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The article presents the case study of a 27 year old woman at 21 weeks’ gestation. Fetal echocardiography revealed multiple cardiac rhabdomyomas, with the largest lesion in the left ventricle Neurosonography and fetal magnetic resonance imaging demonstrated cerebral tubers. The kidneys appeared normal. Fetal tuberous sclerosis was suspected,

Background & Aims: Bulevirtide (BLV) is a small lipopeptide agent that specifically binds to the sodium taurocholate cotransporting polypeptide (NTCP) bile salt transporter and HBV/HDV receptor on the surface of human hepatocytes and inhibits HDV and HBV entry. As a satellite virus of HBV, HDV virions are formed after assembly of HDV RNA with the HBV envelope proteins (HBsAg). Because both viruses exist as eight different genotypes, this creates a potential for high diversity in the HBV/HDV combinations. To investigate the sensitivity of various combinations of HBV/HDV genotypes to BLV, clinical and laboratory strains were assessed., Methods: For the laboratory strains, the different envelopes from HBV genotypes A through H were combined with HDV genotypes 1-8 in cotransfection assays. Clinical plasma isolates were obtained from clinical studies and academic collaborations to maximise the diversity of HBV/HDV genotypes tested., Results: The mean BLV EC 50 against HDV laboratory strains ranged from 0.44 to 0.64 nM. Regardless of HBV and HDV genotypes, the clinical isolates showed similar sensitivities to BLV with mean values that ranged from 0.2 to 0.73 nM., Conclusions: These data support the use of BLV in patients infected with any HBV/HDV genotypes., Impact and Implications: This study describes the potent activity of BLV against multiple laboratory strains spanning all HBV/HDV A-H/1-8 genotype combinations and the most diverse collection of HDV clinical samples tested to date, including HBV/HDV genotype combinations less frequently observed in the clinic. Overall, all isolates and laboratory strains displayed similar in vitro nanomolar sensitivity to BLV. This broad-spectrum antiviral activity of BLV has direct implications on potential simplified treatment for any patient infected with HDV, regardless of genotype, and supports the new 2023 EASL Clinical Practice Guidelines on HDV that recommend antiviral treatment for all patients with CHD., Competing Interests: DA and JH report no conflicts of interest. RMat, YL, SX, SC, RM, SM, TAe, BH, TY, LM, DH, AS, RMar, DM, CR, EM, CM, and HM are employees and stockholders of Gilead Sciences. Tas and PL are consultants for Gilead Sciences. SU is a co-applicant and co-inventor on patents protecting Hepcludex (bulevirtide/Hepcludex) and consultant for Gilead Sciences. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2023 The Author(s).)

Transient absorption spectroscopy is utilized extensively for measurements of bound- and quasibound-state dynamics of atoms and molecules. The extension of this technique into the extreme ultraviolet (XUV) region with attosecond pulses has the potential to attain unprecedented time resolution. Here we apply this technique to aligned-in-space molecules. The XUV pulses are much shorter than the time during which the molecules remain aligned, typically [Formula: see text]100 fs. However, transient absorption is not an instantaneous probe, because long-lived coherences re-emit for picoseconds to nanoseconds. Due to dephasing of the rotational wavepacket, it is not clear if these coherences will be evident in the absorption spectrum, and whether the properties of the initial excitations will be preserved. We studied Rydberg states of N[Formula: see text] and O[Formula: see text] from 12 to 23 eV. We were able to determine the polarization direction of the electronic transitions, and hence identify the symmetry of the final states.

Background and Objectives: Virtual simulators have played a vital role in preparing surgeons for laparoscopic and robotic procedures in gynecologic surgery. The efficacy of the simulator was evaluated to improve basic (trainee) laparoscopic skills and assess training levels., Methods: This prospective, comparative study was conducted in volunteer residents in the obstetrics and gynecology training program of Université Laval. Study participants performed 9 laparoscopic simulator tasks on 2 different occasions. Skills improvement between sessions and differences between junior and senior residents were examined., Results: Thirteen junior and 11 senior residents participated in the study. Junior trainees significantly improved their speed of execution, accuracy, and maintenance of horizontal view. Senior trainees mainly accelerated their rapidity in completing different tasks. They performed better than junior trainees, with economy of movements, and tended toward greater precision, speed of execution, and safe retraction in various tasks., Conclusion: Virtual simulators are useful pedagogic tools that could benefit both junior and senior residents. Integration into the residency curricula should be considered.

Cancer somatic mutations can generate neoantigens that distinguish malignant from normal cells. However, the personalized identification and validation of neoantigens remains a major challenge. Here we discover neoantigens in human mantle-cell lymphomas by using an integrated genomic and proteomic strategy that interrogates tumour antigen peptides presented by major histocompatibility complex (MHC) class I and class II molecules. We applied this approach to systematically characterize MHC ligands from 17 patients. Remarkably, all discovered neoantigenic peptides were exclusively derived from the lymphoma immunoglobulin heavy- or light-chain variable regions. Although we identified MHC presentation of private polymorphic germline alleles, no mutated peptides were recovered from non-immunoglobulin somatically mutated genes. Somatic mutations within the immunoglobulin variable region were almost exclusively presented by MHC class II. We isolated circulating CD4 + T cells specific for immunoglobulin-derived neoantigens and found these cells could mediate killing of autologous lymphoma cells. These results demonstrate that an integrative approach combining MHC isolation, peptide identification, and exome sequencing is an effective platform to uncover tumour neoantigens. Application of this strategy to human lymphoma implicates immunoglobulin neoantigens as targets for lymphoma immunotherapy.

Anthracyclines are among the most effective yet most toxic drugs used in the oncology clinic. The nucleosome-remodeling SWI/SNF complex, a potent tumor suppressor, is thought to promote sensitivity to anthracyclines by recruiting topoisomerase IIa (TOP2A) to DNA and increasing double-strand breaks. In this study, we discovered a novel mechanism through which SWI/SNF influences resistance to the widely used anthracycline doxorubicin based on the use of a forward genetic screen in haploid human cells, followed by a rigorous single and double-mutant epistasis analysis using CRISPR/Cas9-mediated engineering. Doxorubicin resistance conferred by loss of the SMARCB1 subunit of the SWI/SNF complex was caused by transcriptional upregulation of a single gene, encoding the multidrug resistance pump ABCB1. Remarkably, both ABCB1 upregulation and doxorubicin resistance caused by SMARCB1 loss were dependent on the function of SMARCA4, a catalytic subunit of the SWI/SNF complex. We propose that residual SWI/SNF complexes lacking SMARCB1 are vital determinants of drug sensitivity, not just to TOP2A-targeted agents, but to the much broader range of cancer drugs effluxed by ABCB1. Cancer Res; 76(19); 5810-21. ©2016 AACR., Competing Interests: of Potential Conflicts of Interest No potential conflicts of interest were disclosed., (©2016 American Association for Cancer Research.)

Soft x-ray microscopy is a powerful imaging technique that provides sub-micron spatial resolution, as well as chemical specificity using core-level near-edge x-ray absorption fine structure (NEXAFS). Near the carbon K-edge (280-300 eV) biological samples exhibit high contrast, and the detailed spectrum contains information about the local chemical environment of the atoms. Most soft x-ray imaging takes place on dedicated beamlines at synchrotron facilities or at x-ray free electron laser facilities. Tabletop femtosecond laser systems are now able to produce coherent radiation at the carbon K-edge and beyond through the process of high harmonic generation (HHG). The broad bandwidth of HHG is seemingly a limitation to imaging, since x-ray optical elements such as Fresnel zone plates require monochromatic sources. Counter-intuitively, the broad bandwidth of HHG sources can be beneficial as it permits chemically-specific hyperspectral imaging. We apply two separate techniques - Fourier transform spectroscopy, and lensless holographic imaging - to obtain images of an object simultaneously at multiple wavelengths using an octave-spanning high harmonic source with photon energies up to 30 eV. We use an interferometric delay reference to correct for nanometer-scale fluctuations between the two HHG sources.

Aim: To describe the training, supervision and quality of care components of integrated Community Case Management (iCCM) programmes and to draw lessons learned from existing evaluations of those programmes., Methods: Scoping review of reports from 29 selected iCCM programmes purposively provided by stakeholders containing any information relevant to understand quality of care issues., Results: The number of people reached by iCCM programmes varied from the tens of thousands to more than a million. All programmes aimed at improving access of vulnerable populations to health care, focusing on the main childhood illnesses, managed by Community Health Workers (CHW), often selected bycommunities. Training and supervision were widely implemented, in different ways and intensities, and often complemented with tools (eg, guides, job aids), supplies, equipment and incentives. Quality of care was measured using many outcomes (eg, access or appropriate treatment). Overall, there seemed to be positive effects for those strategies that involved policy change, organisational change, standardisation of clinical practices and alignment with other programmes. Positive effects were mostly achieved in large multi-component programmes. Mild or no effects have been described on mortality reduction amongst the few programmes for which data on this outcome was available to us. Promising strategies included teaming-up of CHW, micro-franchising or social franchising. On-site training and supervision of CHW have been shown to improve clinical practices. Effects on caregivers seemed positive, with increases in knowledge, care seeking behaviour, or caregivers' basic disease management. Evidence on iCCM is often of low quality, cannot relate specific interventions or the ways they are implemented with outcomes and lacks standardisation; this limits the capacity to identify promising strategies to improve quality of care., Conclusion: Large, multi-faceted, iCCM programmes, with strong components of training, supervision, which included additional support of equipment and supplies, seemed to improve selected quality of care outcomes. However, current evaluation and reporting practices need to be revised in a new research agenda to address the methodological challenges of iCCM evaluations.

Rationale: Viral myocarditis is a life-threatening illness that may lead to heart failure or cardiac arrhythmias. A major causative agent for viral myocarditis is the B3 strain of coxsackievirus, a positive-sense RNA enterovirus. However, human cardiac tissues are difficult to procure in sufficient enough quantities for studying the mechanisms of cardiac-specific viral infection., Objective: This study examined whether human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) could be used to model the pathogenic processes of coxsackievirus-induced viral myocarditis and to screen antiviral therapeutics for efficacy., Methods and Results: hiPSC-CMs were infected with a luciferase-expressing coxsackievirus B3 strain (CVB3-Luc). Brightfield microscopy, immunofluorescence, and calcium imaging were used to characterize virally infected hiPSC-CMs for alterations in cellular morphology and calcium handling. Viral proliferation in hiPSC-CMs was quantified using bioluminescence imaging. Antiviral compounds including interferonβ1, ribavirin, pyrrolidine dithiocarbamate, and fluoxetine were tested for their capacity to abrogate CVB3-Luc proliferation in hiPSC-CMs in vitro. The ability of these compounds to reduce CVB3-Luc proliferation in hiPSC-CMs was consistent with reported drug effects in previous studies. Mechanistic analyses via gene expression profiling of hiPSC-CMs infected with CVB3-Luc revealed an activation of viral RNA and protein clearance pathways after interferonβ1 treatment., Conclusions: This study demonstrates that hiPSC-CMs express the coxsackievirus and adenovirus receptor, are susceptible to coxsackievirus infection, and can be used to predict antiviral drug efficacy. Our results suggest that the hiPSC-CM/CVB3-Luc assay is a sensitive platform that can screen novel antiviral therapeutics for their effectiveness in a high-throughput fashion., (© 2014 American Heart Association, Inc.)

Energy-phase coupling inside f-2f nonlinear interferometers poses stringent limits on the tolerable pulse-to-pulse energy fluctuations of phase stable laser systems. Here we report a coupling coefficient of -220±20  mrad per 1% energy increase at 800 nm. We also report coefficients from +320 to +820  mrad per 1% energy increase in the 1140-1550 nm (signal) range. Finally, we report coefficients from -180 to +30  mrad per 1% energy variation in the 1636-1940 nm range.

We demonstrate an alternative approach for attosecond polarization gating. A setup composed of four quartz wedges and a quarter-wave plate allows an easy adjustment of the temporal gate-width and of the total dispersion. A numerical simulation of the pulse propagation beyond the carrier-envelope approximation enables a calibration of the setup and provides a flexible choice of the desired temporal polarization. An electron imaging spectrometer is used to measure the electron momentum distribution resulting from the ionization of xenon with our optical gated laser pulses. This allows us to measure the orientation of the polarization plane in the most intense temporal slice of the laser pulse. We compare the experimental results to theory and we numerically show the robustness of the method against non-ideal laser parameters.