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Rajamannar Thennati,1 Sanjay Kumar Singh,1 Nitin Nage,1 Yena Patel,1 Sandip Kumar Bose,1 Vinod Burade,2 Ranjit Sudhakar Ranbhor1 1Sun Pharmaceutical Industries Limited, 2Sun Pharmaceutical Advanced Research Center, Vadodara, Gujarat, India Introduction: Regulatory agencies recommend a stepwise approach for demonstrating biosimilarity between a proposed biosimilar and reference biological product emphasizing for functional and structural characterization to trace if there is any difference which may impact safety and efficacy. We studied the comparative structural and biological attributes of recombinant human chorionic gonadotropin (rhCG), SB005, with reference product, Ovidrel® and Ovitrelle®. Recombiant hCG was approved in 2000 by the US Food and Drug Administration for the induction of final follicular maturation, early luteinization in infertile women as part of assisted reproductive technology program. It is also indicated for the induction of ovulation and pregnancy in ovulatory infertile patients whose cause of infertility is not due to ovarian failure. Materials and methods: Primary structure was studied by intact mass analysis, peptide fingerprinting, peptide mass fingerprinting and sequence coverage analysis. Higher order structure was studied by circular dichroism, ultraviolet-visible spectroscopy, fluorescence spectroscopy, and disulfide bridge analysis. Different isoforms of reference product and SB005 were identified using capillary isoelectric focusing and capillary zone electrophoresis. Glycosylation was studied by N-glycan mapping using LC-ESI-MS, point of glycosylation, released glycan analysis using ultra performance liquid chromatography and sialic acid analysis. Product related impurities such as oligomer content analysis and oxidized impurities were studied using size exclusion chromatography and reverse phase high performance liquid chromatography, respectively. Biological activity in term of potency of reference product and SB005 was studied by in vivo analysis.Results and Conclusion: In this study we have compared analytical similarity of recombinant rhCG (SB005) produced at Sun Pharmaceuticals with the reference product with respect to its primary, higher order structure, isoforms, charge variants, glycosylation, sialyation pattern, pharmacodynamic and in vivo efficacy. Our studies show that the in house produced rhCG has a high degree of structural and functional similarity with the reference product available in the market. Keywords: human chorionic gonadotropin, rhCG, biosimilarity, characterization, comparability, Ovidrel®, Ovitrelle®

Cognitive deficits occur in up to 30% of patients with early Parkinson's disease, some of which are thought to result from dysfunction within the fronto-striatal dopaminergic network. Recently, it has been shown that a common functional polymorphism (Val(158)Met) in the catechol-O-methyltransferase (COMT) gene is associated with changes in executive performance in tasks that have a fronto-striatal basis. This is thought to relate to changes in cortical dopamine levels as catechol-O-methyltransferase is the main mode of inactivation for dopamine in frontal areas. However to date, no study has investigated dopamine turnover as a function of this genetic polymorphism in Parkinson's disease. We, therefore, set out to investigate in vivo changes in presynaptic dopamine storage in patients with idiopathic Parkinson's disease as a function of the catechol-O-methyltransferase Val(158)Met polymorphism using (18)F-DOPA positron emission tomography. Twenty patients with Parkinson's disease (10 homozygous for Val/Val and 10 for Met/Met catechol-O-methyltransferase polymorphisms) underwent (18)F-DOPA positron emission tomography using a prolonged imaging protocol. The first dynamic scan was acquired from 0 to 90 min (early), and the second scan (late) from 150 to 210 min post-intravenous radioligand administration. Patients were matched for age, sex, verbal IQ, disease duration and severity of motor features. (18)F-DOPA influx constants (Ki) were calculated and compared for frontal and striatal regions. Late scan mean frontal and striatal Ki values were significantly reduced in both Parkinson's disease groups relative to early scan Ki values. Met/Met patients had significantly higher late scan Ki values compared with their Val/Val counterparts in anterior cingulate, superior frontal and mid-frontal regions but early frontal Ki values were not different between the two groups. As late Ki values reflect rates of dopamine metabolism to 3,4-dihydroxyphenylacetic acid and homovanillic acid, our results indicate that Met homozygotes have higher presynaptic dopamine levels in frontal regions than Val homozygotes, which may help to explain how this genotypic variation may influence the fronto-striatal cognitive deficits of Parkinson's disease. [ABSTRACT FROM AUTHOR]

Objective: While there is robust evidence of elevated dopamine synthesis capacity once a psychotic disorder has developed, little is known about whether it is altered prior to the first episode of frank illness. The authors addressed this issue by measuring dopamine synthesis capacity in individuals at ultra-high risk of psychosis and then following them to determine their clinical outcome.Method: This prospective study included 30 patients who met standard criteria for being at ultra-high risk of psychosis and 29 healthy volunteers. Participants were scanned using [(18)F]6-fluoro-L-dopa positron emission tomography. The ultra-high-risk patients were scanned at presentation and followed up for at least 3 years to determine their clinical outcome. Six patients had comorbid schizotypal personality disorder and were excluded from the analysis (data are provided for comparison). Of the remaining patients, nine developed a psychotic disorder (psychotic transition group) and 15 did not (nontransition group).Results: There was a significant effect of group on striatal dopamine synthesis capacity. The psychotic transition group had greater dopamine synthesis capacity in the striatum (effect size=1.18) and its associative subdivision (effect size=1.24) than did the healthy comparison subjects and showed a positive correlation between dopamine synthesis capacity and symptom severity. Dopamine synthesis capacity was also significantly greater in the psychotic transition group than in the nontransition group.Conclusions: These findings provide evidence that the onset of frank psychosis is preceded by presynaptic dopaminergic dysfunction. Further research is needed to determine the specificity of elevated dopamine synthesis capacity to particular psychotic disorders. [ABSTRACT FROM AUTHOR]

Levodopa-induced dyskinesias are a common complication of long-term therapy in Parkinson's disease. Although both pre- and post-synaptic mechanisms seem to be implicated in their development, the precise physiopathology of these disabling involuntary movements remains to be fully elucidated. Abnormalities in glutamate transmission (over expression and phosphorylation of N-methyl-D-aspartate receptors) have been associated with the development of levodopa-induced dyskinesias in animal models of Parkinsonism. The role of glutamate function in dyskinetic patients with Parkinson's disease, however, is unclear. We used (11)C-CNS 5161 [N-methyl-3(thyomethylphenyl)cyanamide] positron emission tomography, a marker of activated N-methyl-D-aspartate receptor ion channels, to compare in vivo glutamate function in parkinsonian patients with and without levodopa-induced dyskinesias. Each patient was assessed with positron emission tomography twice, after taking and withdrawal from levodopa. Striatal and cortical tracer uptake was calculated using a region of interest approach. In the 'OFF' state withdrawn from levodopa, dyskinetic and non-dyskinetic patients had similar levels of tracer uptake in basal ganglia and motor cortex. However, when positron emission tomography was performed in the 'ON' condition, dyskinetic patients had higher (11)C-CNS 5161 uptake in caudate, putamen and precentral gyrus compared to the patients without dyskinesias, suggesting that dyskinetic patients may have abnormal glutamatergic transmission in motor areas following levodopa administration. These findings are consistent with the results of animal model studies indicating that increased glutamatergic activity is implicated in the development and maintenance of levodopa-induced dyskinesias. They support the hypothesis that blockade of glutamate transmission may have a place in the management of disabling dyskinesias in Parkinson's disease. [ABSTRACT FROM AUTHOR]

Disabling fatigue is a symptom in a number of neurological diseases, including multiple sclerosis, stroke and Parkinson's disease. We used ¹⁸F-dopa and ¹¹C-DASB [N,N-dimethyl-2-(2-amino-4-cyanophenylthio) benzylamine] positron emission tomography, markers of dopamine storage capacity and serotonin transporter availability, to investigate whether fatigue in Parkinson's disease is associated with dopaminergic and serotonergic dysfunction in basal ganglia and limbic circuits. Ten patients with Parkinson's disease and fatigue and 10 patients without fatigue had a ¹⁸F-dopa scan. Seven patients with and eight patients without fatigue also had a ¹¹C-DASB scan. The two groups were matched for age, disease duration and severity and daily intake of levodopa equivalent units. None had a history of depression or sleep disturbance. Using a region of interest analytical approach, we found that patients with fatigue had significantly lower serotonin transporter binding than patients without fatigue in the caudate, putamen, ventral striatum and thalamus. Striatal ¹⁸F-dopa uptake was similar in the fatigued and non-fatigued groups. Voxel-based analysis localized further relative serotonin transporter binding reductions in the cingulate and amygdala of the fatigue group, and ¹⁸F-dopa uptake reductions in the caudate and insula. We conclude that fatigue in Parkinson's disease is associated with reduced serotonergic function in the basal ganglia and limbic structures. Insular dopaminergic dysfunction could also play a role. These findings imply that strategies to increase brain level of serotonin would be a rational approach for relieving fatigue symptoms in Parkinson's disease and may also be relevant to alleviating fatigue in other clinical conditions. [ABSTRACT FROM AUTHOR]

The corpus callosum (CC), the largest commissure of the brain, connects the two cerebral hemispheres and lies at the bottom of the longitudinal fissure. The antero-posterior diameter of the CC was larger in males than in females, but this difference was not significant. Again, the length of CC increased with age and there was also a positive significant correlation between the antero-posterior diameters of the CC with the antero-posterior diameter of the brain. This cross sectional descriptive study was performed into four categories: Group A (20-29 years), Group B (30-39 years), Group C (40-49 years) and Group D (50 years and above). The specimens were collected from morgue in the department of Forensic Medicine, Mymensingh Medical College, Bangladesh by purposive sampling technique Octy 2016 to Octy 2017. The antero-posterior diameter of CC was measured by using thread. The mean maximum antero-posterior diameter of corpus callosum was 8.25 cm in group D and minimum was 7.92 cm in Group A. When the diameter was compared between sexes in different age groups, it was significant in Group D and moderately significant in Group C. There was a positive correlation between antero-posterior diameter of corpus callosum and age of individual and it was statistically not significant. For statistical analysis, differences between age and sex groups were analyzed by using students unpaired 't' test. The present study will help to increase the information pool on the antero-posterior diameter of CC of Bangladeshi people and thus will minimize the dependency on foreign standards and also have diagnostic importance for the neurosurgeons and radiologists for clinical investigation and surgery.

The vermiform appendix is a tubular, blind-ended secondary lymphoid organ located near the caecum, often referred to as the "tonsil of the abdomen" due to the abundance of lymphoid follicles in its histology. The presence of germinal centers, which are indicators of lymphatic tissue response to antigens and subsequent antibody production, helps assess the immune status of individuals. By counting these germinal centers, researchers can evaluate the immune status of the Bangladeshi population across different age and sex groups. This study was conducted at Mymensingh Medical College, approximately 120 km north of Dhaka, the capital of Bangladesh. Samples were randomly selected from the local population between 2016 and 2017, including 40 vermiform appendices from various age groups: Group A (up to 20 years), Group B (21-40 years), Group C (41-60 years) and Group D (over 60 years). After obtaining ethical approval, the germinal centers, identified by their lighter staining in the center of lymphoid follicles, were counted under a microscope (X4 objective, X10 eyepiece). The average number of germinal centers per age group was then calculated. The study found that the mean±SD number of germinal centers was 3.20±1.66, 2.40±0.66, 1.50±1.11 and 0.30±0.45 across the advancing age groups. The mean differences of number of germinal center between A&B, B&C were statistically non significant at p= or >0.05 level, difference between group C&D, A&C was statistically significant at p<0.05 level and differences between group B&D, A&D were statistically highly significant at p<0.001 level. Mean±SD number of germinal center of vermiform appendix in male was higher (3.60±1.02, 2.42±0.49, 1.50±1.26 and 0.33±0.47 in Group A, B, C and D respectively) than in female (2.80±1.17, 2.33±0.94, 1.30±0.87 and 0.25±0.43 in Group A, B, C and D respectively) but mean difference between sexes in the different groups was statistically non significant at p=or >0.05 level. Overall, the study observed a gradual decline in the number of germinal centers with increasing age.

Monogenic blood diseases are among the most common genetic disorders worldwide. These diseases result in significant pediatric and adult morbidity, and some can result in death prior to birth. Novel ex vivo hematopoietic stem cell (HSC) gene editing therapies hold tremendous promise to alter the therapeutic landscape but are not without potential limitations. In vivo gene editing therapies offer a potentially safer and more accessible treatment for these diseases but are hindered by a lack of delivery vectors targeting HSCs, which reside in the difficult-to-access bone marrow niche. Here, we propose that this biological barrier can be overcome by taking advantage of HSC residence in the easily accessible liver during fetal development. To facilitate the delivery of gene editing cargo to fetal HSCs, we developed an ionizable lipid nanoparticle (LNP) platform targeting the CD45 receptor on the surface of HSCs. After validating that targeted LNPs improved messenger ribonucleic acid (mRNA) delivery to hematopoietic lineage cells via a CD45-specific mechanism in vitro, we demonstrated that this platform mediated safe, potent, and long-term gene modulation of HSCs in vivo in multiple mouse models. We further optimized this LNP platform in vitro to encapsulate and deliver CRISPR-based nucleic acid cargos. Finally, we showed that optimized and targeted LNPs enhanced gene editing at a proof-of-concept locus in fetal HSCs after a single in utero intravenous injection. By targeting HSCs in vivo during fetal development, our Systematically optimized Targeted Editing Machinery (STEM) LNPs may provide a translatable strategy to treat monogenic blood diseases before birth., Competing Interests: Competing interests statement:R.P., M.J.M., and W.H.P. are inventors on a U.S. Provisional Patent Application (No. 63/623,674) related to the technology described in the manuscript.

The structure-property relationship considering isomerism-tuned photoluminescence and efficient catalytic activity of silver nanoclusters (NCs) is exclusive. Asymmetrical dithiophosphonate NH 4 [S 2 P(OR)( p -C 6 H 4 OCH 3 )] ligated first atomically precise silver NCs [Ag 21 {S 2 P(OR)( p -C 6 H 4 OCH 3 )} 12 ]PF 6 {where, R = n Pr ( 1 ), Et ( 2 )} were established by single-crystal X-ray diffraction and characterized by electrospray ionization mass spectrometry, NMR ( 31 P, 1 H, 2 H), X-ray photoelectron spectroscopy, UV-visible, energy-dispersive X-ray spectroscopy, Fourier transforms infrared, thermogravimetric analysis, etc. NCs 1 and 2 consist of eight silver atoms in a cubic framework and enclose an Ag@Ag 12 -centered icosahedron to constitute an Ag 21 core of T h symmetry, which is concentrically inscribed within the S 24 snub-cube, P 12 cuboctahedron, and the O 12 truncated tetrahedron formed by 12 dithiophosphonate ligands. These NCs facilitate to be an eight-electron superatom (1S 2 1P 6 ), in which eight capping Ag atoms exhibit structural isomerism with documented isoelectronic [Ag 21 {S 2 P(O i Pr) 2 } 12 ]PF 6, 3 . In contrast to 3 , the stapling of dithiophosphonates in 1 and 2 triggered bluish emission within the 400 to 500 nm region at room temperature. The density functional theory study rationalized isomerization and optical properties of 1 , 2 , and 3 . Both ( 1 , and 2 ) clusters catalyzed a decarboxylative acylarylation reaction for rapid oxindole synthesis in 99% yield under ambient conditions and proposed a multistep reaction pathway. Ultimately, this study links nanostructures to their physical and catalytic properties.

Parieto-occipital sulcus is one of the major sulcus of the cerebral hemisphere which separates the occipital lobe from the parietal lobe. Morphology of this sulcus varies with age, sex, manual skill, handedness and in many diseases. For various clinical investigations and surgery, detailed morphological knowledge of this sulcus is very much essential for the surgeons and radiologists. This study is carried out to establish a normal standard in length of the parieto-occipital sulcus in different age and sex groups of Bangladeshi people. A cross-sectional, descriptive type of study was conducted in the department of Anatomy, Mymensingh Medical College, Bangladesh from July 2016 to July 2017. About 60 specimens were collected from medico-legal cases and divided into four age groups including, Group A (20-29 years), Group B (30-39 years), Group C (40-49 years) and Group D (50 years and above). The mean length of parieto-occipital sulcus was 3.92±0.559cm to 3.29±0.434 cm in male and 3.81±0.715cm to 3.03±0.551cm in female. The difference in mean length of the parieto-occipital sulcus for both left and right hemisphere between male and female was statistically non-significant in all age groups. For statistical analysis, differences between age and sex groups were analyzed by using students unpaired 't' test. In this study, the length of the parieto-occipital sulcus showed gradual decreasing values with advancing age.

We report a recyclable and efficient catalyst system based on a nickel-benzene tricarboxylic acid metal-organic framework (Ni-BTC MOF) for the borylation of aryl halides, including aryl chlorides, with bis (pinacolato)diboron, affording aryl boronate esters in high yields (up to >99% yield) with high selectivity. This protocol demonstrates broad functional group tolerance. Catalyst can be recyclable up to four times, and gram-scale reactions further highlights the usefulness of this method. In situ EPR experiments confirmed the formation of catalytically active Ni(I) species.

This cross-sectional descriptive purposive study was conducted among 150 (70 right and 80 left) fully ossified dry human scapulae of Bangladeshi people from January 2019 to December 2019 in the Department of Anatomy, Mymensingh Medical College, Mymensingh. Shape of the glenoid cavity was observed as pear, oval or inverted comma shape. Morphometric parameters such as length and breadth of glenoid cavity were measured by digital Vernier slide calipers. In this study, 19.13% cases were found inverted comma shaped, 35.65% cases were oval and 45.22% cases were pear shaped. The mean±SD length of glenoid cavity was 37.5±3.61 mm and 36.19±3.68 mm on right and left sided scapulae respectively and mean±SD breadth was 23.6±2.73 mm on right and 23.42±2.75 mm on left side respectively. Mean±SD glenoid cavity index was 62.89±4.39 on right and 64.61±4.74 on left sided scapulae. Morphometric analysis of glenoid fossa of scapula might help clinicians in shoulder and its associated diseases.

Plant-microbe associations define a key interaction and have significant ecological and biotechnological perspectives. In recent times, plant-associated microbes from extreme environments have been extensively explored for their multifaceted benefits to plants and the environment, thereby gaining momentum in global research. Plant-associated extremophiles highlight ubiquitous occurrences, inhabiting extreme habitats and exhibiting enormous diversity. The remarkable capacity of extremophiles to exist in extreme environmental conditions is attributed to the evolution of adaptive mechanisms in these microbes at genetic and physiological levels. In addition, the plant-associated extremophiles have a major impact in promoting plant growth and development and conferring stress tolerance to the host plant, thereby contributing immensely to plant adaptation and survival in extreme conditions. Considering the major impact of plant-associated extremophiles from a socio-economic perspective, the article discusses their significance in emerging biotechnologies with a key focus on their ecological role and dynamic interaction with plants. Through this article, the authors aim to discuss and understand the favorable impact and dynamics of plant-associated extremophiles and their biotechnological utilities.

Femoral morphometric variation is a dynamic system for different region, which is influenced by geographical, physiological and environmental factors, due to the adaptation, functional and remodeling responses of bones. This descriptive cross-sectional study was conducted on 150 (64 right and 86 left) fully ossified dry human femur of Bangladeshi people to find out the variation of mid shaft antero-posterior and transverse diameter of femur. Sample was collected in the Department of Anatomy, Mymensingh Medical College (MMC), Bangladesh from January 2019 to December 2019. All samples were assessed to eliminate fractured, pathologically damaged and remodeled bones. The diameters were measured with the help of digital Vernier slide calipers. The mean±SD mid shaft antero-posterior diameter of right and left femur were 25.03±2.86 mm and 25.54±2.65mm respectively. The mean±SD transverse diameter of right and left femur was 24.24±2.43mm and 24.54±2.38mm respectively. The knowledge of variations in the parameters of dry femora will help the orthopedicians for the treatment and management of femoral shaft fracture. These data also provide information about mid shaft diameter of femur of Bangladeshi people and to compare these data to those from various other races. Thus it could contribute for the design of well-fitting prosthesis which suits the Bangladeshi population. This value may be considered while making a best-fit femoral prosthesis.

This cross-sectional descriptive purposive study was done on 150 (70 right and 80 left) fully ossified dry human scapulae of Bangladeshi people to find out the variation in length of acromiocoracoid and acromioglenoid distance. Sample collection was carried out in the Department of Anatomy, Mymensingh Medical College, Bangladesh from January to December 2019. Any kind of damaged or broken scapulae were excluded to maintain standard measurement. Length of these distances was measured with the help of digital Vernier slide calipers. The mean±SD acromiocoracoid distance were 35.8±4.64 mm and 36.32±5.55 mm on right and left sided scapulae respectively and the mean±SD acromioglenoid distance were 27.69±3.43 mm on right sided scapulae and 28.18±3.26 mm on left sided scapulae. These data are important to compare Bangladeshi scapulae to those from various other races that could contribute to demographic studies of shoulder disease probability and management in Bangladeshi population.

A recyclable protocol using a CeO 2 -nanorod catalyst for borylation of alkyl halides with B 2 pin 2 (pin = OCMe 2 CMe 2 O) is reported. A wide range of synthetically useful alkyl boronate esters are readily obtained from primary and secondary alkyl electrophiles, including unactivated alkyl chlorides, demonstrating broad utility and functional group tolerance. Preliminary investigation revealed an involvement of in situ formed catalytically active boryl species. The catalyst can be reused for up to six runs without appreciable loss in activity. In addition, we have demonstrated the use of this recyclable catalyst for the borylation of aryl halides with B 2 pin 2 , providing valuable aryl boronate esters under neat conditions.

Introduction: Fetuses with large lung lesions including congenital cystic adenomatoid malformations (CCAMs) are at risk for cardiopulmonary compromise. Prenatal maternal betamethasone and cyst drainage for micro- and macrocystic lesions respectively have improved outcomes yet some lesions remain large and require resection before birth (open fetal surgery, OFS), at delivery via an Ex Utero Intrapartum Treatment (EXIT), or immediately post cesarean section (section-to-resection, STR). We sought to compare prenatal characteristics and outcomes in fetuses undergoing OFS, EXIT, or STR to inform decision-making and prenatal counseling., Methods: A single institution retrospective review was conducted evaluating patients undergoing OFS, EXIT, or STR for prenatally diagnosed lung lesions from 2000 to 2021. Specimens were reviewed by an anatomic pathologist. Lesions were divided into "CCAMs" (the largest pathology group) and "all lung lesions" since pathologic diagnosis is not possible during prenatal evaluation when care decisions are made. Prenatal variables included initial, greatest, and final CCAM volume-ratio (CVR), betamethasone use/frequency, cyst drainage, and the presence of hydrops. Outcomes included survival, ECMO utilization, NICU length of stay (LOS), postnatal nitric oxide use, and ventilator days., Results: Sixty-nine percent (59 of 85 patients) of lung lesions undergoing resection were CCAMs. Among patients with pathologic diagnosis of CCAM, the initial, largest, and final CVRs were greatest in OFS followed by EXIT and STR patients. Similarly, the incidence of hydrops was significantly greater and the rate of hydrops resolution was lower in the OFS group. Although the rate of cyst drainage did not differ between groups, maternal betamethasone use varied significantly (OFS 60.0%, EXIT 100.0%, STR 74.3%; p = 0.0378). Notably, all OFS took place prior to 2014. There was no difference in survival, ventilator days, nitric oxide, NICU LOS, or ECMO between groups. In multiple variable logistic modeling, determinants of survival to NICU discharge among patients undergoing resection with a pathologic diagnosis of CCAM included initial CVR <3.5 and need for <3 maternal betamethasone doses., Conclusion: For CCAMs that remain large despite maternal betamethasone or cyst drainage, surgical resection via OFS, EXIT, or STR are viable options with favorable and comparable survival between groups. In the modern era there has been a shift from OFS and EXIT procedures to STR for fetuses with persistently large lung lesions. This shift has been fueled by the increased use of maternal betamethasone and introduction of a Special Delivery Unit during the study period and the appreciation of similar fetal and neonatal outcomes for STR vs. EXIT and OFS with reduced maternal morbidity associated with a STR. Accordingly, efforts to optimize multidisciplinary perinatal care for fetuses with large lung lesions are important to inform patient selection criteria and promote STR as the preferred surgical approach in the modern era., Level of Evidence: Level IV., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Treatment of vitiligo is still a challenge in dermatology. Literature is sparse on the definitive clinical role of basic fibroblast growth factor (bFGF) in vitiligo patients., Aims: We decided to generate a consensus in an attempt to answer some critical questions related to the management of vitiligo and the role of bFGF., Materials and Methods: A Delphi method among 21 experts across India was conducted. A consensus (agreement was 75% or greater) was taken on 27 statements on the prevalence, epidemiology, and treatment of vitiligo and the role of bFGF in the management of vitiligo. The consensus process was completed after two rounds., Results: Topical corticosteroid therapy is the first-line therapy for vitiligo; however, its adverse effects are widely known, especially in sensitive areas. Topical calcineurin inhibitors are preferred in stable vitiligo of the face, neck, genitals, or intertriginous regions as an alternative to topical corticosteroids. Topical bFGF is a relatively newer therapy with a promising role in stable vitiligo. bFGF is safe and effective in inducing repigmentation of vitiligo lesions. Combination therapy of bFGF with other topical therapies, phototherapy, and surgical procedures can be beneficial in patients of vitiligo., Conclusion: This consensus would complement the currently available literature on bFGF and help the practitioner to recognize the unmet need in the treatment of vitiligo., Competing Interests: There are no conflicts of interest., (Copyright: © 2023 Indian Journal of Dermatology.)

Delivery of mRNA-based therapeutics to the perinatal brain holds great potential in treating congenital brain diseases. However, nonviral delivery platforms that facilitate nucleic acid delivery in this environment have yet to be rigorously studied. Here, we screen a diverse library of ionizable lipid nanoparticles (LNPs) via intracerebroventricular (ICV) injection in both fetal and neonatal mice and identify an LNP formulation with greater functional mRNA delivery in the perinatal brain than an FDA-approved industry standard LNP. Following in vitro optimization of the top-performing LNP (C3 LNP) for codelivery of an adenine base editing platform, we improve the biochemical phenotype of a lysosomal storage disease in the neonatal mouse brain, exhibit proof-of-principle mRNA brain transfection in vivo in a fetal nonhuman primate model, and demonstrate the translational potential of C3 LNPs ex vivo in human patient-derived brain tissues. These LNPs may provide a clinically translatable platform for in utero and postnatal mRNA therapies including gene editing in the brain.

Context The cerebellum is a part of the hindbrain and consists of cortical gray matter (GM) at the surface and a medullary core of white matter (WM). The GM contains a cell body of neurons that helps process and transmit any command type through nerve fibers found in the WM. The main functions of GM in the central nervous system empower persons to control motor activity, recollection, and passion. So, this research aims to assess the thickness of GM at the summit and bottom of folia by histologically studying the cerebellum cortex. Methods The collection of data was a descriptive type of cross-sectional study. The method was the purposive type. This study was conducted from August 2016 to March 2017, and the research was carried out at Mymensingh Medical College's Department of Anatomy, Bangladesh. Specimens containing cerebellum were preserved from Bangladeshi cadavers according to sexes and ages ranging in years. We chose fresh specimens from people who died within the last 12 hours and preserved them in 10% formol saline. The size of the tissue that was collected for the histological study was not more than 2 cm 2 and not more than 4-5 mm thick. Then the tissue was placed in 10% formol saline. This fluid was used for quick fixation and partial dehydration of the tissue. After dehydration, each tissue segment is processed for infiltration and embedding separately. Every section was stained with hematoxylin and eosin stain (H&E) before being coated with dibutyl phthalate polystyrene xylene (DPX) coverslips on slides. Result The mean (±SD) thickness of GM at the summit of folium was 886.2±29.7µm in Group A, 925.2±25.9µm in Group B, 912.7±22.3µm in Group C, and 839.9±40.7µm in Group D. Mean (±SD) GM thickness at the bottom of the fissure was 395.6±12.2 µm, 403.9±26.0µm, 380.4±23.4 µm, and 375.8±28.8 µm in Groups A, B, C, and D respectively. Conclusion The thickness of the cortex is an essential factor in the normal development process, and it was similar in the current study. Normal aging, Alzheimer's disease, and other dementias cause reduced GM which makes the cortical sheet thin. Huntington's disease, corticobasal degeneration, amyotrophic lateral sclerosis, and schizophrenia are all examples of neurological disorders. Cortical thinning is typically locally localized, and the progression of atrophy can thus disclose much about a disease's history and causal variables. The present study correspondingly found that GM was reduced after the age of 50 years onward. Furthermore, longitudinal investigations of cortical atrophy have the potential to be extremely useful in measuring the efficacy of a wide range of treatments., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Nitu et al.)

An efficient anti -Markovnikov selective transition metal- and solvent-free Lewis base-mediated protoboration of aromatic and aliphatic alkenes with bis(pinacolato)diboron (B 2 pin 2 ) as the boron reagent is reported. This protocol is practical and demonstrates broad substrate scope and good functional-group tolerance on alkenes to give synthetically useful alkyl boronate esters in excellent yields under mild reaction conditions. The gram-scale reaction further highlighted the usefulness of this method.

Since the early 1980's, with the clinical advent of in vitro fertilization resulting in so-called "test tube babies," a wide array of ethical considerations and concerns regarding artificial womb technology (AWT) have been described. Recent breakthroughs in the development of extracorporeal neonatal life support by means of AWT have reinitiated ethical interest about this topic with a sense of urgency. Most of the recent ethical literature on the topic, however, pertains not to the more imminent scenario of a physiologically improved method of neonatal care through AWT, but instead to the remote scenario of "complete ectogenesis" that imagines human gestation occurring entirely outside of the womb. This scoping review of the ethical literature on AWT spans from more abstract concerns about complete ectogenesis to more immediate concerns about the soon-to-be-expected clinical life support of what we term the fetal neonate or fetonate. Within an organizing framework of different stages of human gestational development, from conception to the viable premature infant, we discuss both already identified and newly emerging ethical considerations and concerns regarding AWT and the care of the fetonate.

The preparation of high-nuclearity silver nanoclusters in quantitative yield remains exclusive and their potential applications in the catalysis of organic reactions are still undeveloped. Here, we have synthesized a quantum dot (QD)-based catalyst, [Ag 62 S 13 (SBu t ) 32 ](PF 6 ) 4 (denoted as Ag 62 S 12 -S) in excellent yield that enables the direct synthesis of pharmaceutically precious 3,4-dihydroquinolinone in 92% via a decarboxylative radical cascade reaction of cinnamamide with α-oxocarboxylic acid under mild reaction conditions. In comparison, a superatom [Ag 62 S 12 (SBu t ) 32 ](PF 6 ) 2 (denoted as Ag 62 S 12 ) with identical surface anatomy and size, but without a central S 2- atom in the core, gives an improved yield (95%) in a short time and exhibits higher reactivity. Multiple characterization techniques (single-crystal X-ray diffraction, nuclear magnetic resonance ( 1 H and 31 P), electrospray ionization mass spectrometry, energy dispersive X-ray spectroscopy, Brunauer-Emmett-Teller (BET), Fourier-transform infrared spectroscopy, X-ray photoelectron spectroscopy, and thermogravimetric analysis) confirm the formation of Ag 62 S 12 -S. The BET results expose the total active surface area in supporting a single e - transfer reaction mechanism. Density functional theory reveals that leaving the central S atom of Ag 62 S 12 -S leads to higher charge transfer from Ag 62 S 12 to the reactant, accelerates the decarboxylation process, and correlates the catalytic properties with the structure of the nanocatalyst.

Purpose of Review: The development of modern gene editing tools alongside promising innovations in gene sequencing and prenatal diagnostics as well as a shifting regulatory climate around targeted therapeutics offer an opportunity to address monogenic diseases prior to the onset of pathology. In this review, we seek to highlight recent progress in preclinical studies evaluating the potential in-utero gene editing as a treatment for monogenic diseases that cause morbidity or mortality before or shortly after birth., Recent Findings: There has been significant recent progress in clinical trials for postnatal gene editing. Corresponding advances have been made with respect to in-utero cell and enzyme replacement therapies. These precedents establish the foundation for 'one-shot' treatments by way in-utero gene editing. Compelling preclinical data in liver, pulmonary and multisystemic diseases demonstrate the potential benefits of in-utero editing approaches., Summary: Recent proof-of-concept studies have demonstrated the safety and feasibility of in-utero gene editing across multiple organ systems and in numerous diseases. Clinical translation will require continued evolution of vectors and editing approaches to maximize efficiency and minimize unwanted treatment effects., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

In utero hematopoietic cell transplantation (IUHCT) is an experimental treatment for congenital hemoglobinopathies, including Sickle cell disease and thalassemias. One of the principal advantages of IUHCT is the predisposition of the developing fetus toward immunologic tolerance. This allows for engraftment across immune barriers without immunosuppression and, potentially, decreased susceptibility to graft-versus-host disease (GVHD). We demonstrate fetal resistance to GVHD following T cell-replete allogeneic hematopoietic cell transplantation compared with the neonate. We show that this resistance is associated with elevated fetal serum interleukin-10 conducive to the induction of regulatory T cells (Tregs). Finally, we demonstrate that the adoptive transfer of Tregs from IUHCT recipients to neonates uniformly prevents GVHD, recapitulating the predisposition to tolerance observed after fetal allotransplantation. These findings demonstrate fetal resistance to GVHD following hematopoietic cell transplantation and elucidate Tregs as important contributors., Competing Interests: Conflict of Interest The authors have declared that no conflict of interest exists., (Copyright © 2022 ISEH -- Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.)

Background: Enteral nutrition is a critical intervention that supports the growth of children with pulmonary hypoplasia (PH). We explored the experiences of caregivers and providers caring for children with PH to better understand gaps in knowledge transfer and identify barriers and facilitators to caregiving to inform interventions that may improve support., Methods: This qualitative study included 10 interviews with caregivers and 10 clinical team members at a single integrated care program for children with PH. An inductive and iterative coding strategy was employed to produce a codebook. After cluster analysis, themes were generated to capture participant sentiments., Results: Themes were defined along a care continuum (1) initiation, (2) adaptation, and (3) maintenance that represented distinct phases of adjustment to enteral nutrition support (1) in the perinatal period and initial neonatal intensive care unit (NICU) admission, (2) from discharge planning through the family's first days at home and establishment of a stable feeding regime, and (3) through long-term follow-up and weaning. Notable subthemes included uncertainty, partnerships in training, and obstacles to adaptation., Conclusions: Among children with PH, the caregiver-provider relationship during the perinatal and NICU course is critical to promoting caregiver adaptation to the needs of the child. Ongoing considerations to support resource alignment and transition to a stable feeding regimen may facilitate caregiver adjustment to a "new normal," culminating in successful growth and/or weaning. These findings will inform interventions focused on training curricula, discharge planning, and the provision of follow-up in the context of an integrated care program for PH., (© 2022 American Society for Parenteral and Enteral Nutrition.)

Physical systems that exhibit brain-like behaviour are currently under intense investigation as platforms for neuromorphic computing. We show that discontinuous metal films, comprising irregular flat islands on a substrate and formed using simple evaporation processes, exhibit correlated avalanches of electrical signals that mimic those observed in the cortex. We further demonstrate that these signals meet established criteria for criticality. We perform a detailed experimental investigation of the atomic-scale switching processes that are responsible for these signals, and show that they mimic the integrate-and-fire mechanism of biological neurons. Using numerical simulations and a simple circuit model, we show that the characteristic features of the switching events are dependent on the network state and the local position of the switch within the complex network. We conclude that discontinuous films provide an interesting potential platform for brain-inspired computing.

Over the past decade, the reactivity of 2-phosphaethynolate (OCP - ), a heavier analogue of the cyanate anion, has been the subject of momentous interest in the field of modern organometallic chemistry. It is used as a precursor to novel phosphorus-containing heterocycles and as a ligand in decarbonylative processes, serving as a synthetic equivalent of a phosphinidene derivative. This perspective aims to describe advances in the reactivities of phosphaethynolate and arsaethynolate anions (OCE - ; E = P, As) with main-group element, transition metal, and f-block metal scaffolds. Further, the unique structures and bonding properties are discussed based on spectroscopic and theoretical studies.

Background: Previous studies have assessed the prevalence and nature of traumatic injuries due to legal intervention in adults. The purpose of this study is to characterize and understand legal intervention trauma in children., Methods: The National Trauma Data Bank (NTDB) was queried from 2007 to 2015. Patients (0-18 years old) who sustained injuries due to legal intervention were compared to those injured from other causes in the general NTDB population. Descriptive statistics were used to characterize the study population. Multivariate logistic regression models were utilized to predict firearm trauma and mortality., Results: 622 patients sustained injuries involving legal intervention. Compared to general NTDB pediatric population, those who sustained legal intervention injuries were more likely to be older (age 16.5 vs. 10.6, p < 0.01), male (91.96% vs. 34.95%, p < 0.01), test positive for illegal drugs (64.64% vs. 38.35%, p < 0.01) or alcohol (26.36% vs. 17.25%, p < 0.01), and be African-American (44.37% vs. 17.00%, p < 0.01), Latino (22.82% vs. 15.10%, p < 0.01), or Native American (0.96% vs.. 0.94%, p < 0.01). Logistic regression models identified an 11% increased odds (95% CI 1.02-1.21, p = 0.02) of death among African-Americans when compared to other racial groups receiving legal intervention trauma. African-American status was associated with a 12% increased odds (95% CI 1.02-1.22, p = 0.01) of firearm trauma when compared to other racial groups receiving legal intervention trauma., Conclusion: Legal intervention-related pediatric trauma disproportionately affects the African-American population. This is particularly pronounced in cases of firearm related injuries., Level of Evidence: III., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Congenital disorders resulting in pathological protein deficiencies are most often treated postnatally with protein or enzyme replacement therapies. However, treatment of these disorders in utero before irreversible disease onset could significantly minimize disease burden, morbidity, and mortality. One possible strategy for the prenatal treatment of congenital disorders is in utero delivery of messenger RNA (mRNA). mRNA is a nucleic acid therapeutic that has previously been investigated as a platform for protein replacement therapies and gene editing technologies. While viral vectors have been explored to induce intracellular expression of mRNA, they are limited in their clinical application due to risks associated with immunogenicity and genomic integration. As an alternative to viral vectors, safe and efficient in utero mRNA delivery can be achieved using ionizable lipid nanoparticles (LNPs). While LNPs have demonstrated potent in vivo mRNA delivery to the liver following intravenous administration, intra-amniotic delivery has the potential to deliver mRNA to cells and tissues beyond those in the liver, such as in the skin, lung, and digestive tract. However, LNP stability in fetal amniotic fluid and how this stability affects mRNA delivery has not been previously investigated. Here, we engineered a library of LNPs using orthogonal design of experiments (DOE) to evaluate how LNP structure affects their stability in amniotic fluid ex utero and whether a lead candidate identified from these stability measurements enables intra-amniotic mRNA delivery in utero. We used a combination of techniques including dynamic light scattering (DLS), transmission electron microscopy (TEM), and chromatography followed by protein content quantification to screen LNP stability in amniotic fluids. These results identified multiple lead LNP formulations that are highly stable in amniotic fluids ranging from small animals to humans, including mouse, sheep, pig, and human amniotic fluid samples. We then demonstrate that stable LNPs from the ex utero screen in mouse amniotic fluid enabled potent mRNA delivery in primary fetal lung fibroblasts and in utero following intra-amniotic injection in a murine model. This exploration of ex utero stability in amniotic fluids demonstrates a means by which to identify novel LNP formulations for prenatal treatment of congenital disorders via in utero mRNA delivery., (Copyright © 2021. Published by Elsevier B.V.)

Organoboron reagents represent a unique class of compounds because of their utility in modern synthetic organic chemistry, often affording unprecedented reactivity. The transformation of the carbon-boron bond into a carbon-X (X = C, N, and O) bond in a stereocontrolled fashion has become invaluable in medicinal chemistry, agrochemistry, and natural products chemistry as well as materials science. Over the past decade, first-row d-block transition metals have become increasingly widely used as catalysts for the formation of a carbon-boron bond, a transformation traditionally catalyzed by expensive precious metals. This recent focus on alternative transition metals has enabled growth in fundamental methods in organoboron chemistry. This review surveys the current state-of-the-art in the use of first-row d-block element-based catalysts for the formation of carbon-boron bonds.

There is currently a great deal of interest in the use of nanoscale devices to emulate the behaviors of neurons and synapses and to facilitate brain-inspired computation. Here, it is shown that percolating networks of nanoparticles exhibit stochastic spiking behavior that is strikingly similar to that observed in biological neurons. The spiking rate can be controlled by the input stimulus, similar to "rate coding" in biology, and the distributions of times between events are log-normal, providing insights into the atomic-scale spiking mechanism. The stochasticity of the spiking behavior is then used for true random number generation, and the high quality of the generated random bit-streams is demonstrated, opening up promising routes toward integration of neuromorphic computing with secure information processing.

In utero gene therapy has the potential to treat lethal and morbid perinatal diseases before birth. Small fetal size, a tolerogenic immune system, and dosing efficiency make the fetus a compelling patient. Numerous clinical, social, and institutional factors must be considered to achieve the promise of genetic treatment before birth., Competing Interests: Declaration of Interests The authors declare no conflicts of interest., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

In utero base editing has the potential to correct disease-causing mutations before the onset of pathology. Mucopolysaccharidosis type I (MPS-IH, Hurler syndrome) is a lysosomal storage disease (LSD) affecting multiple organs, often leading to early postnatal cardiopulmonary demise. We assessed in utero adeno-associated virus serotype 9 (AAV9) delivery of an adenine base editor (ABE) targeting the Idua G→A (W392X) mutation in the MPS-IH mouse, corresponding to the common IDUA G→A (W402X) mutation in MPS-IH patients. Here we show efficient long-term W392X correction in hepatocytes and cardiomyocytes and low-level editing in the brain. In utero editing was associated with improved survival and amelioration of metabolic, musculoskeletal, and cardiac disease. This proof-of-concept study demonstrates the possibility of efficiently performing therapeutic base editing in multiple organs before birth via a clinically relevant delivery mechanism, highlighting the potential of this approach for MPS-IH and other genetic diseases., (© 2021. The Author(s).)