Nerve fibre organisation in the human optic nerve and chiasm: what do we really know?

A recent anatomical study of the human optic chiasm cast doubt on the widespread assumption that nerve fibres travelling in the human optic nerve and chiasm are arranged retinotopically. Accordingly, a scoping literature review was performed to determine what is known about the nerve fibre arrangement in these structures. Meta-analysis suggested that the average number of fibres in each optic nerve was 1.023 million with an inter-individual range of approximately 50% of the mean. Loss of nerve fibres with age (approximately 3,400 fibres/year) could not account for this variability. The review suggested that there might be a retinotopic arrangement of nerve fibres in the orbital portion of the optic nerve but that this arrangement is most likely to be lost posteriorly with a more random distribution of nerve fibres at the chiasm. Limited studies have looked at nerve fibre arrangement in the chiasm. In summary, the chiasm is more 'H-shaped' than 'X-shaped': nerve fibre crossings occur paracentrally with nerves in the centre of the chiasm travelling coronally and in parallel. There is interaction between crossed and uncrossed fibres which are widely distributed. The review supports the non-existence of Wilbrand's knee. Considerable further work is required to provide more precise anatomical information, but this review suggests that the assumed preservation of retinotopy in the human optic nerve and chiasm is probably not correct.

Screening for Adulthood ADHD and Comorbidities in a Tertiary Mental Health Center Using EarlyDetect: A Machine Learning-Based Pilot Study.

Screening for adult Attention-Deficit/Hyperactivity Disorder (ADHD) and differentiating ADHD from comorbid mental health disorders remains to be clinically challenging. A screening tool for ADHD and comorbid mental health disorders is essential, as most adult ADHD is comorbid with several mental health disorders. The current pilot study enrolled 955 consecutive patients attending a tertiary mental health center in Canada and who completed EarlyDetect assessment, with 45.2% of patients diagnosed with ADHD. The best ADHD classification model using composite scoring achieved a balanced accuracy of 0.788, showing a 2.1% increase compared to standalone ADHD screening, detecting four more patients with ADHD per 100 patients. The classification model including ADHD with comorbidity was also successful (balanced accuracy = 0.712). The results suggest the novel screening method can improve ADHD detection accuracy and inform the risk of ADHD with comorbidity, and may further inform specific comorbidity including MDD and BD.

Individualized identification of sexual dysfunction of psychiatric patients with machine-learning.

Sexual dysfunction (SD) is prevalent in patients with mental health disorders and can significantly impair their quality of life. Early recognition of SD in a clinical setting may help patients and clinicians to optimize treatment options of SD and/or other primary diagnoses taking SD risk into account and may facilitate treatment compliance. SD identification is often overlooked in clinical practice; we seek to explore whether patients with a high risk of SD can be identified at the individual level by assessing known risk factors via a machine learning (ML) model. We assessed 135 subjects referred to a tertiary mental health clinic in a Western Canadian city using health records data, including age, sex, physician's diagnoses, drug treatment, and the Arizona Sexual Experiences Scale (ASEX). A ML model was fitted to the data, with SD status derived from the ASEX as target outcomes and all other variables as predicting variables. Our ML model was able to identify individual SD cases-achieving a balanced accuracy of 0.736, with a sensitivity of 0.750 and a specificity of 0.721-and identified major depressive disorder and female sex as risk factors, and attention deficit hyperactivity disorder as a potential protective factor. This study highlights the utility of SD screening in a psychiatric clinical setting, demonstrating a proof-of-concept ML approach for SD screening in psychiatric patients, which has marked potential to improve their quality of life.

Synthesis of fused 1,2-naphthoquinones with cytotoxic activity using a one-pot three-step reaction.

A method for the synthesis of fused 1,2-naphthoquinones, as analogues of biologically active natural terpene quinones, is described. The intermediate polycyclic naphthalenes were prepared by a one-pot palladium-catalysed process from simple alkynes, one of which was made from an optically pure biomass-derived levoglucosenone. The prepared methoxy-substituted naphthalenes were subsequently transformed in one step to 1,2-naphthoquinones by a trivalent-iodine-mediated oxidation. The naphthoquinone products were found to have cytotoxic properties.

The long-term impact of the Leprosy Post-Exposure Prophylaxis (LPEP) program on leprosy incidence: A modelling study.

BACKGROUND: The Leprosy Post-Exposure Prophylaxis (LPEP) program explored the feasibility and impact of contact tracing and the provision of single dose rifampicin (SDR) to eligible contacts of newly diagnosed leprosy patients in Brazil, India, Indonesia, Myanmar, Nepal, Sri Lanka and Tanzania. As the impact of the programme is difficult to establish in the short term, we apply mathematical modelling to predict its long-term impact on the leprosy incidence. METHODOLOGY: The individual-based model SIMCOLEP was calibrated and validated to the historic leprosy incidence data in the study areas. For each area, we assessed two scenarios: 1) continuation of existing routine activities as in 2014; and 2) routine activities combined with LPEP starting in 2015. The number of contacts per index patient screened varied from 1 to 36 between areas. Projections were made until 2040. PRINCIPAL FINDINGS: In all areas, the LPEP program increased the number of detected cases in the first year(s) of the programme as compared to the routine programme, followed by a faster reduction afterwards with increasing benefit over time. LPEP could accelerate the reduction of the leprosy incidence by up to six years as compared to the routine programme. The impact of LPEP varied by area due to differences in the number of contacts per index patient included and differences in leprosy epidemiology and routine control programme. CONCLUSIONS: The LPEP program contributes significantly to the reduction of the leprosy incidence and could potentially accelerate the interruption of transmission. It would be advisable to include contact tracing/screening and SDR in routine leprosy programmes.

Leprosy post-exposure prophylaxis with single-dose rifampicin (LPEP): an international feasibility programme.

BACKGROUND: Innovative approaches are required for leprosy control to reduce cases and curb transmission of Mycobacterium leprae. Early case detection, contact screening, and chemoprophylaxis are the most promising tools. We aimed to generate evidence on the feasibility of integrating contact tracing and administration of single-dose rifampicin (SDR) into routine leprosy control activities. METHODS: The leprosy post-exposure prophylaxis (LPEP) programme was an international, multicentre feasibility study implemented within the leprosy control programmes of Brazil, India, Indonesia, Myanmar, Nepal, Sri Lanka, and Tanzania. LPEP explored the feasibility of combining three key interventions: systematically tracing contacts of individuals newly diagnosed with leprosy; screening the traced contacts for leprosy; and administering SDR to eligible contacts. Outcomes were assessed in terms of number of contacts traced, screened, and SDR administration rates. FINDINGS: Between Jan 1, 2015, and Aug 1, 2019, LPEP enrolled 9170 index patients and listed 179 769 contacts, of whom 174 782 (97·2%) were successfully traced and screened. Of those screened, 22 854 (13·1%) were excluded from SDR mainly because of health reasons and age. Among those excluded, 810 were confirmed as new patients (46 per 10 000 contacts screened). Among the eligible screened contacts, 1182 (0·7%) refused prophylactic treatment with SDR. Overall, SDR was administered to 151 928 (86·9%) screened contacts. No serious adverse events were reported. INTERPRETATION: Post-exposure prophylaxis with SDR is safe; can be integrated into different leprosy control programmes with minimal additional efforts once contact tracing has been established; and is generally well accepted by index patients, their contacts, and health-care workers. The programme has also invigorated local leprosy control through the availability of a prophylactic intervention; therefore, we recommend rolling out SDR in all settings where contact tracing and screening have been established. FUNDING: Novartis Foundation.

The long-term impact of the leprosy post-exposure prophylaxis (LPEP) program on leprosy incidence: a modelling study

The Leprosy Post-Exposure Prophylaxis (LPEP) program explored the feasibility and impact of contact tracing and the provision of SDR to eligible contacts of newly diagnosed leprosy patients in states or districts of Brazil, India, Indonesia, Myanmar, Nepal, Sri Lanka and Tanzania. This study investigated the long-term impact of the LPEP program on the leprosy new case detection rate (NCDR). Our results show that LPEP could reduce the NCDR beyond the impact of the routine leprosy control programme and that many new cases could be prevented. The benefit of LPEP increases gradually over time. LPEP could accelerate the time of reaching predicted NCDR levels of 2040 under routine program by up to six years. Furthermore, we highlighted how the impact varies between countries due to differences in the number of contacts per index patient screened and differences in leprosy epidemiology and national control programme. Generally, including both household contacts and neighbours (> 20 contacts per index patient) would yield the highest impact.

Leprosy post-exposure prophylaxis with single-dose rifampicin (LPEP): an international feasibility programme

Background: Innovative approaches are required for leprosy control to reduce cases and curb transmission of Mycobacterium leprae. Early case detection, contact screening, and chemoprophylaxis are the most promising tools. We aimed to generate evidence on the feasibility of integrating contact tracing and administration of single-dose rifampicin (SDR) into routine leprosy control activities. Methods The leprosy post-exposure prophylaxis (LPEP) programme was an international, multicentre feasibility study implemented within the leprosy control programmes of Brazil, India, Indonesia, Myanmar, Nepal, Sri Lanka, and Tanzania. LPEP explored the feasibility of combining three key interventions: systematically tracing contacts of individuals newly diagnosed with leprosy; screening the traced contacts for leprosy; and administering SDR to eligible contacts. Outcomes were assessed in terms of number of contacts traced, screened, and SDR administration rates. Findings Between Jan 1, 2015, and Aug 1, 2019, LPEP enrolled 9170 index patients and listed 179 769 contacts, of whom 174782 (97·2%) were successfully traced and screened. Of those screened, 22 854 (13·1%) were excluded from SDR mainly because of health reasons and age. Among those excluded, 810 were confirmed as new patients (46 per 10 000 contacts screened). Among the eligible screened contacts, 1182 (0·7%) refused prophylactic treatment with SDR. Overall, SDR was administered to 151 928 (86·9%) screened contacts. No serious adverse events were reported. Interpretation Post-exposure prophylaxis with SDR is safe; can be integrated into different leprosy control programmes with minimal additional efforts once contact tracing has been established; and is generally well accepted by index patients, their contacts, and health-care workers. The programme has also invigorated local leprosy control through the availability of a prophylactic intervention; therefore, we recommend rolling out SDR in all settings where contact tracing and screening have been established(AU).

Enantioselective Synthesis of All-Carbon Quaternary Centers Structurally Related to Amaryllidaceae Alkaloids.

Enantioselective synthesis of all-carbon quaternary centers remains a considerable challenge for synthetic organic chemists. Here, we report a two-step protocol to synthesize such centers including tandem cyclization/Suzuki cross-coupling followed by halocarbocyclization. During this process, two rings, three new C-C bonds and a stereochemically defined all-carbon quaternary center are formed. The absolute configuration of this center is controlled by the stereochemistry of the adjacent stereocenter, which derives from an appropriate enantioenriched starting material. Using this method, we synthesized polycyclic compounds structurally similar to Amaryllidaceae alkaloids in high enantiomeric excesses. Because these products resemble naturally occurring compounds, our protocol can be used to synthesize various potentially bioactive compounds.

Bioinspired total synthesis of tetrahydrofuran lignans by tandem nucleophilic addition/redox isomerization/oxidative coupling and cycloetherification reactions as key steps.

A very short three-step approach to trans,trans,trans-2,5-diaryl-3,4-dimethyltetrahydrofuran lignans is reported. The carbon skeleton is assembled in a single step based on an unprecedented tandem reaction consisting of 1,2-addition of aryllithium reagents to α,ß-unsaturated aldehydes, ruthenium-catalyzed redox isomerization of the resulting alkoxides to enolates and their dimerization triggered by single electron oxidation. The resulting 2,3-dialkyl-1,4-diketones form with moderate to good d/l-diastereoselectivity and are transformed to the target tetrahydrofuran lignans by reduction and diastereoselective cycloetherification.

Assessment and management of sexual dysfunction in the context of depression.

Sexual dysfunction (SD) is pervasive and underreported, and its effects on quality of life are underestimated. Due in part to its bidirectional relationship with depression, SD can be difficult to diagnose; it is also a common side effect of many antidepressants, leading to treatment noncompliance. While physicians often count on patients to spontaneously report SD, treatment is optimized when the clinician instead performs a thorough assessment of sexual functioning before and during drug therapy using a standardized questionnaire such as the Arizona Sexual Experiences Scale (ASEX). Separating the effects of the disorder from those of medications is challenging; we present a concise, evidence-based schematic to assist physicians in minimizing treatment-emergent sexual dysfunction (TESD) while treating depression. Vascular, hormonal, neurogenic, and pharmacological factors should be considered when a patient presents with SD. We also recommend that physicians obtain patient information about baseline and historical sexual functioning before prescribing a drug that may lead to SD and follow up accordingly. When the goal is to treat depression while attenuating the risk of sexual symptoms, physicians may wish to consider agomelatine, bupropion, desvenlafaxine, moclobemide, trazodone, vilazodone, and vortioxetine.

Adult ADHD and comorbid disorders: clinical implications of a dimensional approach.

Attention-deficit/hyperactivity disorder (ADHD) in the adult population is frequently associated with comorbid psychiatric diseases that complicate its recognition, diagnosis and management.The prevalence of ADHD in the general adult population is 2.5% and it is associated with substantial personal and individual burden. The most frequent comorbid psychopathologies include mood and anxiety disorders, substance use disorders, and personality disorders. There are strong familial links and neurobiological similarities between ADHD and the various associated psychiatric comorbidities. The overlapping symptoms between ADHD and comorbid psychopathologies represent challenges for diagnosis and treatment. Guidelines recommend that when ADHD coexists with other psychopathologies in adults, the most impairing condition should generally be treated first.Early recognition and treatment of ADHD and its comorbidities has the potential to change the trajectory of psychiatric morbidity later in life. The use of validated assessment scales and high-yield clinical questions can help identify adults with ADHD who could potentially benefit from evidence-based management strategies.

Functional Recovery in Major Depressive Disorder: Focus on Early Optimized Treatment.

OBJECTIVE: This article presents the case that a more rapid, individualized approach to treating major depressive disorder (MDD) may increase the likelihood of achieving full symptomatic and functional recovery for individual patients and that studies show it is possible to make earlier decisions about appropriateness of treatment in order to rapidly optimize that treatment. DATA SOURCES: A PubMed search was conducted using terms including major depressive disorder, early improvement, predictor, duration of untreated illness, and function. English-language articles published before September 2015 were included. Additional studies were found within identified research articles and reviews. STUDY SELECTION: Thirty antidepressant studies reporting predictor criteria and outcome measures are included in this review. DATA EXTRACTION: Studies were reviewed to extract definitions of predictors, outcome measures, and results of the predictor analysis. Results were summarized separately for studies reporting effects of early improvement, baseline characteristics, and duration of untreated depression. RESULTS: Shorter duration of the current depressive episode and duration of untreated depression are associated with better symptomatic and functional outcomes in MDD. Early improvement of depressive symptoms predicts positive symptomatic outcomes (response and remission), and early functional improvement predicts an increased likelihood of functional remission. CONCLUSIONS: The approach to treatment of depression that exhibits the greatest potential for achieving full symptomatic and functional recovery is early optimized treatment: early diagnosis followed by rapid individualized treatment. Monitoring symptoms and function early in treatment is crucial to ensuring that patients do not remain on ineffective or poorly tolerated treatment, which may delay recovery and heighten the risk of residual functional deficits.

Scientific Misconduct in India: Causes and Perpetuation.

Along with economic strength, space technology and software expertise, India is also a leading nation in fraudulent scientific research. The problem is worsened by vested interests working in concert for their own benefits. These self-promoting cartels, together with biased evaluation methods and weak penal systems, combine to perpetuate scientific misconduct. Some of these issues are discussed in this commentary, with supporting examples and possible solutions.

Dexmedetomidine Attenuates Neurotoxicity Induced by Prenatal Propofol Exposure.

BACKGROUND: Anesthetic agents (eg, isoflurane, propofol) may cause neurodegeneration in the developing brains and impair animals' learning ability. Dexmedetomidine (DEX), a selective alpha 2-adrenoreceptor agonist, has antiapoptotic properties in several brain injury models. Here, we tested whether DEX can protect the brain from neurodegeneration in rats exposed to propofol in utero. MATERIALS AND METHODS: Fetal rats of embryonic day 20 were exposed in utero for 1 hour to propofol anesthesia with DEX or saline, or no anesthesia (control). The fetal brains were harvested 6 hours later. Cleaved caspase-3 levels and the relative number of ionized calcium-binding adaptor molecule 1 (IBA1)-positive cells were assessed by Western blot and immunohistochemistry. Learning and memory functions of the offspring in a separate cohort were assessed at postnatal day 35 by using an 8-arm radial maze. RESULTS: Propofol anesthesia in pregnant rats augmented caspase-3 activation by 217% in the brain tissues of fetal rats and increased the number of IBA1-positive cells in the cortex by 40% and in the thalamus by 270%. Juvenile rats exposed prenatally to propofol were not different than controls on spontaneous locomotor activity, but made more errors of omission and took longer to complete visiting all 8 arms on days 1, 2, and 3 across a 5-day test in the radial arm maze. This neurocognitive deficit was prevented by administration of DEX (5.0 µg/kg, IP), which also significantly inhibited propofol-induced caspase-3 activation and microglial response in the fetal brains. CONCLUSIONS: DEX attenuates neuronal injury induced by maternal propofol anesthesia in the fetal brains, providing neurocognitive protection in the offspring rats.

Highly functionalized and potent antiviral cyclopentane derivatives formed by a tandem process consisting of organometallic, transition-metal-catalyzed, and radical reaction steps.

A simple modular tandem approach to multiply substituted cyclopentane derivatives is reported, which succeeds by joining organometallic addition, conjugate addition, radical cyclization, and oxygenation steps. The key steps enabling this tandem process are the thus far rarely used isomerization of allylic alkoxides to enolates and single-electron transfer to merge the organometallic step with the radical and oxygenation chemistry. This controlled lineup of multiple electronically contrasting reactive intermediates provides versatile access to highly functionalized cyclopentane derivatives from very simple and readily available commodity precursors. The antiviral activity of the synthesized compounds was screened and a number of compounds showed potent activity against hepatitis C and dengue viruses.

Liquid chromatography tandem mass spectrometry method for determination of antidiabetic chalcones derivative S001-469 in rat plasma, urine and feces: application to pharmacokinetic study.

A sensitive and selective liquid chromatography tandem mass spectrometry assay was developed for quantitation of a novel antidiabetic chalcones derivative S001-469 in rat matrices. Plasma and urine samples were prepared by double liquid-liquid extraction with diethyl ether and feces by protein precipitation using acetonitrile. Chromatographic elution was carried on cyano guard column (30 mm × 4.6 mm i.d., 5 µm) in isocratic mode at a flow rate of 0.75 mL/min using mobile phase comprising of methanol: ammonium acetate buffer (pH 4.6, 10 mM) (90:10, v/v). Run time was 6 min. Detection was achieved by employing positive ionization mode on a triple-quadrupole LC-MS/MS system with an electrospray ionization (ESI) source. The calibration curves were linear over the range of 0.78-400 ng/mL for all 3 matrices. The method was validated and proved reliable through high and consistent intra- and inter- day accuracy and precision (<15%) values. Recoveries was >85% from spiked plasma, urine and feces samples. S001-469 was stable in plasma at room temperature till 8 h and at -60 °C for 30 d and 3 freeze-thaw cycles.

Bioanalytical LC-MS/MS method development and validation of novel antidiabetic candidate S007-1261 in rat plasma and its application to pharmacokinetic and oral bioavailability studies.

A sensitive and selective LC-MS/MS method has been developed and validated for CDRI antidiabetic candidate S007-1261 in rat plasma using 16-dehydropregnenolone as an internal standard. The API 4000 triple quadrupole LC-MS/MS system was operated under multiple reaction monitoring mode using electrospray ionization technique in positive mode. The sample processing method involves 2-step liquid-liquid extraction using n-hexane as an extracting solvent. The analyte was chromatographed on RP 18, waters column (3.5 µm, 2.1 mm i.d. × 30 mm) with guard using acetonitrile and ammonium acetate buffer (pH 5.0, 10 mM) in 90:10 (v/v) composition at a flow rate of 0.40 mL min(-1). The chromatographic run time was 5.30 min. Calibration curve shows linearity over concentration range 1.56-200 ng mL(-1). The lower limit of detection was 0.39 ng mL(-1) and lower limit of quantitation was 1.56 ng mL(-1). The inter- and intra-day accuracy and precision were found to be within the assay variability limits as per US FDA guidelines. The absolute recovery of S007-1261 was found to be >90%. S007-1261 does not show any stability problems as it was stable at room temperature for 8 h. S007-1261 was also stable up to 3 freeze-thaw cycles and can be stored up to 30 days at -60 °C. The assay was successfully applied to both oral (40 mg kg(-1)) and intravenous (10 mg kg(-1)) pharmacokinetic studies in male Sprague-Dawley rats. The oral bioavailability of S007-1261 was found to be 33.61%.