Autosomal recessive Adams–Oliver syndrome caused by homozygous mutation in EOGT,encoding an EGF domain-specific O-GlcNAc transferase

Autosomal recessive Adams–Oliver syndrome was diagnosed in three remotely related Bedouin consanguineous families. Genome-wide linkage analysis ruled out association with known Adams–Oliver syndrome genes, identifying a single-homozygosity ∼1.8-Mb novel locus common to affected individuals (LOD score 3.37). Whole-exome sequencing followed by Sanger sequencing identified only a single mutation within this locus, shared by all affected individuals and found in patients from five additional apparently unrelated Bedouin families: a 1-bp deletion mutation in a predicted alternative splice variant of EOGT, leading to a putative truncated protein. RT-PCR demonstrated that the EOGT-predicted alternative splice variant is ubiquitously expressed. EOGT encodes EGF-domain-specific O-linked N-acetylglucosamine transferase, responsible for extracellular O-GlcNAcylation of epidermal growth factor-like domain-containing proteins, and is essential for epithelial cell-matrix interactions. F-actin staining in diseased fibroblasts showed apparently intact cell cytoskeleton and morphology, suggesting the EOGT mutation acts not through perturbation of cytoskeleton but through other mechanisms yet to be elucidated.     

Meeting the unmet needs of clinicians from AI systems showcased for cardiology with deep-learning–based ECG analysis

Despite their great promise, artificial intelligence (AI) systems have yet to become ubiquitous in the daily practice of medicine largely due to several crucial unmet needs of healthcare practitioners. These include lack of explanations in clinically meaningful terms, handling the presence of unknown medical conditions, and transparency regarding the system’s limitations, both in terms of statistical performance as well as recognizing situations for which the system’s predictions are irrelevant. We articulate these unmet clinical needs as machine-learning (ML) problems and systematically address them with cutting-edge ML techniques. We focus on electrocardiogram (ECG) analysis as an example domain in which AI has great potential and tackle two challenging tasks: the detection of a heterogeneous mix of known and unknown arrhythmias from ECG and the identification of underlying cardio-pathology from segments annotated as normal sinus rhythm recorded in patients with an intermittent arrhythmia. We validate our methods by simulating a screening for arrhythmias in a large-scale population while adhering to statistical significance requirements. Specifically, our system 1) visualizes the relative importance of each part of an ECG segment for the final model decision; 2) upholds specified statistical constraints on its out-of-sample performance and provides uncertainty estimation for its predictions; 3) handles inputs containing unknown rhythm types; and 4) handles data from unseen patients while also flagging cases in which the model’s outputs are not usable for a specific patient. This work represents a significant step toward overcoming the limitations currently impeding the integration of AI into clinical practice in cardiology and medicine in general.

For decades, researchers have been applying machine-learning (ML) algorithms to medical tasks with the goal of incorporating insights derived from data into real-world medical applications (1). Medical artificial intelligence (AI) can potentially be used to increase personalization, reduce physician cognitive load, aid decision-making, enable preventive medicine through predictions, automate analysis of medical images and health records, and much more (2–5). Recently, deep learning (DL), a branch of ML focusing on algorithms that can learn directly from raw data (e.g., physiological signals), has risen to prominence. Such algorithms are responsible for many of the current state-of-the-art results reported in the literature for medical AI tasks, with several works claiming to surpass a human doctor’s performance (5) in cases such as automatic diagnosis of breast cancer from mammography scans (6); of melanoma from skin images (7); of pathology from optical coherence tomography scans (8); assessing rehospitalization and in-hospital death risks via analysis of electronic health records (9); arrhythmia detection from electrocardiograms (ECG) analysis (10); and more. However, this slew of research successes has so far not led to widespread adoption of DL-based solutions in the day-to-day practice of medicine and in the healthcare industry in general. Over the past two years, the clinical community has responded to the recent results reported by AI researchers via several top-tier review and opinion papers (1, 2, 11–13), in which leading clinicians addressed some specific shortcomings in recent state-of-the-art medical AI solutions, which prevent them from being incorporated into clinical practice.Here, we consolidate the most frequently mentioned shortcomings voiced by leading physicians and researchers into what we term the “unmet needs” of clinicians from medical AI. We focus specifically on shortcomings that most critically prevent clinical adoption of medical AI solutions according to the recent medical literature. We formulate these unmet needs in a manner actionable by ML researchers. We define each unmet need accurately, demonstrate how it can be met for electrocardiogram (ECG) analysis tasks, and describe our contributions with respect to it. Our work goes beyond the usual search for better model architectures or improved accuracy and focus on the challenges of clinical usefulness. To clarify, although widespread adoption of AI in the clinic is also impeded by broad systemic issues such as regulatory, legal or ethical considerations, lack of standardized data formats, integration with existing infrastructure, and others, this work focuses only on the shortcomings of the AI systems themselves.     

Immunization with HIV-1 gp41 subunit virosomes induces mucosal antibodies protecting nonhuman primates against vaginal SHIV challenges

Human immunodeficiency virus (HIV)-1 is mainly transmitted mucosally during sexual intercourse. We therefore evaluated the protective efficacy of a vaccine active at mucosal sites. Macaca mulatta monkeys were immunized via both the intramuscular and intranasal routes with an HIV-1 vaccine made of gp41-subunit antigens grafted on virosomes, a safe delivery carrier approved in humans with self-adjuvant properties. Six months after 13 vaginal challenges with simian-HIV (SHIV)-SF162P3, four out of five vaccinated animals remained virus-negative, and the fifth was only transiently infected. None of the five animals seroconverted to p27gag-SIV. In contrast, all 6 placebo-vaccinated animals became infected and seroconverted. All protected animals showed gp41-specific vaginal IgAs with HIV-1 transcytosis-blocking properties and vaginal IgGs with neutralizing and/or antibody-dependent cellular-cytotoxicity activities. In contrast, plasma IgGs totally lacked virus-neutralizing activity. The protection observed challenges the paradigm whereby circulating antiviral antibodies are required for protection against HIV-1 infection and may serve in designing a human vaccine against HIV-1-AIDS.     

Lecithin-Based Microemulsions for Targeted Delivery of Ceramide AP into the Stratum Corneum: Formulation, Characterizations, and In Vitro Release and Penetration Studies

Purpose

To improve the solubility and penetration of Ceramide AP (CER [AP]) into the stratum corneum that potentially restores the barrier function of aged and affected skin.

Methods

CER [AP] microemulsions (MEs) were formulated using lecithin, Miglyol® 812 (miglyol) and water-1,2 pentandiol (PeG) mixture as amphiphilic, oily and hydrophilic components, respectively. The nanostructure of the MEs was revealed using electrical conductivity, differential scanning calorimeter (DSC) and electron paramagnetic resonance (EPR) techniques. Photon correlation spectroscopy (PCS) was used to measure the sizes and shape of ME droplets. The release and penetration of the CER into the stratum corneum was investigated in vitro using a multi-layer membrane model.

Results

The MEs exhibited excellent thermodynamic stability (>2 years) and loading capacity (0.5% CER [AP]). The pseudo-ternary phase diagrams of the MEs were obtained and PCS results showed that the droplets are spherical in shape and bigger in size. In vitro investigations showed that the MEs exhibited excellent rate and extent of release and penetration.

Conclusions

Stable lecithin-based CER [AP] MEs that significantly enhance the solubility and penetration of CER [AP] into the stratum corneum were developed. The MEs also have better properties than the previously reported polyglycerol fatty acid surfactant-based CER [AP] MEs.     

Intracortical responses in human and monkey primary auditory cortex support a temporal processing mechanism for encoding of the voice onset time phonetic parameter

This study tests the hypothesis that temporal response patterns in primary auditory cortex are potentially relevant for voice onset time (VOT) encoding in two related experiments. The first experiment investigates whether temporal responses reflecting VOT are modulated in a way that can account for boundary shifts that occur with changes in first formant (F1) frequency, and by extension, consonant place of articulation. Evoked potentials recorded from Heschl's gyrus in a patient undergoing epilepsy surgery evaluation are examined. Representation of VOT varies in a manner that reflects the spectral composition of the syllables and the underlying tonotopic organization. Activity patterns averaged across extended regions of Heschl's gyrus parallel changes in the subject's perceptual boundaries. The second experiment investigates whether the physiological boundary for detecting the sequence of two acoustic elements parallels the psychoacoustic result of approximately 20 ms. Population responses evoked by two-tone complexes with variable tone onset times (TOTs) in primary auditory cortex of the monkey are examined. Onset responses evoked by both the first and second tones are detected at a TOT separation as short as 20 ms. Overall, parallels between perceptual and physiological results support the relevance of a population-based temporal processing mechanism for VOT encoding.     

Oncolytic herpes simplex virus mutants are more efficacious than wild-type adenovirus Type 5 for the treatment of high-risk neuroblastomas in preclinical models

BACKGROUND: High-risk neuroblastoma (Nb) is incurable using current treatment regimens in the majority of patients. Oncolytic virotherapy is a novel approach being tested for several types of adult cancers. OBJECTIVES: To compare the susceptibility of Nb tumor models to oncolytic adenovirus and HSV mutants and delineate the mechanisms of resistance or sensitivity. METHODS: Human Nb cell lines were used to determine susceptibility to adenovirus type 5 wild-type and HSV1 mutant (NV1066) infection, adenovirus receptor expression, support of NV1066 replication, and induction of apoptosis. Human xenograft tumors in immunodeficient mice were evaluated for histological effects and tumor response to intratumoral injection of an oncolytic HSV mutant. RESULTS: All eight Nb cell lines tested in culture were relatively resistant to infection with wild type and attenuated adenoviruses. Cells expressed the cocksackie-adenovirus attachment receptor (CAR) but had low or absent expression of the internalization receptors (alphavbeta3, alphavbeta5 integrins). In contrast, all cells were uniformly sensitive to infection with the attenuated HSV mutant, NV1066. Productive virus replication and induction of apoptosis were observed in HSV-infected cells. CHLA-20 and LAN-5 xenograft tumors injected with a single dose of NV1066 showed a significant antitumor response, and the animals had a prolonged survival post infection in comparison to the PBS-treated control group. HSV injected tumors showed extensive areas of necrosis and morphologic evidence of apoptosis. CONCLUSIONS: Nb tumor models are resistant to adenovirus mediated oncolysis but highly sensitive to HSV mediated oncolysis. Further studies of HSV virotherapy as a novel treatment for Nb are warranted.