicative of altered nucleolar function. A key role of the nucleolus is to transcribe ribosomal RNA (rRNA) to drive ribosomal biogenesis. Here we take advantage of the robust, in vivo system of Drosophila oogenesis to define the roles and downstream mechanisms whereby PGs regulate the nucleolus. We find that the altered nucleolar morphology due to PG loss is not due to reduced rRNA transcription. Instead, loss of PGs results in increased rRNA transcription and overall protein translation. PGs modulate these nucleolar functions by tightly regulating nuclear actin, which is enriched in the nucleolus. Specifically, we find that loss of PGs results in both increased nucleolar actin and changes in its form. Increasing nuclear actin, by either genetic loss of PG signaling or overexpression of nuclear targeted actin (NLS-actin), results in a round nucleolar morphology. Further, loss of PGs, overexpression of NLS-actin or loss of Exportin 6, all manipulations that increase nuclear actin levels, results in increased RNAPI-dependent transcription. Together these data reveal PGs carefully balance the level and forms of nuclear actin to control the level of nucleolar activity required for producing fertilization competent oocytes.

HEMATOLOGIC AND BIOCHEMICAL VALUES OF FREE-RANGING HAWKSBILL SEA TURTLES (ERETMOCHELYS IMBRICATA) IN GLOVER'S REEF, BELIZE.

Blood samples were obtained from the dorsal cervical sinus of free-ranging hawksbill sea turtles (Eretmochelys imbricata) collected at Glover's Reef Marine Reserve, 42 km east of the coast of Belize, for hematology and plasma biochemistry analysis. Unknown sex, subadult turtles (N = 32) were sampled in 2013 (n = 22) and 2017 (n = 10). To provide a more robust data set, parameters that did not have statistically significant differences were pooled and treated as a single population. Eleven hematologic parameters were evaluated; of these, five were pooled. Twenty-three plasma biochemical parameters were evaluated; of these, 15 were pooled. The PCV observed in this study (mean 33.44%) was double that observed in two studies of juvenile hawksbills in Dubai (means 17% and 16%), whereas the total WBC count was half that observed in immature and adult hawksbills sampled in the Galápagos (mean 2.91 × 103 versus 5.3 × 103/µl). Total protein and albumin were lower than regionally similar, adult female hawksbills in Brazil (means 3.36 versus 5.45 g/dl and 0.93 versus 2.11 g/dl, respectively). Globulins were higher (mean 2.43 versus 1.06 and 0.5 g/dl), driving the albumin:globulin ratio lower than that observed in two studies of juvenile hawksbills in Dubai (0.4:1 versus 1.1:1 and 1:1, respectively). These findings represent a geographically distinct population from previous reports, highlight the variability in blood parameters from disparate populations, and reaffirm the vital importance of considering a multitude of variables when interpreting reptilian blood values. The similarities in the majority of values observed in 2013 and 2017 provide confidence in the stability of these parameters in this population.

COVID-19 and Fidelity to the Sobriety Treatment and Recovery Teams Model.

OBJECTIVE: Quick access to substance use treatment is associated with better outcomes, but little is known about COVID-19's impact on access and retention. This study examined the relationship between COVID-19-related practice changes and quick access fidelity outcomes of the Sobriety Treatment and Recovery Teams (START) program, which serves families with co-occurring substance use and child abuse/neglect. METHOD: This study was a retrospective cohort comparison. On March 23, 2020, most START child welfare and treatment services were shifted to a virtual format because of the COVID-19 pandemic. Families referred to the program between that date and March 23, 2021, were compared with families served the year before (i.e., March 23, 2019, to March 22, 2020). Cohorts were compared across nine fidelity outcomes (e.g., number of days to complete four treatment sessions), with differences assessed using chi-square tests and independent samples t tests. RESULTS: Referrals to START were 14% lower during the first COVID-19 year than in the prior year, with a greater percentage of referred cases being accepted during COVID-19. Transition to virtual service provision was not related to quick access fidelity outcomes; however, adults referred in the year before COVID-19 were more likely to complete four treatment sessions than adults referred during the first COVID-19 year. CONCLUSIONS: In this study, quick access to services and initial engagement did not appear to be negatively affected by virtual service provision resulting from COVID-19. However, during COVID-19, fewer adults completed four treatment sessions. In a largely virtual treatment environment, additional engagement and pre-treatment services may be necessary.

A case report of mucinous tubular and spindle cell carcinoma of the kidney.

Mucinous tubular and spindle cell carcinoma (MTSCC) is a rare type of kidney tumor that has only recently been described, with less than eighty cases in the literature. This was only recognized as a specific entity in the World Health Organization 2004 classification of Renal Cell Carcinoma (RCC). MTSCCs are polymorphic renal neoplasms characterized by small, elongated tubules lined by cuboidal cells with cords of spindled cells separated by pale mucinous stroma. We report the case of a 57 year old lady who had an incidental finding of a mass in her right kidney. The radiological features were consistent with a RCC and following a multidisciplinary team discussion she underwent a laparoscopic radical nephrectomy. Macroscopic examination revealed a well circumscribed 6.5 × 6 × 6.5 cm right lower pole mass. Histologically it was composed of elongated tubules, small tubules and papillary structures with a necrotic centre. The cells demonstrated cuboidal and spindle cell morphology. Histological grade was Fuhrman grade 2. The majority of MTSCCs are indolent, and there are only two reports of distant metastases which responded favorably to adjuvant sunitinib. To date there is no international consensus on long term surveillance of these patients. Due of the favorable prognosis with this type of tumor, MTSCC must be differentiated from papillary renal cell carcinoma to avoid administration of excessive adjuvant treatment to patients.

Mycosynthesis of Zinc Oxide Nanoparticles Exhibits Fungal Species Dependent Morphological Preference.

Filamentous fungi can synthesize a variety of nanoparticles (NPs), a process referred to as mycosynthesis that requires little energy input, do not require the use of harsh chemicals, occurs at near neutral pH, and do not produce toxic byproducts. While NP synthesis involves reactions between metal ions and exudates produced by the fungi, the chemical and biochemical parameters underlying this process remain poorly understood. Here, the role of fungal species and precursor salt on the mycosynthesis of zinc oxide (ZnO) NPs is investigated. This data demonstrates that all five fungal species tested are able to produce ZnO structures that can be morphologically classified into i) well-defined NPs, ii) coalesced/dissolving NPs, and iii) micron-sized square plates. Further, species-dependent preferences for these morphologies are observed, suggesting potential differences in the profile or concentration of the biochemical constituents in their individual exudates. This data also demonstrates that mycosynthesis of ZnO NPs is independent of the anion species, with nitrate, sulfate, and chloride showing no effect on NP production. These results enhance the understanding of factors controlling the mycosynthesis of ceramic NPs, supporting future studies that can enable control over the physical and chemical properties of NPs formed through this "green" synthesis method.

A hybrid method to improve efficiency of patient specific SRS and SBRT QA using 3D secondary dose verification.

PURPOSE: Patient Specific QA (PSQA) by direct phantom measurement for all intensity modulated radiation therapy (IMRT) cases is labor intensive and an inefficient use of the Medical Physicist's time. The purpose of this work was to develop a hybrid quality assurance (QA) technique utilizing 3D dose verification as a screening tool to determine if a measurement is necessary. METHODS: This study utilized Sun Nuclear DoseCHECK (DC), a 3D secondary verification software, and Fraction 0, a trajectory log IMRT QA software. Twenty-two Lung stereotactic body radiation therapy (SBRT) and thirty single isocentre multi-lesion SRS (MLSRS) plans were retrospectively analysed in DC. Agreement of DC and the TPS dose for selected dosimetric criteria was recorded. Calculated 95% confidence limits (CL) were used to establish action limits. All cases were delivered and measured using the Sun Nuclear stereotactic radiosurgery (SRS) MapCheck. Trajectory logs of the delivery were used to calculate Fraction 0 results for the same criteria calculated by DC. Correlation of DC and Fraction 0 results were calculated. Phantom measured QA was compared to Fraction 0 QA results for the cases which had DC criteria action limits exceeded. RESULTS: Correlation of DC and Fraction 0 results were excellent, demonstrating the same action limits could be used for both and DC can predict Fraction 0 results. Based on the calculated action limits, zero lung SBRT cases and six MLSRS cases were identified as requiring a measurement. All plans that passed the DC screening had a passing measurement based PSQA and agreed with Fraction 0 results. CONCLUSION: Using 95% CL action limits of dosimetric criteria, a 3D secondary dose verification can be used to determine if a measurement is required for PSQA. This method is efficient for it is part of the normal clinical workflow when verifying any clinical treatment. In addition, it can drastically reduce the number of measurements needed for PSQA.

Preliminary evidence that misalignment between sleep and circadian timing alters risk-taking preferences.

Decision-making has been shown to suffer when circadian preference is misaligned with time of assessment; however, little is known about how misalignment between sleep timing and the central circadian clock impacts decision-making. This study captured naturally occurring variation in circadian alignment (i.e., alignment of sleep-wake timing with the central circadian clock) to examine if greater misalignment predicts worse decision-making. Over the course of 2 weeks, 32 late adolescent drinkers (aged 18-22 years; 61% female; 69% White) continuously wore actigraphs and completed two overnight in-laboratory visits (Thursday and Sunday) in which both dim-light melatonin onset (DLMO) and behavioural decision-making (risk taking, framing, and strategic reasoning tasks) were assessed. Sleep-wake timing was assessed by actigraphic midsleep from the 2 nights prior to each in-laboratory visit. Alignment was operationalised as the phase angle (interval) between average DLMO and average midsleep. Multilevel modelling was used to predict performance on decision-making tasks from circadian alignment during each in-laboratory visit; non-linear associations were also examined. Shorter DLMO-midsleep phase angle predicted greater risk-taking under conditions of potential loss (B = -0.11, p = 0.06), but less risk-taking under conditions of potential reward (B = 0.14, p = 0.03) in a curvilinear fashion. Misalignment did not predict outcomes in the framing and strategic reasoning tasks. Findings suggest that shorter alignment in timing of sleep with the central circadian clock (e.g., phase-delayed misalignment) may impact risky decision-making, further extending accumulating evidence that sleep/circadian factors are tied to risk-taking. Future studies will need to replicate findings and experimentally probe whether manipulating alignment influences decision-making.

Assessment of Pain, Healing Time, and Wound Contraction in Postoperative Auricular Defects Healing Secondarily With and Without the Use of a Porcine Xenograft, a Pilot Study.

BACKGROUND: Postoperative auricular defects heal well with secondary intention healing (SIH); however, potential complications include postoperative pain, perichondritis, and chondritis. OBJECTIVE: To compare postoperative pain and wound healing in auricular defects healing by secondary intention with and without the placement of a porcine xenograft. MATERIALS AND METHODS: Twenty-one subjects were enrolled in the study. The primary outcome was self-reported pain, measured on a 0 to 10 scale for 14 postprocedure days. Secondary outcomes included time to greater than 90% of reepithelialization and degree of wound contraction. RESULTS: There was a 1 to 2 point difference in median pain scores between the porcine graft and control groups during postoperative days 4 to 7, 12, and 13. Time to 90% or greater reepithelialization was not statistically different between groups (p = .94). The average wound contraction was 34.1% for the porcine group and 34.0% for the control group (p = .95). CONCLUSION: In this pilot study, overall pain scores were low in both groups. Placement of a porcine xenograft resulted in a slight reduction of median pain compared with traditional SIH. Patients in the control group were more likely to require analgesics. Similar rates of reepithelialization and degree of wound contracture were observed.

Optimizing Botox regimens in patients with adductor spasmodic dysphonia and essential tremor of voice: A 31-year experience.

Objective: The purpose of this study was to quantitatively compare the effectiveness of unilateral and bilateral botulinum toxin A (BTX-A) injections for mitigating undesirable weak/breathy voice quality and dysphagia for patients with adductor spasmodic dysphonia and/or essential tremor of voice (ETV). Methods: Data were collected from the medical records of 319 patients, yielding three treatment cohorts: patients who received an equal dose bilateral injection regimen (BL=) throughout their course of treatment at VUMC, patients who switched to a unilateral injection regimen (UL), and patients who switched to an unequal dose bilateral injection regimen (BL≠). Changes in length of improvement, duration of weak/breathy voice, and dysphagia severity were compared. Results: The BL = treatment group reported the longest duration of improved voice. Shorter periods of improved voice were reported at baseline by patients who later switched to UL or BL ≠ injection regimens. Patients receiving UL injections reported significantly reduced weak/breathy voice and dysphagia. Patients receiving BL ≠ injections reported increased length of improved voice; however, dysphagia symptoms increased. Ninety-two percent of patients with ETV switched to a UL regimen, with 61% of patients transitioning within the first three injections. Conclusions: Patients with pronounced dysphagia and extended periods of weak/breathy voice may benefit from a UL injection approach to mitigate side effects from BTX-A without sacrificing improved voice outcomes. For patients seeking to extend their length of improved voice, a BL ≠ injection regimen may be effective provided the adverse side effects from BTX-A are minimal. Patients with ETV may benefit from a UL injection approach at the outset of their course of treatment with BTX-A. Level of evidence: III.

Syntheses and studies of deuterated Imdiazo[1,2-a]pyridine-3-carboxamides with potent anti-tuberculosis activity and improved metabolic properties.

The imidazo[1,2-a]pyridine-3-carboxyamides (IAPs) are a unique class of compounds endowed with impressive nanomolar in vitro potency against Mycobacterium tuberculosis (Mtb) as exemplified by clinical candidate Telacebec (Q203). These compounds target mycobacterial respiration through inhibition of the QcrB subunit of cytochrome bc1:aa3 super complex resulting in bacteriostatic efficacy in vivo. Our labs have had a long-standing interest in the design and development of IAPs. However, some of these compounds suffer from short in vivo half-lives, requiring multiple daily dosing or the addition of a cytochrome P450 inhibitor for murine efficacy evaluations. Deuteration has been shown to decrease metabolism as the C-D bond is stronger than the CH bond. Herein we describe our efforts on design and synthesis of potent deuterated IAPs and the effect that deuteration has upon metabolism through microsomal stability studies.

The 24-hour rhythm in alcohol craving and individual differences in sleep characteristics and alcohol use frequency.

BACKGROUND: Evidence implicates sleep/circadian factors in alcohol use, suggesting the existence of a 24-h rhythm in alcohol craving, which may vary by individual differences in sleep factors and alcohol use frequency. This study sought to (1) replicate prior findings of a 24-h rhythm in alcohol craving, and (2) examine whether individual differences in sleep timing, sleep duration, or alcohol use frequency are related to differences in the timing of the peak of the craving rhythm (i.e., the acrophase) or magnitude of fluctuation of the rhythm (i.e., amplitude). Finally, whether such associations varied by sex or racial identity was explored. METHODS: Two-hundred fifteen adult drinkers (21 to 35 years of age, 72% male, 66% self-identified as White) completed a baseline assessment of alcohol use frequency and then smartphone reports of alcohol craving intensity six times a day across 10 days. Sleep timing was also recorded each morning of the 10-day period. Multilevel cosinor analysis was used to test the presence of a 24-h rhythm and to estimate acrophase and amplitude. RESULTS: Multilevel cosinor analysis revealed a 24-h rhythm in alcohol craving. Individual differences in sleep timing or sleep duration did not predict rhythm acrophase or amplitude. However, alcohol use frequency moderated this rhythm wherein individuals who used alcohol more frequently in the 30 days prior to beginning the study had higher mean levels of craving and greater rhythm amplitudes (i.e., greater rhythmic fluctuations). Associations did not vary by sex or racial identity. CONCLUSIONS: Results show that alcohol craving exhibits a systematic rhythm over the course of the 24 h and that the frequency of alcohol use may be relevant to the shape of this rhythm. Consideration of daily rhythms in alcohol craving may further our understanding of the mechanisms that drive alcohol use.

Striatal dopamine synthesis capacity and its association with negative symptoms upon resolution of positive symptoms in first-episode schizophrenia and delusional disorder.

RATIONALE: How striatal dopamine synthesis capacity (DSC) contributes to the pathogenesis of negative symptoms in first-episode schizophrenia (SZ) and delusional disorder (DD) has seldom been explored. As negative symptoms during active psychotic episodes can be complicated by secondary influences, such as positive symptoms, longitudinal investigations may help to clarify the relationship between striatal DSC and negative symptoms and differentiate between primary and secondary negative symptoms. OBJECTIVE: A longitudinal study was conducted to examine whether baseline striatal DSC would be related to negative symptoms at 3 months in first-episode SZ and DD patients. METHODS: Twenty-three first-episode age- and gender-matched patients (11 DD and 12 SZ) were consecutively recruited through an early intervention service for psychosis in Hong Kong. Among them, 19 (82.6%) patients (9 DD and 10 SZ) were followed up at 3 months. All patients received an 18F-DOPA PET/MR scan at baseline. RESULTS: Baseline striatal DSC (Kocc;30-60) was inversely associated with negative symptoms at 3 months in first-episode SZ patients (rs = - 0.80, p = 0.010). This association remained in SZ patients even when controlling for baseline negative, positive, and depressive symptoms, as well as cumulative antipsychotic dosage (ß = - 0.69, p = 0.012). Such associations were not observed in first-episode DD patients. Meanwhile, the severity of negative symptoms at 3 months was associated with more positive symptoms in DD patients (rs = 0.74, p = 0.010) and not in SZ patients. CONCLUSIONS: These findings highlight the role of striatal DSC in negative symptoms upon resolution of active psychotic episodes among first-episode SZ patients. Baseline striatal dopamine activity may inform future symptom expression with important treatment implications.

Cubic Crystal Structure Formation and Optical Properties within the Ag-BII-MIV-X (BII = Sr, Pb; MIV = Si, Ge, Sn; X = S, Se) Family of Semiconductors.

Quaternary chalcogenide semiconductors are promising materials for energy conversion and nonlinear optical applications, with properties tunable primarily by varying the elemental composition and crystal structure. Here, we first analyze the connections among several cubic crystal structure types, as well as the orthorhombic Ag2PbGeS4-type structure, reported for select members within the Ag-BII-MIV-X (BII = Sr, Pb; MIV = Si, Ge, Sn; X = S, Se) compositional space. Focusing on the Ag-Pb-Si-S and Ag-Sr-Sn-S systems, we show that one structure type, with the formulas Ag2Pb3Si2S8 and Ag2Sr3Sn2S8, is favored. We have prepared powder and single-crystal samples of Ag2Pb3Si2S8 and Ag2Sr3Sn2S8, showing that each takes on the noncentrosymmetric cubic space group I4̅3d and is isostructural to the previously reported compound Ag2Sr3Ge2Se8. Through hybrid density functional theory calculations, these cubic compounds are demonstrated to be (quasi-)direct band gap semiconductors with high densities of states at the band maxima. The band-gap energies are measured by reflectance spectroscopy as 1.95(3) and 2.66(4) eV for Ag2Pb3Si2S8 and Ag2Sr3Sn2S8, respectively. We further measure the optical properties and show the electronic band structures of three other isostructural AI-BII-MIV-X-type materials, i.e., Ag2Sr3Si2S8, Ag2Sr3Ge2S8, and Ag2Sr3Ge2Se8, showing that the band gaps can be predictably tuned by element substitution. Detailed visual analyses of the different structures and of their relationships with other members of the Ag-BII-MIV-X compositional family provide a basis for a broader understanding of the structure formation and optoelectronic properties within the quaternary chalcogenide semiconductor family.