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Using acoustic vortex tweezers (AVT) to spatially accumulate microbubbles (MBs) shows promise for enhancing drug delivery efficiency and reducing off-target effects. The strong echogenicity of accumulated MBs also improves diagnostics via conventional ultrasound (US) B-mode imaging. However, the annular high-pressure distribution of AVT inhibits MBs inflow at the inlet, reducing MBs collection. The spatial resolution of US B-mode imaging further limits theranostic applications of AVT-mediated MBs accumulation. To address these challenges, we integrated an AVT waveform with volumetric super-resolution imaging (VSRI) to monitor the dynamic growth of MBs cluster during accumulation. We used a 5-MHz 2D array transducer for VSRI, employing plane wave pulses interleaved with accumulating pulses to retain MBs at a flow rate of 0.023-0.047 mL/s in a 3-mm vessel phantom. An asymmetrical AVT waveform (AVT*) was produced by modulating the pressure at the MBs inlet compared to the outlet. The effectiveness was validated in rat cerebral vessels for real-time volumetric tracking of MBs clusters. Microscopy observations showed that AVT* could quickly gather flowing MBs into cluster without repelling them at a flow rate of 0.023 mL/s. Statistical results indicated that microscopic data correlated better with VSRI than with B-mode images, suggesting VSRI suffices to detect the dynamics of AVT*-actuated MBs accumulation in real-time. Additionally, VSRI detected a significant increase in MBs cluster size over time during AVT* in the superior sagittal sinus of the rat brain. These findings demonstrate that the proposed strategy can accumulate the flowing MBs at a desired location and simultaneously observe this phenomenon.

The nonlinear susceptibility in the terahertz region is expected to have a non-negligible imaginary part originating from the momentum-dependent scattering time of free carriers, but it has been scarcely reported. By utilizing an intense 4 THz beam from a terahertz free electron laser, we investigated the azimuth angle dependence of the third harmonic generation (THG) from semiconductors. The observed angular anisotropy of THG revealed the contribution of the imaginary part of the nonlinear susceptibility originating from the momentum-scattering time relation in addition to its real part originating from the band nonparabolicity. The results provide a deeper understanding of nonlinear optics in the terahertz region.

Study Design: Retrospective, Multicenter., Objective: Determine if posterior column osteotomies (PCO) at time of conversion from growth friendly instrumentation (GFI) to definitive fusion in early onset scoliosis (EOS) graduates impacts outcomes., Summary of Background Data: Increasing spinal rigidity following treatment of EOS with GFI can limit curve correction at time of conversion to definitive spinal fusion. PCO are often employed at the time of fusion to improve flexibility. This technique's efficacy has not been studied., Methods: EOS patients with GFI undergoing conversion to fusion were grouped by those that did or did not have PCO. Patients with inadequate radiographs, <2 years follow-up, or three-column osteotomies at time of fusion were excluded., Results: 832 patients met inclusion criteria. 175 (21%) patients had PCO. Age at index surgery was younger (6.6 vs. 7.4 y, P =0.0009) and the mean duration of GFI was greater (6.2 vs. 5.5 y, P =0.009) in the PCO group. Prior to fusion, curve magnitude was similar between the groups (PCO=61.9 degrees, no PCO=59.3 degrees, P=0.18). On average 4.4 osteotomies (range: 1 - 12) were performed for the PCO group and EBL (PCO=820 cc vs no PCO=752 cc, P<0.01) and surgical time (PCO=403 min vs no PCO=349 min, P<0.01) were greater. Postoperatively, mean curve correction (PCO=16.6, no PCO=14.4 degrees, P=0.18) was similar. Accounting for preoperative curve magnitude, there was a relationship between number of PCOs and curve correction (P=0.04). There was no relationship between degrees of correction per osteotomy and duration of GFI (P=0.12). Postoperative complications at 2 years were similar (PCO=25% vs no PCO=27%, P=0.63)., Conclusion: EOS graduates achieve minimal correction at time of conversion regardless of whether PCOs are performed. PCOs increase EBL and operative time but have a similar complication rate. More PCOs resulted in more correction, though less than that anticipated in a previously uninstrumented spine., Level of Evidence: III., Competing Interests: Although the authors have no disclosures related to the study, please find the Conflicts of Interests as follows: The authors report no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Standard surgical management for the terrible triad of the elbow (TTE) has been established since 2004, yet postoperative complications are common and consensus on optimal management is absent. Different surgical algorithms for treating TTE and their efficacy have been reported worldwide, yet evidence from Vietnam remains limited., Methods: Ten cases diagnosed with TTE admitted to the Hospital of Traumatology and Orthopedics, a tertiary orthopedic center in Ho Chi Minh City, were presented to demonstrate the effectiveness and rate of postoperative complications following our stepwise surgical procedures using the anconeus-triceps lateral flap approach. The intraoperative "drop sign", quantitative assessment of pain and level of upper arm disability (via VAS and QuickDASH score) was mentioned to assess the algorithm's benefit. All patients' information was retrieved from medical records from August 2022 to January 2024., Results: All 10 cases required repair of the lateral ligament complex and underwent surgery within 2 days of hospitalization. Immediate postoperative imaging revealed no drop sign, and none of the patients experienced elbow dislocation nor the need for repeated surgery, and a full range of elbow motion was demonstrated at 3-6 months follow-up., Conclusion: TTE is a challenging injury that almost always obligates surgical correction. The anconeus-triceps lateral flap approach, with its advantages of better visualization and preservation of certain essential stabilizing muscles of the elbow, was demonstrated to yield a high success rate and low postoperative complication rate., Competing Interests: The authors have no competing interests to disclose., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Study Design: Retrospective, Multicenter., Objective: Assess curve progression and occurrence of revision surgery following tether breakage after vertebral body tethering (VBT)., Summary of Background Data: Tether breakage after VBT is common with rates up to 50% reported. In these cases, it remains unknown whether the curve will progress or remain stable., Methods: Adolescent and juvenile idiopathic scoliosis patients in a multicenter registry with ≥2 year-follow-up after VBT were reviewed. Broken tethers were listed as postoperative complications and identified by increased screw divergence of >5° on serial radiographs. Revision procedures and curve magnitude at subsequent visits were recorded., Results: Of 186 patients who qualified for inclusion, 84 (45.2%) patients with tether breakage were identified with a mean age at VBT of 12.4±1.4 years and mean curve magnitude at index procedure of 51.8°±8.1°. Tether breakage occurred at a mean of 30.3±11.8 months and mean curve of 33.9°±13.2°. Twelve patients (12/84, 14.5%) underwent 13 revision procedures after VBT breakage, including 6 tether revisions and 7 conversions to fusion. All tether revisions occurred within 5 months of breakage identification. No patients with curves <35° after breakage underwent revision. Revision rate was greatest in skeletally immature (Risser 0-3) patients with curves ≥35° at time of breakage (Risser 0-3: 9/17, 53% vs. Risser 4-5: 3/23, 13%, P=0.01).Curves increased by 3.1° and 3.7° in the first and second year, respectively. By two years, 15/30 (50%) progressed >5° and 8/30 (26.7%) progressed greater than 10°. Overall, 66.7% (40/60) reached a curve magnitude >35° at their latest follow-up, and 14/60 (23.3%) reached a curve magnitude greater than 45°. Skeletal maturity did not affect curve progression after tether breakage (P>0.26), but time to rupture did (P=0.048)., Conclusion: While skeletal immaturity and curve magnitude were not independently associated with curve progression, skeletally immature patients with curves ≥35° at time of rupture are most likely to undergo additional surgery. Most patients can expect progression at least 5° in the first two years after tether breakage, though longer-term behavior remains unknown., Level of Evidence: III., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Leishmaniasis, an infectious disease caused by pathogenic Leishmania parasites, affects millions of people in developing countries, and its re-emergence in developed countries, particularly in Europe, poses a growing public health concern. The limitations of current treatments and the absence of effective vaccines necessitate the development of novel therapeutics. In this study, we focused on identifying small molecule inhibitors which prevents the interaction between peroxin 5 (PEX5) and peroxisomal targeting signal 1 (PTS1), pivotal for kinetoplastid parasite survival. The Leishmania donovani PEX5, containing a C-terminal tetratricopeptide repeat (TPR) domain, was expressed and purified, followed by the quantification of kinetic parameters of PEX5-PTS1 interactions. A fluorescence polarization-based high-throughput screening assay was developed and small molecules inhibiting the Ld PEX5-PTS1 interaction were discovered through the screening of a library of 51,406 compounds. Based on the confirmatory assay, nine compounds showed half maximal inhibitory concentration (IC 50 ) values ranging from 3.89 to 24.50 µM. In silico docking using a homology model of Ld PEX5 elucidated that the molecular interactions between Ld PEX5 and the inhibitors share amino acids critical for PTS1 binding. Notably, compound P20 showed potent activity against the growth of L. donovani promastigotes, L. major promastigotes, and Trypanosoma brucei blood stream form, with IC 50 values of 12.16, 19.21, and 3.06 μM, respectively. The findings underscore the potential of targeting Ld PEX5-PTS1 interactions with small molecule inhibitors as a promising strategy for the discovery of new anti-parasitic compounds.

Background: Intertrochanteric fractures are highly prevalent among the elderly population, with approximately 90% occurring in individuals aged over 65. These geriatric fractures are associated with elevated mortality rates and significant functional impairment. Common treatment modalities for unstable intertrochanteric fractures include proximal femoral nail antirotation (PFNA) and the InterTan nail (IT). PFNA and IT are frequently employed due to their lower failure rates and favorable biomechanical properties, resulting in positive clinical outcomes for the management of unstable intertrochanteric fractures. The unique design of the IT nail, featuring two cephalocervical screws within an integrated mechanism, permits linear intraoperative compression and rotational stability of the neck and head fragment. In this study, we assess the clinical outcomes of IT nail utilization in the treatment of intertrochanteric fractures at the Hospital for Traumatology and Orthopedics., Methods: This study comprises a retrospective analysis and case series report. Between February 2021 and August 2021, we retrospectively evaluated 35 patients who underwent treatment with the IT nail for unstable intertrochanteric fractures. Epidemiological data, operative duration, intraoperative blood loss, intraoperative blood transfusion requirements, length of hospital stay, bone healing rates, and IT nail-related complications were recorded., Results: The mean age of the patients was 70.97 ± 16.97 years, with a mean operative time of 60 minutes, mean intraoperative blood loss of 160.86 ± 72.8 ml, mean intraoperative blood transfusion volume of 203.43 ± 189.29 ml, and a mean hospital stay of 7 days. Bone healing was observed in 97.14% of cases., Conclusions: The treatment of unstable intertrochanteric fractures using the IT nail in elderly patients was successful. Our findings indicate favorable clinical outcomes in terms of surgical duration, intraoperative blood loss, hospitalization duration, and union rates for elderly patients. Further investigations are warranted to validate these early results.

Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) is the causative pathogen of coronavirus disease-19 (COVID-19). The COVID-19 pandemic has resulted in millions of deaths and widespread socio-economic damage worldwide. Therefore, numerous studies have been conducted to identify effective measures to control the spreading of the virus. Among various potential targets, the 3 chymotrypsin-like protease (3CLpro), also known as Mpro, stands out as the key protease of SARS-CoV-2, playing an essential role in virus replication and assembly, is the most prospective. In this study, we modified the commercial vector, pETM33-Nsp5-Mpro (plasmid # 156475, Addgene, USA), by inserting an autocleavage site (AVLQ) of 3CLpro and 6 × His-tag encoding sequences before and after the Nsp5-Mpro sequence, respectively. This modification enabled the expression of 3CLpro as an authentic N terminal protease (au3CLpro), which was purified to electrophoretic homogeneity by a single-step chromatography using two tandem Glutathione- and Ni-Sepharose columns. The enzyme au3CLpro demonstrated significantly higher activity (3169 RFU/min/μg protein) and catalytic efficiency (K cat /K m of 0.007 μM -1 .s- 1 ) than that of the 3CLpro (com3CLpro) expressed from the commercial vector (pETM33-Nsp5-Mpro) with specific activity 889 RFU/min/μg and K cat /K m of 0.0015 μM -1 .s- 1 , respectively. Optimal conditions for au3CLpro activity included a 50 mM Tris-HCl buffer at pH 7, containing 150 mM NaCl and 0.1 mg/ml BSA at 37 °C., Competing Interests: Declaration competing of interest The authors declare that they have no conflict of interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The protozoan parasite Leishmania donovani is the causative agent of visceral leishmaniasis (VL), a potentially fatal disease if left untreated. Given the limitations of current therapies, there is an urgent need for new, safe, and effective drugs. To discover novel antileishmanial compounds from previously unexplored chemical spaces, we conducted a high-throughput screening (HTS) of 2562 natural compounds, assessing their activity against L. donovani promastigotes and intracellular amastigotes. Utilizing the criteria of ≥70% parasite growth inhibition and ≥70% host cell (THP-1) viability, we selected 100 inhibitors for half-maximal inhibitory concentration (IC 50 ) value determination. Twenty-six compounds showed activities in both forms of Leishmania with a selectivity index of over 3. Clustering analysis resulted in four chemical clusters with scaffolds of lycorine (cluster 1), 5-hydroxy-9,10-dihydro-4 H ,8 H -pyrano[2,3- f ]chromene-4,8-dione (cluster 2), and semi-synthetic derivatives of ansamycin macrolide (cluster 4). The enantiomer of lycorine, BMD-NP-00820, showed the highest anti-amastigote activity with an IC 50 value of 1.74 ± 0.27 μM and a selectivity index (SI) > 29. In cluster 3, the most potent compound had an IC 50 value of 2.20 ± 0.29 μM with an SI > 23, whereas in cluster 4, with compounds structurally similar to the tuberculosis drug rifapentine, BMD-NP-02085 had an IC 50 value of 1.76 ± 0.28 μM, but the SI value was 7.5. Taken together, the natural products identified from this study are a potential source for the discovery of antileishmanial chemotypes for further development.

Objective: Treatment for Chiari malformation type I (CM-I) often includes surgical intervention in both pediatric and adult patients. The authors sought to investigate fundamental differences between these populations by analyzing data from pediatric and adult patients who required CM-I decompression., Methods: To better understand the presentation and surgical outcomes of both groups of patients, retrospective data from 170 adults and 153 pediatric patients (2000-2019) at six institutions were analyzed., Results: The adult CM-I patient population requiring surgical intervention had a greater proportion of female patients than the pediatric population (p < 0.0001). Radiographic findings at initial clinical presentation showed a significantly greater incidence of syringomyelia (p < 0.0001) and scoliosis (p < 0.0001) in pediatric patients compared with adult patients with CM-I. However, presenting signs and symptoms such as headaches (p < 0.0001), ocular findings (p = 0.0147), and bulbar symptoms (p = 0.0057) were more common in the adult group. After suboccipital decompression procedures, 94.4% of pediatric patients reported symptomatic relief compared with 75% of adults with CM-I (p < 0.0001)., Conclusions: Here, the authors present the first retrospective evaluation comparing adult and pediatric patients who underwent CM-I decompression. Their analysis reveals that pediatric and adult patients significantly differ in terms of demographics, radiographic findings, presentation of symptoms, surgical indications, and outcomes. These findings may indicate different clinical conditions or a distinct progression of the natural history of this complex disease process within each population, which will require prospective studies to better elucidate.

We report on the third harmonic generation (THG) in InSb semiconductor irradiated by a terahertz (THz) free electron laser (FEL). The conversion of 4 THz (wavelength 70 µm) FEL outputs into its third harmonic 12 THz was observed. We found that by tuning the sample temperature to 360 K, high conversion efficiency up to 1% can be obtained and is the highest in the THz and FIR regions below 10 THz. We also discuss the observed intensity dependence of the THG with the nonlinear order lower than 3 when the pumping intensity was high.

The active form of discoidin domain receptors (DDRs) is expressed in cell surface and regulated post-translationally by glucose. The DDR2 and DDR1 transfected in HEK293 cells were expressed mainly in their active forms with sizes of 130 and 120 kDa, respectively. DDRs were observed predominantly as 100 kDa proteins in glucose-depleted culture conditions. However, transfection of endothelial growth factor receptor (EGFR) in HEK293 cells resulted in the expression of only one form regardless of glucose concentration. Vascular smooth muscle cells, HT1080s, and MDA-MB-231 cancer cells expressed DDRs in their active forms in high glucose concentrations, which did not occur with EGFR. In diabetic rats, DDRs were expressed at high levels in arterial tissue but EGFR was not highly expressed. Taken together, these results suggest that DDRs expression depends on glucose concentration it may cooperate in the development of atherosclerosis and kidney fibroblasts, promoting nephropathy in diabetic rats.

Sonogenetics is an emerging approach that harnesses ultrasound for the manipulation of genetically modified cells. The great penetrability of ultrasound waves enables the non-invasive application of external stimuli to deep tissues, particularly advantageous for brain stimulation. Genetically encoded ultrasound mediators, a set of proteins that respond to ultrasound-induced bio-effects, play a critical role in determining the effectiveness and applications of sonogenetics. In this context, we will provide an overview of these ultrasound-responsive mediators, delve into the molecular mechanisms governing their response to ultrasound stimulation, and summarize their applications in neuromodulation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wang, Phan, Kao, Yeh and Lin.)

Conformational restriction was addressed towards the development of more selective and effective antileishmanial agents than currently used drugs for treatment of Leishmania donovani; the causative parasite of the fatal visceral leishmaniasis. Five types of cyclopentane-based conformationally restricted miltefosine analogs that were previously explored in literature as anticancer AKT-inhibitors were reprepared and repurposed as antileishmanial agents. Amongst, positions-1 and 2 cis-conformationally-restricted compound 1a and positions-2 and 3 trans-conformationally-restricted compound 3b were highly potent eliciting sub-micromolar IC 50 values for inhibition of infection and inhibition of parasite number compared with the currently used miltefosine drug that showed low micromolar IC 50 values for inhibition of infection and inhibition of parasite number. Compounds 1a and 3b eradicated the parasite without triggering host cells cytotoxicity over more than one log concentration interval which is a superior performance compared to miltefosine. In silico studies suggested that conformational restriction conserved the conformer capable of binding LdAKT-like kinase while it might be possible that it excludes other conformers mediating undesirable effects and/or toxicity of miltefosine. Together, this study presents compounds 1a and 3b as antileishmanial agents with superior performance over the currently used miltefosine drug., 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 © 2023 Elsevier Inc. All rights reserved.)

A chromone-peptidyl hybrids series was synthesised and rationally repurposed towards identification of potential antileishmanial hits against visceral leishmaniasis. Three hybrids 7c , 7n , and 7h showed potential IC 50 values (9.8, 10, and 12 µM, respectively) which were comparable to erufosine IC 50 (9.8 µM) but lower potency than miltefosine IC 50 (3.5 µM). Preliminary assessment of cytotoxicity using human THP-1 cells presented chromone-peptidyl hybrids 7c and 7n as non-cytotoxic up to 100 µM while erufosine and miltefosine had CC 50 of 19.4 µM and >40 µM, respectively. In silico studies pinpointed the N - p -methoxyphenethyl substituent at the peptidyl moiety together with the oxygen-based substituted functions of the phenyl ring of the chromone moiety as crucial players in binding to Ld CALP. Together, these findings present chromone-peptidyl hybrids 7c and 7n as potential and anticipated non-cytotoxic antileishmanial hit compounds for possible development of potential antileishmanial agents against visceral leishmaniasis.

A series of rosmarinic acid-β-amino-α-ketoamide hybrids were synthesized and rationally repurposed towards the identification of new antileishmanial hit compounds. Two hybrids, 2g and 2h, showed promising activity (IC 50 values of 9.5 and 8.8 μM against Leishmania donovani promastigotes, respectively). Their activities were comparable to erufosine. In addition, cytotoxicity evaluation employing human THP-1 cells revealed that the two hybrids 2g and 2h possess no cytotoxic effects up to 100 µM, while erufosine possessed cytotoxicity with CC 50 value of 19.4 µM. In silico docking provided insights into structure-activity relationship emphasizing the importance of the aliphatic chain at the α-carbon of the cinnamoyl carbonyl group establishing favorable binding interactions with Ld CALP and L ARG in both hybrids 2g and 2h . In light of these findings, hybrids 2g and 2h are suggested as potential safe antileishmanial hit compounds for further development of anti-leishmanial agents.

Objective: Segmental spinal dysgenesis (SSD) is a rare congenital spinal abnormality affecting the thoracic and lumbar region of the spine, as well as the spinal cord of neonates and infants. The purpose of the study was to analyze our institution's surgical case series to provide insights into our best practices to contribute to SSD management principles, while conducting a comprehensive literature review., Methods: Following institutional review board approval, a retrospective review of SSD surgical cases was examined to observe clinical findings, radiographic findings, management, surgical intervention, and outcomes. Keywords in the comprehensive literature review included SSD, congenital spinal dysgenesis, congenital spinal stenosis, spinal aplasia, and surgery., Results: Three cases underwent successful surgical management with either improvement or maintenance of neurological baseline. Patients were diagnosed at an average age of 2.7 months, while surgical intervention averaged at 40.3 months with fecal incontinence, neurogenic bladders, spinal cord compression, clubfoot, and concerns for worsening spinal deformity as surgical indicators. The average time for follow-up was 33.7 months and no complications were reported., Conclusions: Operative management for SSD is a clinically complex decision that requires multidisciplinary input and care. Patients should be observed at neurological baseline and receive intervention at the appropriate time to allow sufficient growth for functioning without permitting drastic disease progression. Consideration of patient size and spinal instrumentation are significant towards surgical success., (© 2023. The Author(s), under exclusive licence to Scoliosis Research Society.)

Pluripotent stem cell therapy exhibits self-renewal capacity and multi-directional differentiation potential and is considered an important regenerative approach for the treatment of several diseases. However, insufficient cell transplantation efficiency, uncontrollable differentiation, low cell viability, and difficult tracing limit its clinical applications and treatment outcome. Ultrasound (US) has mechanical, cavitation, and thermal effects that can produce different biological effects on organs, tissues, and cells. US can be combined with different US-responsive particles for enhanced physical-chemical stimulation and drug delivery. In the meantime, US also can provide a noninvasive and harmless imaging modality for deep tissue in vivo. An in-depth evaluation of the role and mechanism of action of US in stem cell therapy would enhance understanding of US and encourage research in this field. In this article, we comprehensively review progress in the application of US alone and combined with US-responsive particles for the promotion of proliferation, differentiation, migration, and in vivo detection of stem cells and the potential clinical applications., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: The pro-inflammatory cytokine interferon-gamma (IFN-γ) is reported to be an agent that boosts the immune modulation of mesenchymal stem cells (MSCs). However, the effects of IFN-γ on the chondrogenic potential of treated MSCs have not been evaluated in depth. This study aimed to evaluate the effects of IFN-γ on the immune modulation and chondrogenic potential of human umbilical cord-derived MSCs (hUC-MSCs)., Methods: UC-MSCs were isolated and expanded following published protocols. They were characterized as MSCs before their use in further experiments. The UC-MSCs were treated with IFN-γ at 10 ng/mL for 48 h. Changes in phenotype were investigated based on changes in MSC markers, immunomodulatory genes (TGF-β, IL-4, and IDO) for immune modulation, and cartilage-related genes during the induction of differentiation (Col1a2, Col2a1, Sox9, Runx2, and Acan) for chondrogenic potential., Results: IFN-γ-treated UC-MSCs maintained MSC markers and exhibited decreased expression of transcriptional regulatory factors in chondrogenesis (Sox9 and Runx2) and the extracellular matrix-specific genes Col1a2 and Acan but not Col2a1 compared to non-treated cells (p < 0.05). Furthermore, the immunomodulatory capability of IFN-γ-treated UC-MSCs was clearly revealed through their increased expression of IDO and IL-4 and decreased expression of TGF-β compared to non-treated cells (p < 0.05)., Conclusion: This study demonstrated that UC-MSCs treated with IFN-γ at 10 ng/mL had reduced expression of chondrocyte-specific genes; however, they maintained multi-lineage differentiation and exhibited immunomodulatory properties., (© 2023. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

High power conversion efficiency (PCE) and stretchability are the dual requirements for the wearable application of polymer solar cells (PSCs). However, most efficient photoactive films are mechanically brittle. In this work, highly efficient (PCE = 18%) and mechanically robust (crack-onset strain (COS) = 18%) PSCs are acheived by designing block copolymer (BCP) donors, PM6-b-PDMSx (x = 5k, 12k, and 19k). In these BCP donors, stretchable poly(dimethylsiloxane) (PDMS) blocks are covalently linked with the PM6 blocks to effectively increase the stretchability. The stretchability of the BCP donors increases with a longer PDMS block, and PM6-b-PDMS 19k :L8-BO PSC exhibits a high PCE (18%) and 9-times higher COS value (18%) compared to that (COS = 2%) of the PM6:L8-BO-based PSC. However, the PM6:L8-BO:PDMS 12k ternary blend shows inferior PCE (5%) and COS (1%) due to the macrophase separation between PDMS and active components. In the intrinsically stretchable PSC, the PM6-b-PDMS 19k :L8-BO blend exhibits significantly greater mechanical stability PCE 80% ((80% of the initial PCE) at 36% strain) than those of the PM6:L8-BO blend (PCE 80% at 12% strain) and the PM6:L8-BO:PDMS ternary blend (PCE 80% at 4% strain). This study suggests an effective design strategy of BCP P D to achieve stretchable and efficient PSCs., (© 2023 Wiley-VCH GmbH.)

To realize efficient, green solvent-processable organic solar cells (OSCs), considerable effort has been expended on the development of conjugated materials with both superior optoelectrical properties and processability. However, molecular design strategies that enhance solubility often reduce crystalline/electrical properties of the materials. In this study, we develop three new guest small-molecule acceptors (SMAs) (Y-4C-4O, Y-6C-4O, and Y-12C-4O) featuring inner side chains consisting of terminal oligo(ethylene glycol) (OEG) groups and alkyl spacers of different lengths. When a host SMA (Y6) and guest SMA (Y- n C-4O) are mixed, favorable interactions between these materials lead to the formation of "alloy-like" composites. The alloy-like SMA composites enable sufficient processing in o -xylene to afford suitable blend-film morphologies. It is also found that the lengths of the alkyl spacers in guest SMAs have a significant impact on the performance of the o -xylene-processed OSCs. The PM6:Y6:Y-4C-4O blend achieves a maximum power conversion efficiency (PCE) of 17.03%, outperforming PM6:Y6:Y-6C-4O (PCE = 15.85%) and PM6:Y6:Y-12C-4O (PCE = 12.12%) OSCs. The high PCE of the PM6:Y6:Y-4C-4O device is mainly attributed to the well-intermixed morphology and superior crystalline/electrical properties, which result from the high compatibility of the Y6:Y-4C-4O composites with PM6. Thus, we demonstrate that an alloy-like SMA composite based on well-designed OEG-incorporated Y-series SMAs can afford green solvent-processable, high-performance OSCs.

Up to date, there are still significantly unmet clinical needs for treatment of the fatal visceral leishmaniasis; a neglected tropical disease. Herein, a recently reported antileishmanial hit sulfuretin analog suffering from a low potency and a problematic aqueous solubility that hindered further development was used as a starting point. A mitigation rational via incorporation of O 6 -aminoalkyl moiety suggest structures analogous to literature-known compounds as cholinesterase inhibitors. Consequently, preparation and repurposing of a library of these compounds unveiled their potential activity against the parasite Leishmania donovani promastigotes. Further evaluation against intracellular form of the parasite and host cells suggested compounds 2a, 2c, and 2o derived from sulfuretin analogs bearing 2'-methoxy or 2',5'-dimethoxy substituents at ring-B as promising lead compounds with potential activity and acceptable safety window relative to the standard edelfosine. In silico simulation predicted plausible binding modes of these compounds to L. donovani fumarate reductase. Together this work presents compound 2o as a potential lead compound for further development., 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 © 2023 Elsevier Masson SAS. All rights reserved.)

Amongst different forms of leishmaniasis, visceral leishmaniasis caused by L. donovani is highly mortal. Identification of new hit compounds might afford new starting points to develop novel therapeutics. In this lieu, a rationally designed small library of bestatin analogs-4-quinolone hybrids were prepared and evaluated. Analysis of SAR unveiled distinct profiles for hybrids type 1 and type 2, which might arise from their different molecular targets. Amongst type 1 bestatin analog-4-quinolone hybrids, hybrid 1e was identified as potential hit inhibiting growth of L. donovani promastigotes by 91 and 53% at 50 and 25 μM concentrations, respectively. Meanwhile, hybrid 2j was identified amongst type 2 bestatin analog-4-quinolone hybrids as potential hit compound inhibiting growth of L. donovani promastigotes by 50 and 38% at 50 and 25 μM concentrations, respectively. Preliminary safety evaluation of the promising hit compounds showed that they are 50-100 folds safer against human derived monocytic THP-1 cells relative to the drug erufosine. In silico study was conducted to predict the possible binding of hybrid 1e with methionine aminopeptidases 1 and 2 of L. donovani. Molecular dynamic simulations verified the predicted binding modes and provide more in depth understanding of the impact of hybrid 1e on LdMetAP-1 and LdMetAP-2., 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 © 2023. Published by Elsevier Masson SAS.)

SQ109 is a tuberculosis drug candidate that has high potency against Mycobacterium tuberculosis and is thought to function at least in part by blocking cell wall biosynthesis by inhibiting the MmpL3 transporter. It also has activity against bacteria and protozoan parasites that lack MmpL3, where it can act as an uncoupler, targeting lipid membranes and Ca 2+ homeostasis. Here, we synthesized 18 analogs of SQ109 and tested them against M. smegmatis , M. tuberculosis , M. abscessus , Bacillus subtilis , and Escherichia coli , as well as against the protozoan parasites Trypanosoma brucei , T. cruzi , Leishmania donovani , L. mexicana , and Plasmodium falciparum . Activity against the mycobacteria was generally less than with SQ109 and was reduced by increasing the size of the alkyl adduct, but two analogs were ∼4-8-fold more active than SQ109 against M. abscessus , including a highly drug-resistant strain harboring an A309P mutation in MmpL3. There was also better activity than found with SQ109 with other bacteria and protozoa. Of particular interest, we found that the adamantyl C-2 ethyl, butyl, phenyl, and benzyl analogs had 4-10× increased activity against P. falciparum asexual blood stages, together with low toxicity to a human HepG2 cell line, making them of interest as new antimalarial drug leads. We also used surface plasmon resonance to investigate the binding of inhibitors to MmpL3 and differential scanning calorimetry to investigate binding to lipid membranes. There was no correlation between MmpL3 binding and M. tuberculosis or M. smegmatis cell activity, suggesting that MmpL3 is not a major target in mycobacteria. However, some of the more active species decreased lipid phase transition temperatures, indicating increased accumulation in membranes, which is expected to lead to enhanced uncoupler activity.

Leishmaniasis is an infectious disease caused by obligate intracellular protozoa of the genus Leishmania with high infection and death rates in developing countries. New drugs with better pharmacological performance with regards to safety, efficacy, toxicity, and drug resistance than those/the ones currently used are urgently needed. Trypanothione synthetase (TryS) is an attractive target for the development of drugs against leishmaniasis because it is specific and essential to kinetoplastid parasites. In this study, Leishmaniamajor TryS was expressed and purified, and the kinetic parameters of purified TryS were determined. To identify novel inhibitors of LmTryS, a high-throughput screening (HTS) assay was developed and used to screen a library of 35,040 compounds. In the confirmatory assay, 42 compounds displayed half maximal inhibitory concentration (IC 50 ) values < 50 μM and six of them corresponded to novel structures with IC 50 ranging from 9 to 19 μM against LmTryS enzyme activity. Of the six inhibitors, TS001 showed the highest activity against growth of L. major promastigotes, L. donovani promastigotes, and Trypanosoma brucei brucei Lister 427 with IC 50 values of 17, 26, and 31 μM, respectively. An in silico docking study using a homology model of LmTryS predicted the molecular interactions between LmTryS and the inhibitors., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2022. Published by Elsevier Inc.)

Organic solar cells (OSCs) based on conjugated block copolymers (CBCs) have gained considerable attention owing to their simple one-pot solution process. However, their power conversion efficiencies (PCEs) require significant improvement. Furthermore, the majority of efficient CBC-based OSCs are processed using environmentally toxic halogenated solvents. Herein, we develop a new CBC (PBDB-T- b -PY5BDT) and demonstrate efficient and stable OSCs achieved by a halogen-free solution process. We design a (D 1 -A 1 )- b -(D 1 -A 2 )-type CBC (PBDB-T- b -PY5BDT) that shares the same benzodithiophene (BDT) units in donor and acceptor blocks. This alleviates unfavorable molecular interactions between the blocks at their interfaces. The PBDB-T- b -PY5BDT-based devices exhibit a high PCE (10.55%), and they show good mechanical, thermal, and storage stabilities. Importantly, we discuss the potential of our OSCs by preparing two different control systems: one based on a binary polymer blend (PBDB-T:PY5BDT) and another based on a conjugated random copolymer (CRC, PBDB-T- r -PY5BDT). We demonstrate that the photovoltaic performance, device stability, and mechanical robustness of the CBC-based OSCs exceed those of the binary all-polymer solar cells and CRC-based OSCs.

Background: Mid-aortic syndrome (MAS) is characterized by the congenital coarctation of the abdominal aorta, abdominal and limb claudication, and hypertension. The etiology of this disorder is very diverse and often manifests in conjunction with Takayasu's arteritis, Williams-Beurens syndrome, and neurofibromatosis. The isolated mid-aortic syndrome is very rare with only a few cases reported in the literature., Case Presentation: A 45 years old man was admitted to the Emergency Department with sudden muscle weakness and facial paralysis on the left side. Imaging studies reveal right middle cerebral artery infarction at the M1 section. Incidental findings include multiple moderate to severe stenoses in the right internal carotid artery, and total abdominal aorta occlusion. A variant at the ELN gene (Elastin, OMIM*130,160): c.1768G > A/wt (p.Ala590Thr) was identified., Conclusion: This is the first reported case of ELN related mid-aortic syndrome in Vietnam which was diagnosed through careful clinical and genetic workup. The finding of mid-aortic syndrome, in this case, was incidental and the decision to reverse the occlusion was postponed as there was no immediate risk of renal failure or reduced blood flow to the lower limb., (© 2022. The Author(s).)

Intrinsically stretchable organic solar cells (IS-OSCs), consisting of all stretchable layers, are attracting significant attention as a future power source for wearable electronics. However, most of the efficient active layers for OSCs are mechanically brittle due to their rigid molecular structures designed for high electrical and optical properties. Here, a series of new polymer donors (P D s, PhAmX) featuring phenyl amide (N 1 ,N 3 -bis((5-bromothiophen-2-yl)methyl)isophthalamide, PhAm)-based flexible spacer (FS) inducing hydrogen-bonding (H-bonding) interactions is developed. These P D s enable IS-OSCs with a high power conversion efficiency (PCE) of 12.73% and excellent stretchability (PCE retention of >80% of the initial value at 32% strain), representing the best performances among the reported IS-OSCs to date. The incorporation of PhAm-based FS enhances the molecular ordering of P D s as well as their interactions with a Y7 acceptor, enhancing the mechanical stretchability and electrical properties simultaneously. It is also found that in rigid OSCs, the PhAm5:Y7 blend achieves a much higher PCE of 17.5% compared to that of the reference PM6:Y7 blend. The impact of the PhAm-FS linker on the mechanical and photovoltaic properties of OSCs is thoroughly investigated., (© 2022 Wiley-VCH GmbH.)

Digital Health Literacy (DHL) helps online users with navigating the infodemic and co-existing conspiracy beliefs to avoid mental distress and maintain well-being. We aimed to investigate the association between DHL and future anxiety (FA); and examine the potential mediation roles of information satisfaction and fear of COVID-19 (F-CoV). A web-based cross-sectional survey was carried out among 1631 Taiwanese university students aged 18 years and above from June 2021 to March 2022. Data collected were socio-demographic characteristics (sex, age, social status, university location), information satisfaction, F-CoV, DHL and FA (using Future Dark scale). The linear regression model was used to explore factors associated with FA. The pathway analysis was further used to evaluate the direct and indirect relationship between DHL and FA. A higher score of DHL (B = -0.21; 95% CI, -0.37, -0.06; p = 0.006), and information satisfaction (B = -0.16; 95% CI, -0.24, -0.08; p < 0.001) were associated with a lower FA score, whereas a higher F-CoV score was associated with a higher FA score (B = 0.43; 95% CI, 0.36, 0.50; p < 0.001). DHL showed the direct impact (B = -0.1; 95% CI, -0.17, -0.04; p = 0.002) and indirect impact on FA as mediated by information satisfaction (B = -0.04; 95% CI, -0.06, -0.01; p = 0.002) and F-CoV (B = -0.06, 95% CI, -0.08, -0.04; p < 0.001). Strategic approaches to promote DHL, information satisfaction, lower F-CoV are suggested to reduce FA among students.

Nonfused ring acceptors (NFRAs) have attracted significant attention for nonfullerene organic solar cells (OSCs) owing to their chemical tunability and facile synthesis. In this study, a benzotriazole-based NFRA with chlorinated end groups (Triazole-4Cl) is developed to realize highly efficient and thermally stable NFRA-based OSCs; an analogous NFRA with nonchlorinated end groups (Triazole-H) is synthesized for comparison. Triazole-4Cl film exhibits the high-order packing structure and the near-infrared absorption capability, which are advantageous in charge transport and light harvesting of the resulting OSCs. In particular, the strong crystalline behavior of Triazole-4Cl results in enhanced self-aggregation, leading to high charge carrier mobility. Owing to these properties, a PBDB-T (polymer donor):Triazole-4Cl OSC demonstrates a high short-circuit current, fill factor, and power conversion efficiency (PCE = 10.46%), outperforming a PBDB-T:Triazole-H OSC (PCE = 7.65%). In addition, the thermal stability of a PBDB-T:Triazole-4Cl OSC at an elevated temperature of 120 °C exceeds that of a PBDB-T:Triazole-H OSC. This is mainly attributed to the significantly higher cold crystallization temperature of Triazole-4Cl (205.9 °C). This work provides useful guidelines for the design of NFRAs to achieve efficient and thermally stable NFRA-based OSCs., (© 2022 Wiley-VCH GmbH.)

Biomacromolecules are known to feature complex three-dimensional shapes that are essential for their function. Among natural products, ambiguous molecular shapes are a rare phenomenon. The hexapeptide tryptorubin A can adopt one of two unusual atropisomeric configurations. Initially hypothesized to be a non-ribosomal peptide, we show that tryptorubin A is the first characterized member of a new family of ribosomally synthesized and posttranslationally modified peptides (RiPPs) that we named atropopeptides. The sole modifying enzyme encoded in the gene cluster, a cytochrome P450 monooxygenase, is responsible for the atropospecific formation of one carbon-carbon and two carbon-nitrogen bonds. The characterization of two additional atropopeptide biosynthetic pathways revealed a two-step maturation process. Atropopeptides promote pro-angiogenic cell functions as indicated by an increase in endothelial cell proliferation and undirected migration. Our study expands the biochemical space of RiPP-modifying enzymes and paves the way towards the chemoenzymatic utilization of atropopeptide-modifying P450s., (© 2022 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Direct growth inhibition of infectious organisms coupled with immunomodulation to counteract the immunosuppressive environment might be a beneficial therapeutic approach. Herein, a library of sulfuretin analogs were developed with potential capabilities to inhibit production of the immunosuppressive PGE 2 and elicit direct growth inhibition against Leishmania donovani ; the major causative agent of the fatal visceral leishmaniasis. Amongst explored library members bearing diverse methoxy and/or hydroxy substitution patterns at rings B and A, analog 1i retaining the C6-hydroxy moiety at ring-A, but possessing methoxy moieties in place of the polar dihydroxy moieties of sulfuretin ring-B, as well as analog 1q retaining the sulfuretin's polar dihydroxy moieties at ring-B, but incorporating a C6-methoxy moiety instead of the C6-hydroxy moiety at ring-A, were the most promising hit compounds. Cytotoxicity evaluation suggested that analog 1i possesses a safety profile inducing the death of the parasite rather than host cells. In silico simulation provided insights into their possible binding with Leishmania donovani fumarate reductase. The current investigation presents sulfuretin analogs 1i and 1q as potential hit compounds for further development of multifunctional therapeutic agents against visceral leishmaniasis.

Background: Risk communication is necessary to improve the booster vaccination rate, but Vietnam does not have a system to collect and disclose such information. Therefore, the purpose of this study was to clarify adverse reactions and their frequency in the early period after booster vaccination, and to obtain primary data for improving the booster vaccination rate. Methods: A cross-sectional survey was conducted among adults aged ≥18 years. Clinical data were collected 14 days after booster vaccination by using a standard questionnaire. Results: A total of 1322 participants were included with median age = 23 and sex ratio (Male/Female) = 0.53. AstraZeneca was the most commonly used vaccine for the first and second doses, while Pfizer was the most commonly used vaccine for booster shots. Injection site pain, fatigue, and myalgia were the most common side effect reported (71.9%, 28.1%, and 21.8%, respectively). Compared to previous COVID-19 vaccine injections, 81.9% of participants reported that their symptoms were similar or milder after receiving the booster dose. They were more likely to present injection site pain (OR = 1.43, p < 0.0001) and lymphadenopathy (OR = 4.76, p < 0.0001) after receiving the booster shot. Fever (OR = 0.33, p < 0.0001) and fatigue (OR = 0.77, p = 0.002) were less often reported after booster shots compared to the first and second injections. The severity of symptoms occurring after booster dose versus first and second doses increased significantly with each additional year of age and among participants receiving the Pfizer and Moderna vaccines. Conclusion: Adverse reactions to booster vaccination are minor and their incidence is the same as for the first or the second vaccination. Multicenter studies with larger sample sizes on the side effects and safety of COVID-19 vaccine booster shots need to be conducted to make the population less worried, in order to increase the vaccination rate, to protect individuals’ and communities’ health.

NeuroPace responsive neurostimulation (RNS ® ) therapy was used in a case of intractable focal epilepsy with bifrontal transmantle heterotopia subserving peculiar homotopic motor distribution in a 16-year-old, right-handed male with intractable seizures. Brain MRI demonstrated bifrontal transmantle heterotopia extending from the central sulcus to subjacent lateral ventricles along with polymicrogyria along the overlying cortex suspected to be the motor cortex. Functional MRI demonstrated homotopic distribution of finger and foot motor function (deeper) within the polymicrogyria. Invasive intracranial monitoring with depth electrodes and extraoperative brain mapping revealed eloquent cortical tissue which corresponded to the right leg and right shoulder motor function., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Chronic adversity in early childhood is associated with increased anxiety and a propensity for substance abuse later in adulthood, yet the effects of early life stress (ELS) on brain development remain poorly understood. The zebrafish, Danio rerio, is a powerful model for studying neurodevelopment and stress. Here, we describe a zebrafish model of ELS and identify a role for glucocorticoid signaling during a critical window in development that leads to long-term changes in brain function. Larval fish subjected to chronic stress in early development exhibited increased anxiety-like behavior and elevated glucocorticoid levels later in life. Increased stress-like behavior was only observed when fish were subjected to ELS within a precise time window in early development, revealing a temporal critical window of sensitivity. Moreover, enhanced anxiety-like behavior only emerges after two months post-ELS, revealing a developmentally specified delay in the effects of ELS. ELS leads to increased levels of baseline cortisol, and resulted in a dysregulation of cortisol receptors' mRNA expression, suggesting long-term effects on cortisol signaling. Together, these findings reveal a 'critical window' for ELS to affect developmental reprogramming of the glucocorticoid receptor pathway, resulting in chronic elevated stress., (© 2022. The Author(s).)

SQ109 is an anti-tubercular drug candidate that has completed Phase IIb/III clinical trials for tuberculosis and has also been shown to exhibit potent in vitro efficacy against protozoan parasites including Leishmania and Trypanosoma cruzi spp. However, its in vivo efficacy against protozoa has not been reported. Here, we evaluated the activity of SQ109 in mouse models of Leishmania, Trypanosoma spp. as well as Toxoplasma infection. In the T. cruzi mouse model, 80% of SQ109-treated mice survived at 40 days post-infection. Even though SQ109 did not cure all mice, these results are of interest since they provide a basis for future testing of combination therapies with the azole posaconazole, which acts synergistically with SQ109 in vitro. We also found that SQ109 inhibited the growth of Toxoplasma gondii in vitro with an IC 50 of 1.82 µM and there was an 80% survival in mice treated with SQ109, whereas all untreated animals died 10 days post-infection. Results with Trypanosoma brucei and Leishmania donovani infected mice were not promising with only moderate efficacy. Since SQ109 is known to be extensively metabolized in animals, we investigated the activity in vitro of SQ109 metabolites. Among 16 metabolites, six mono-oxygenated forms were found active across the tested protozoan parasites, and there was a ~6× average decrease in activity of the metabolites as compared to SQ109 which is smaller than the ~25× found with mycobacteria.

Pediatric posterior fossa arteriovenous malformations (AVMs) are rare entities that pose significant cumulative lifetime risk of rupture and require treatment. Microsurgical resection remains a good option for definitively treating posterior fossa AVMs in one setting. The drawback of endovascular embolization is the lower rates of nidus obliteration. Although stereotactic radiosurgery is a safe alternative, it takes several years to achieve the treatment goal all the while predisposing the patient to the risk of AVM rupture.1,2 Accurate localization and visualization remain challenging for microsurgical treatment of posterior fossa AVMs.3-5 Small size of a nidus, prone position, and proximity to eloquent areas make these lesions particularly difficult to localize and resect. We present the operative case of a 6-year-old boy with a small, ruptured posterior fossa AVM. After undergoing hematoma evacuation, the patient underwent microsurgical resection of a small right vermian AVM assisted by the virtual reality platform, Surgical Theater (Gates Mills, OH). Our video demonstrates the utility of a virtual augmented reality platform for addressing the challenges posed by a small posterior fossa AVM with respect to the need for precise three-dimensional localization of small lesions. The patient consented to the procedure. The participants and any identifiable individuals consented to publication of his/her image., (Copyright © Congress of Neurological Surgeons 2022. All rights reserved.)

Introduction: The increasing use of stereoelectroencephalography (SEEG) in the USA and the need for three-dimensional (3D) appreciation of complex spatial relationships between implanted stereotactic EEG depth electrodes and surrounding brain and cerebral vasculature are a challenge to clinicians who are used to two-dimensional (2D) appreciation of cortical anatomy having been traditionally trained on 2D radiologic imaging. Virtual reality and its 3D renderings have grown increasingly common in the multifaceted practice of neurosurgery. However, there exists a paucity in the literature regarding this emerging technology in its utilization of epilepsy surgery., Methods: An IRB-approved, single-center retrospective study identifying all SEEG pediatric patients in which virtual reality was applied was observed., Results: Of the 46 patients identified who underwent an SEEG procedure, 43.5% (20/46) had a 3D rendering (3DR) of their SEEG depth electrodes. All 3DRs were used during patient-family education and discussion among the Epilepsy multidisciplinary team meetings, while 35% (7/20) were used during neuronavigation in surgery. Three successful representative cases of its application were presented., Discussion: Our institution's experience regarding virtual reality in the 3D representation of SEEG depth electrodes and the application to pre-surgical planning, patient-family education, multidisciplinary communication, and intraoperative neuronavigation demonstrate its applicability in comprehensive epilepsy patient care., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

A rational-based process was adopted for repurposing pyrrolidine-based 3-deoxysphingosylphosphorylcholine analogs bearing variable acyl chains, different stereochemical configuration and/or positional relationships. Structural features were highly influential on activity. Amongst, enantiomer 1e having 1,2-vicinal relationship for the -CH 2 O- and the N- acyl moieties, a saturated palmitoyl chain and an opposite stereochemical configuration to natural sphingolipids was the most potent hit compound against promastigotes showing IC 50 value of 28.32 µM. The corresponding enantiomer 1a was 2-fold less potent showing a eudismic ratio of 0.54 in promastigotes. Compounds 1a and 1e inhibited the growth of amastigotes more potently relative to promastigotes. Amongst, enantiomer 1a as the more selective and safer. In silico docking study using a homology model of Leishmania donovani inositol phosphoceramide synthase (IPCS) provided plausible reasoning for the molecular factors underlying the found activity. Collectively, this study suggests compounds 1a and 1e as potential hit compounds for further development of new antileishmanial agents.

Investigating the coil-magnet structure plays a significant role in the design process of the electromagnetic energy harvester due to the effect on the harvester's performance. In this paper, the performance of four different electromagnetic vibration energy harvesters with cylindrical shapes constrained in the same volume were under investigation. The utilized structures are (i) two opposite polarized magnets spaced by a mild steel; (ii) a Halbach array with three magnets and one coil; (iii) a Halbach array with five magnets and one coil; and (iv) a Halbach array with five magnets and three coils. We utilized a completely automatic optimization procedure with the help of an optimization algorithm implemented in Python, supported by simulations in ANSYS Maxwell and MATLAB Simulink to obtain the maximum output power for each configuration. The simulation results show that the Halbach array with three magnets and one coil is the best for configurations with the Halbach array. Additionally, among all configurations, the harvester with two opposing magnets provides the highest output power and volume power density, while the Halbach array with three magnets and one coil provides the highest mass power density. The paper also demonstrates limitations of using the electromagnetic coupling coefficient as a metric for harvester optimization, if the ultimate goal is maximization of output power.

Visceral leishmaniasis (VL) is a fatal infectious disease caused by viscerotropic parasitic species of Leishmania. Current treatment options are often ineffective and toxic, and more importantly, there are no clinically validated drug targets available to develop next generation therapeutics against VL. Topoisomerase IB (TopIB) is an essential enzyme for Leishmania survival. The enzyme is organized as a bi-subunit that is distinct from the monomeric topoisomerase I of human. Based on this unique feature, we synthesized peptides composed of partial amino acid sequences of small subunit of Leishmania donovani (Ld) TopIB to confirm a decrease in catalytic activity by interfering the interaction between the two subunits. One of the synthetic peptides, covering essential amino acids for catalytic activity of LdTopIB, interrupted the enzymatic activity. Next, we examined 151 compounds selected from virtual screening in a functional assay and identified three LRL-TP compounds with a significant decrease in LdTopIB activity (IC 50 of LRL-TP-85: 1.3 μM; LRL-TP-94: 2.9 μM; and LRL-TP-101: 35.3 μM) and no effects on Homo sapiens (Hs) TopIB activity. Based on molecular docking, the protonated tertiary amine of inhibitors formed key interactions with S415 of the large subunit. The EC 50 values of LRL-TP-85, LRL-TP-94, and LRL-TP-101 were respectively 4.9, 1.4, and 27.8 μM in extracellular promastigote assay and 34.0, 53.7, and 11.4 μM in intracellular amastigote assay. Overall, we validated the protein-protein interaction site of LdTopIB as a potential drug target and identified small molecule inhibitors with anti-leishmanial activity., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: The role of an osseous-only posterior fossa decompression (PFD) for Chiari malformation type 1 (CM1) remains controversial. We reviewed long-term outcomes for patients with CM1 undergoing a PFD to evaluate if there was any difference for failure when compared to patients undergoing a PFD with duraplasty (PFDD)., Methods: Consecutive patients surgically treated at a single tertiary pediatric neurosurgery clinic over a 25-year period with at least 5 years of follow-up were evaluated. PFD patients were compared to those that initially received a PFDD. Demographics, surgical indications, surgical approach, outcomes, and complications were reviewed., Results: A total of 60 patients were included in this study of which 25 (41.67%) underwent PFD and 35 (58.33%) underwent PFDD. Mean age at surgery was 7.41 years (range 0.4 to 18 years) with a mean follow-up of 8.23 years (range 5 to 21 years). Those that received a PFD had a lower rate of radiographic syrinx improvement (p = 0.03), especially in the setting of holocord syringes. Failure rate was significantly higher in the PFD group (20% vs 2.90%, p = 0.03). However, complications were significantly higher in the PFDD group (17.14% vs 4.0%, p = 0.04)., Conclusions: PFD provides a safe treatment option with similar clinical improvements and lower post-operative complication rate compared to PFDD, albeit at the cost of greater chance of reoperation, especially in the setting of a holocord syrinx. Patients with a holocord syrinx should be considered for a PFDD as their initial procedure., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Data on aminoglycoside stewardship in critically ill septic patients with acute kidney injury (AKI) needing intermittent hemodialysis (IH) are scarce. The first objective of the study was to evaluate whether aminoglycoside administration occurs before vs after IH in the real-life management of critically ill septic patients with AKI needing IH. The second objective was to assess the delay in achieving a potential reinjection window for a second dose of aminoglycoside, which should be obtained with a postdialysis vs predialysis regimen., Methods: A post hoc observational analysis of a multicenter randomized trial of critically ill patients with AKI needing renal replacement therapy was conducted. Inclusion criteria consisted of any patients receiving IH for AKI during an antimicrobial therapy for a septic episode., Findings: Among 206 of 341 septic patients (60%) receiving aminoglycosides, 90 underwent IH (46 with previous continuous renal replacement therapy and 44 without). Amikacin and gentamicin were administered for a mean (SD) of 2.2 (1.5) and 2.5 (2.1) days with mean (SD) doses of 20.6 (6.6) and 5.4 (2.5) mg/kg, respectively. In the 44 patients undergoing exclusive IH, aminoglycosides were administered in a predialysis in 53% of episodes versus 35% in a postdialysis schedule. The first C min target was obtained earlier with a predialysis vs postdialysis schedule (33.9 [14.2] hours vs 50.9 [12.2] hours, P = 0.009)., Implications: Despite being less frequently used than a predialysis schedule, the postdialysis administration of aminoglycosides remains a regular practice in the intensive care unit. A predialysis schedule of administration in IH reduces the interval time to tolerable aminoglycoside redosing., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: Data on aminoglycoside stewardship in critically ill septic patients with acute kidney injury (AKI) needing continuous renal replacement therapy (CRRT) are scarce. The objectives of the study were to determine, during CRRT, the time window with low likelihood for safe reinjection and the proportion of inappropriate reinjection., Methods: A post hoc observational analysis of a multicenter randomized trial comparing the risk of hemodialysis catheter infection with ethanol lock vs placebo in critically ill patients with AKI was conducted. Eligible patients were adults in intensive care units from 6 French hospitals. Any patient with AKI needing CRRT and receiving an antimicrobial therapy for a septic episode occurring before (≤24 hours) or during CRRT was included. The aminoglycoside orders were left to the physicians' discretion, but high dose once daily was the schedule of aminoglycoside administration., Findings: A total of 145 septic episodes treated by aminoglycosides were analyzed in patients receiving CRRT. A mean (SD) of 1.6 (0.8) amikacin and 1.8 (1.2) gentamicin administrations per patient were observed. During CRRT, C max was 17.3 mg/L (interquartile range, 13.2-22.5 mg/L) for gentamicin and 50 mg/L (interquartile range, 43.7-76.6 mg/L) for amikacin. The plasma drug concentration at 24 hours (C H24 ) was 2.3 mg/L (interquartile range, 1.6-3.2 mg/L) for gentamicin and 9.3 (interquartile range, 6.6-12.0 mg/L) for amikacin. Sixty-five C min dosages remained above the reinjection threshold. Inappropriate reinjection was observed in 11 of 65 episodes (17%). Inappropriate reinjection (defined by, at the reinjection time, C min dosages above the threshold; ie, C min >2 mg/L for gentamicin and >5 mg/L for amikacin) was observed in 17% of analyzed episodes. Most patients did not need reinjection until approximately ≥30 hours after their initial administration., Implications: During CRRT, as indicated by the C H24 value, which was higher than the recommended threshold, the interval to obtain a C min low enough to allow for redosing aminoglycosides is significantly longer than 24 hours. This interval is not always respected and leads to an of inappropriate reinjection rate of 17%. ClinicalTrials.gov identifier: ISRCTNCT00875069., Competing Interests: DISCLOSURES The authors have indicated that they have no conflicts of interest regarding the content of this article., (Copyright © 2021. Published by Elsevier Inc.)

Objective: The authors aimed to describe the natural history and optimal management of persistent syringomyelia after suboccipital craniectomy for Chiari malformation type I (CM-I)., Methods: A cohort of all patients who presented to a tertiary pediatric hospital with newly diagnosed CM-I between 2009 and 2017 was identified. Patients with persistent or worsened syringomyelia were identified on the basis of a retrospective review of medical records and imaging studies. The management of these patients and their clinical courses were then described., Results: A total of 153 children with CM-I and syringomyelia were evaluated between 2009 and 2017. Of these, 115 (68.8%) patients underwent surgical intervention: 40 patients underwent posterior fossa decompression (PFD) alone, 43 underwent PFD with duraplasty, and 32 underwent PFD with duraplasty and fourth ventricle stent placement. Eleven (7.19%) patients had increased syringomyelia on subsequent postoperative imaging. Three of these patients underwent revision surgery because of worsening scoliosis or pain, 2 of whom were lost to follow-up, and 4 were managed nonoperatively with close surveillance and serial MRI evaluations. The syringes decreased in size in 3 patients and resolved completely in 1 patient., Conclusions: Persistent or worsened syringomyelia after CM-I decompression is uncommon. In the absence of symptoms, nonoperative management with close observation is safe for patients with persistent syrinx.

Objective: Children with medically refractory partial-onset epilepsy arising from eloquent cortex present a therapeutic challenge, as many are not suitable for resective surgery. For these patients, responsive neurostimulation may prove to be a potential tool. Although responsive neurostimulation has demonstrated utility in adults, little has been discussed regarding its utility in the pediatric population. In this study, the authors present their institution's experience with responsive neurostimulation via the RNS System through a case series of 5 pediatric patients., Methods: A single-center retrospective study of patients who underwent RNS System implantation at Children's National Hospital was performed., Results: Five patients underwent RNS System implantation. The mean patient age at treatment was 16.8 years, and the average follow-up was 11.2 months. All patients were considered responders, with a seizure frequency reduction of 64.2% without adverse events., Conclusions: All 5 patients experienced medium-term improvements in seizure control after RNS System implantation with decreases in seizure frequency > 50% from baseline preoperative seizure frequency. The authors demonstrated two primary configurations of electrode placement: hippocampal or amygdala placement via an occipitotemporal trajectory, as well as infratemporal surface electrodes and surface electrodes on the primary motor cortex. No adverse events were experienced in this case series.

Objectives: Chiari malformation type 1 (CM1) is an increasingly common incidental finding on magnetic resonance imaging (MRI). The proportion of children with an incidentally discovered CM1 who upon further evaluation require operative intervention for previously unrecognized signs and symptoms of neurological compromise or significant radiographic findings (syringomyelia) is unclear. An extensive long-term single-institution patient series was evaluated to better clarify the likelihood of surgery in patients who present with an incidentally discovered CM1., Methods: This study was conducted using prospective data for patients up to 18 years old that were evaluated for a CM1 at a large tertiary pediatric neurosurgery clinic between February 2009 and June 2019. Patients were excluded if they did not have an incidentally discovered CM1 and at least 12 months of clinical follow-up., Results: A total of 218 consecutive patients were included in this study. The mean age at the initial neurosurgical evaluation was 6.5 years (range 5 months to 18.4 years), and the mean duration of clinical follow-up was 40.6 months (range 12 to 114 months). Initial MR imaging was most commonly obtained for the evaluation of seizures (15.1%), nonspecific headaches (not occipital or tussive) (14.7%), trauma (9.6%), and developmental delay (7.8%). Of the patients studied that eventually required surgery, we identified two groups: those operated before 6 months since presentation and those operated after 6 months. A total of 36 patients (16.5%) underwent a decompression with 22 patients (61.1%) receiving surgery within 6 months and the remaining 14 patients (38.9%) beyond 6 months. Patients undergoing early surgery (10.1%) initially presented with a significant syrinx or were noted to have an occult neurological dysfunction, whereas a smaller subset of patients (6.4%) eventually required surgery over time due to the development of new symptoms or a de novo syrinx. Only the presence of syringomyelia was statistically significant for the need of a surgical intervention, while age, sex and degree of tonsillar herniation were not., Conclusion: Evaluation of a large group of patients with an incidentally discovered Chiari malformation demonstrated that most patients may be managed conservatively, especially in the absence of syringomyelia. However, there is a subset of patients who will go on to develop a de novo syrinx or neurological symptoms that are new or progressive during follow-up, which should be evaluated by imaging of the brain and spinal cord. The presence of syringomyelia was associated with need for early surgical intervention. However, for patients without syringomyelia, surgical intervention is uncommon but may be delayed up to several years after presentation; therefore, long-term clinical follow-up is recommended.