Data-driven learning of structure augments quantitative prediction of biological responses.

Multi-factor screenings are commonly used in diverse applications in medicine and bioengineering, including optimizing combination drug treatments and microbiome engineering. Despite the advances in high-throughput technologies, large-scale experiments typically remain prohibitively expensive. Here we introduce a machine learning platform, structure-augmented regression (SAR), that exploits the intrinsic structure of each biological system to learn a high-accuracy model with minimal data requirement. Under different environmental perturbations, each biological system exhibits a unique, structured phenotypic response. This structure can be learned based on limited data and once learned, can constrain subsequent quantitative predictions. We demonstrate that SAR requires significantly fewer data comparing to other existing machine-learning methods to achieve a high prediction accuracy, first on simulated data, then on experimental data of various systems and input dimensions. We then show how a learned structure can guide effective design of new experiments. Our approach has implications for predictive control of biological systems and an integration of machine learning prediction and experimental design.

Autoencoder neural networks enable low dimensional structure analyses of microbial growth dynamics.

The ability to effectively represent microbiome dynamics is a crucial challenge in their quantitative analysis and engineering. By using autoencoder neural networks, we show that microbial growth dynamics can be compressed into low-dimensional representations and reconstructed with high fidelity. These low-dimensional embeddings are just as effective, if not better, than raw data for tasks such as identifying bacterial strains, predicting traits like antibiotic resistance, and predicting community dynamics. Additionally, we demonstrate that essential dynamical information of these systems can be captured using far fewer variables than traditional mechanistic models. Our work suggests that machine learning can enable the creation of concise representations of high-dimensional microbiome dynamics to facilitate data analysis and gain new biological insights.

Bulevirtide and emerging drugs for the treatment of hepatitis D.

INTRODUCTION: Hepatitis delta virus (HDV) causes acute and chronic liver disease that requires the co-infection of the Hepatitis B virus and can lead to significant morbidity and mortality. Bulevirtide is a recently introduced entry inhibitor drug that acts on the sodium taurocholate cotransporting peptide, thereby preventing viral entry to target cells in chronic HDV infection. The mainstay of chronic HDV therapy prior to bulevirtide was interferon alpha, which has an undesirable side effect profile. AREAS COVERED: We review bulevirtide data from recent clinical trials in Europe and the United States. Challenges to development and implementation of bulevirtide are discussed. Additionally, we review ongoing trials of emerging drugs for HDV, such as pegylated interferon lambda and lonafarnib. EXPERT OPINION: Bulevirtide represents a major shift in treatment for chronic HDV, for which there is significant unmet need. Trials that compared bulevirtide in combination with interferon alpha vs interferon alpha monotherapy demonstrated significant increase in virologic response. Overall, treatment with different doses of bulevirtide were comparable. Bulevirtide was generally well tolerated, and no serious adverse events occurred. Understanding the true prevalence of HDV, as well as continued studies of emerging drugs will prove valuable to the larger goal of eradication of Hepatitis D.

Content Validity of a High-Fidelity Surgical Middle Ear Simulator: A Randomized Prospective International Multicenter Trial.

OBJECTIVE: After demonstration of face validity of a surgical middle ear simulator (SMS) previously, we assessed the content validity of the simulator with otolaryngology residents. STUDY DESIGN: Multicenter randomized prospective international study. SETTING: Four academic institutions. METHODS: Novice participants were randomized into control, low-fidelity (LF), and high-fidelity (HF) groups. Control and LF produced 2 recordings from 2 attempts, and HF produced 4 recordings from 10 attempts, with trials 1, 4, 7, and 10 used for scoring. Three blinded experts graded videos of the simulated stapedectomy operation using an objective skills assessment test format consisting of global and stapedotomy-specific scales. RESULTS: A total of 152 recordings from 61 participants were included. Baseline characteristics did not differ significantly between groups. Depending on the step of the operation, inter-rater reliability ranged from 24 to 90%. For LF and HF, years of training was significantly associated with improved scores in certain objective skills assessment test subparts. HF outperformed the control group on stapes and global scores ( p < 0.05). The HF group demonstrated improvement in global score over trials, but plateaued after four trials. Scores varied greatly for participants from different institutions in certain operative steps, such as transecting incudostapedial joints, likely due to differences in instrumentation and time elapsed since manufacture. CONCLUSION: Practice with SMS led to better performance in both global and stapes-specific scores. Further studies are needed to examine construct validity and to create otology-appropriate grading systems. Variables like instrumentation and decline in flexibility of the simulator after 12 months greatly affect performance on the simulator.

Oxytocin promotes prefrontal population activity via the PVN-PFC pathway to regulate pain.

Neurons in the prefrontal cortex (PFC) can provide top-down regulation of sensory-affective experiences such as pain. Bottom-up modulation of sensory coding in the PFC, however, remains poorly understood. Here, we examined how oxytocin (OT) signaling from the hypothalamus regulates nociceptive coding in the PFC. In vivo time-lapse endoscopic calcium imaging in freely behaving rats showed that OT selectively enhanced population activity in the prelimbic PFC in response to nociceptive inputs. This population response resulted from the reduction of evoked GABAergic inhibition and manifested as elevated functional connectivity involving pain-responsive neurons. Direct inputs from OT-releasing neurons in the paraventricular nucleus (PVN) of the hypothalamus are crucial to maintaining this prefrontal nociceptive response. Activation of the prelimbic PFC by OT or direct optogenetic stimulation of oxytocinergic PVN projections reduced acute and chronic pain. These results suggest that oxytocinergic signaling in the PVN-PFC circuit constitutes a key mechanism to regulate cortical sensory processing.

Closed-loop stimulation using a multiregion brain-machine interface has analgesic effects in rodents.

Effective treatments for chronic pain remain limited. Conceptually, a closed-loop neural interface combining sensory signal detection with therapeutic delivery could produce timely and effective pain relief. Such systems are challenging to develop because of difficulties in accurate pain detection and ultrafast analgesic delivery. Pain has sensory and affective components, encoded in large part by neural activities in the primary somatosensory cortex (S1) and anterior cingulate cortex (ACC), respectively. Meanwhile, studies show that stimulation of the prefrontal cortex (PFC) produces descending pain control. Here, we designed and tested a brain-machine interface (BMI) combining an automated pain detection arm, based on simultaneously recorded local field potential (LFP) signals from the S1 and ACC, with a treatment arm, based on optogenetic activation or electrical deep brain stimulation (DBS) of the PFC in freely behaving rats. Our multiregion neural interface accurately detected and treated acute evoked pain and chronic pain. This neural interface is activated rapidly, and its efficacy remained stable over time. Given the clinical feasibility of LFP recordings and DBS, our findings suggest that BMI is a promising approach for pain treatment.

Frequency Dependent Electrical Stimulation of PFC and ACC for Acute Pain Treatment in Rats.

As pain consists of both sensory and affective components, its management by pharmaceutical agents remains difficult. Alternative forms of neuromodulation, such as electrical stimulation, have been studied in recent years as potential pain treatment options. Although electrical stimulation of the brain has shown promise, more research into stimulation frequency and targets is required to support its clinical applications. Here, we studied the effect that stimulation frequency has on pain modulation in the prefrontal cortex (PFC) and the anterior cingulate cortex (ACC) in acute pain models in rats. We found that low-frequency stimulation in the prelimbic region of the PFC (PL-PFC) provides reduction of sensory and affective pain components. Meanwhile, high-frequency stimulation of the ACC, a region involved in processing pain affect, reduces pain aversive behaviors. Our results demonstrate that frequency-dependent neuromodulation of the PFC or ACC has the potential for pain modulation.

Characterizing T2 iso- and hypo-intense renal masses on MRI: Can templated algorithms improve accuracy?

PURPOSE: To assess if a templated algorithm can improve the diagnostic performance of MRI for characterization of T2 isointense and hypointense renal masses. METHODS: In this retrospective study, 60 renal masses with histopathologic diagnoses that were also confirmed as T2 iso- or hypointense on MRI were identified (mean ± standard deviation, range: 3.9 ± 2.5, 1.0-13.7 cm). Two semi-quantitative diagnostic algorithms were created based on MRI features of renal masses reported in the literature. Three body-MRI trained radiologists provided clinical diagnoses based on their experience and separately provided semiquantitative data for each components of the two algorithms. The algorithms were applied separately by a radiology trainee without additional interpretive input. Logistic regression was used to compare the accuracy of the three methods in distinguishing malignant versus benign lesions and in diagnosing the exact histopathology. Inter-reader agreement for each method was calculated using Fleiss' kappa statistics. RESULTS: The accuracy of the two algorithms and clinical experience were similar (70%, 69%, and 64%, respectively, p = 0.22-0.32), with fair to moderate inter-reader agreement (Fleiss's kappa: r = 0.375, r = 0.308, r = 0.375, respectively, all p < 0.0001). The accuracy of the two algorithms and clinical experience in diagnosing specific histopathology were also no different from each other (34%, 29%, and 32%, respectively, p = 0.49-0.74), with fair to moderate inter-reader agreement (Fleiss's kappa: r = 0.20, r = 0.28, r = 0.375, respectively, all p < 0.0001). CONCLUSION: Semi-quantitative templated algorithms based on MRI features of renal masses did not improve the ability to diagnose T2 iso- and hypointense renal masses when compared to unassisted interpretation by body MR trained subspecialists.

Ultrasound-guided microwave ablation in the treatment of inguinal neuralgia.

Chronic groin pain can be due to a variety of causes and is the most common complication of inguinal hernia repair surgery. The etiology of pain after inguinal hernia repair surgery is often multifactorial though injury to or scarring around the nerves in the operative region, namely the ilioinguinal nerve, genital branch of the genitofemoral nerve, and the iliohypogastric nerve, is thought to be a key factor in causing chronic post-operative hernia pain or inguinal neuralgia. Inguinal neuralgia is difficult to treat and requires a multidisciplinary approach. Radiologists play a key role in the management of these patients by providing accurate image-guided injections to alleviate patient symptoms and identify the pain generator. Recently, ultrasound-guided microwave ablation has emerged as a safe technique, capable of providing durable pain relief in the majority of patients with this difficult to treat condition. The objectives of this paper are to review the complex nerve anatomy of the groin, discuss diagnostic ultrasound-guided nerve injection and patient selection for nerve ablation, and illustrate the microwave ablation technique used at our institution.

MRI characterization of early CNS transport kinetics post intrathecal gadolinium injection: Trends of subarachnoid and parenchymal distribution in healthy volunteers.

PURPOSE: To quantify CSF transport kinetics and brain glymphatic distribution using MRI following intrathecal injection of gadolinium contrast in healthy adults. SUBJECTS AND METHODS: Eight completely healthy volunteer subjects underwent intrathecal injection of gadolinium via image guided lumbar puncture and serial MRI's at six subsequent time points up to 11 h post-injection. Rate of enhancement and deposition were calculated for various regions and lobes of the brain. RESULTS: Normalized cranial data revealed that gadolinium in the intracranial CSF spaces peaked within 1-3 h and started to decrease at 7 h. In some regions of the brain parenchyma, such as the cerebral cortex and white matter, enhancement was increasing after 11 h. Differential rates of uptake between the parietal and frontal (p = 0.0003), cingulate (p = 0.002) and temporal (p = 0.018) lobes were shown as well as a several fold change between various cortical regions. Lastly, a linear regression comparing laterality between 35 cortical regions yielded (R2 = 0.90, p < 0.001) with a slope of 1.01 showing symmetry in uptake. CONCLUSIONS: Gadolinium enhancement after lumbar intrathecal injection demonstrated differential CSF flow and brain parenchymal penetration, which illustrated the distributory function of the glymphatic system.

Transforming the Imaging Experience While Decreasing Sedation Rates.

OBJECTIVE: To evaluate the effect of the MRI-am-a-Hero program on sedation utilization for outpatient pediatric MRI studies. METHODS: The MRI-am-a-Hero program, which utilizes multimedia educational material and popular comic book characters to educate and support pediatric patients during MRI scan, was implemented at the radiology facility of a single tertiary care, academic medical center. The effect of the MRI-am-a-Hero program on sedation utilization for pediatric MRI was retrospectively evaluated using multivariate regressions yielding odds ratio of sedation before and after program implementation. The institutional review board approved the study with HIPAA compliancy. Effectiveness of the program was evaluated while controlling for age, neurological MRI examination, number of examinations in the case, and use of intravenous contrast. Further analysis was performed in subgroups categorized by age, neurological MRI versus nonneurological MRI, and the use of contrast. RESULTS: The percent of MRI cases with sedation decreased from 22.9% to 17.3% after the MRI-am-a-Hero program was implemented. When controlling for other variables, including patient age, neurological MRI, number of examinations in a case, and use of intravenous contrast, the odds of a study being performed with sedation after program implementation are 40% less than the odds before program implementation (odds ratio [OR] 0.60, P < .001). The effect of the program was greatest for patients aged 4 to 7 (OR 0.56, P < .001), followed by patients aged 8 to 11 (OR 0.64, P = .019). It was not statistically significant for patients aged 12 to 15 (OR 0.97, P = .919). CONCLUSION: MRI-am-a-Hero is a generalizable and inexpensive program for reducing sedation utilization for outpatient pediatric MRI studies, especially for patients aged 4 to 11.

Juvenile granulosa cell tumor associated with Maffucci syndrome in pregnancy: A case report.

Juvenile granulosa cell tumor (JGCT) is an extremely rare ovarian tumor that has been associated with Maffucci syndrome. It both secretes hormone and has been postulated to grow in response to hormone. We present a case of a 33-year-old G1P0 asymptomatic woman with a history of Maffucci syndrome found to have a left adnexal mass on routine ultrasonography at 13 weeks gestation. This case demonstrates the sonographic and magnetic resonance imaging (MRI) features of JGCT, as well as the natural progression of the tumor during pregnancy. A follow-up ultrasound 3 weeks after initial diagnosis demonstrated marked growth in size and vascularity of the tumor, prompting unilateral salpingo-oophorectomy. Histopathological findings confirmed the diagnosis of JGCT.

Prostate cancer detection using residual networks.

PURPOSE: To automatically identify regions where prostate cancer is suspected on multi-parametric magnetic resonance images (mp-MRI). METHODS: A residual network was implemented based on segmentations from an expert radiologist on T2-weighted, apparent diffusion coefficient map, and high b-value diffusion-weighted images. Mp-MRIs from 346 patients were used in this study. RESULTS: The residual network achieved a hit or miss accuracy of 93% for lesion detection, with an average Jaccard score of 71% that compared the agreement between network and radiologist segmentations. CONCLUSION: This paper demonstrated the ability for residual networks to learn features for prostate lesion segmentation.

Cough-induced costal cartilage fracture.

We present two cases of atraumatic costal cartilage fracture secondary to violent coughing. Although costal cartilage fractures due to trauma and bony rib fractures due to violent coughing have been described, to our knowledge there have been no prior reported cases of cough-induced costal cartilage fracture. It is important for radiologists to consider costal cartilage fractures, which are often more subtle than osseous injuries, in patients with chest pain, and understand that they may not always be preceded by direct trauma. Identifying this injury is clinically important and will prevent patients from undergoing unnecessary examinations to rule out a cardiac cause of chest pain or a pulmonary embolism.

A Randomized Single-Blinded Trial of Ibuprofen- versus Opioid-Based Primary Analgesic Therapy in Outpatient Otolaryngology Surgery.

OBJECTIVE: To compare the efficacy of pain control and opioid consumption between patients who receive opioid as primary analgesic therapy and those who receive ibuprofen. STUDY DESIGN: Prospective randomized trial. SETTING: Tertiary care academic hospital. SUBJECT AND METHODS: Adult patients undergoing outpatient otolaryngology surgery were assigned to take hydrocodone/acetaminophen or ibuprofen for postoperative analgesia. Patient-recorded pain scores and analgesic consumption were analyzed. RESULTS: Out of 185 recruits, 108 (58%) completed responses. Fifty-six patients (52%) received opioid medication for primary analgesic treatment versus 52 (48%) who received ibuprofen. There was no difference in reported pain scores between the treatment groups. Those who received ibuprofen as primary therapy reported a significantly lower consumption of opioid medication at 2.04 tablets/pills (95% CI, 0.9-3.1) versus 4.86 (3.6-6.1; P = .001). Based on multivariate analysis, male sex and older age exhibited lower reported pain scores, while older age and use of ibuprofen as primary therapy exhibited lower opioid requirements. CONCLUSION: For postoperative pain management in outpatient otolaryngology procedures, ibuprofen as primary therapy can provide equally effective pain control as compared with hydrocodone/acetaminophen while decreasing overall opioid requirement. Prescription pill counts are further described to help guide physician practices in the era of an opioid epidemic.

Clinical Perspective on Passive Audio Vocal Measurement in the Evaluation of Selective Mutism.

Selective Mutism (SM) is an anxiety disorder often diagnosed in early childhood and characterized by persistent failure to speak in certain social situations but not others. Diagnosing SM and monitoring treatment response can be quite complex, due in part to changing definitions of and scarcity of research about the disorder. Subjective self-reports and parent/teacher interviews can complicate SM diagnosis and therapy, given that similar speech problems of etiologically heterogeneous origin can be attributed to SM. The present perspective discusses the potential for passive audio capture to help overcome psychiatry's current lack of objective and quantifiable assessments in the context of SM. We present supportive evidence from two pilot studies indicating the feasibility of using a digital wearable device to quantify child vocalization features affected by SM. We also highlight comparative analyses of passive audio capture and its potential to enhance diagnostic characterizations for SM, as well as possible limitations of such technologies.

Highly Selective Transmission Success of Dengue Virus Type 1 Lineages in a Dynamic Virus Population: An Evolutionary and Fitness Perspective.

Arbovirus transmission is modulated by host, vector, virus, and environmental factors. Even though viral fitness plays a salient role in host and vector adaptation, the transmission success of individual strains in a heterogeneous population may be stochastic. Our large-scale molecular epidemiological analyses of a dengue virus type 1 population revealed that only a subset of strains (16.7%; n = 6) were able to sustain transmission, despite the population being widely dispersed, dynamic, and heterogeneous. The overall dominance was variable even among the "established" lineages, albeit sharing comparable evolutionary characteristics and replication profiles. These findings indicated that virological parameters alone were unlikely to have a profound effect on the survival of viral lineages, suggesting an important role for non-viral factors in the transmission success of lineages. Our observations, therefore, emphasize the strategic importance of a holistic understanding of vector, human host, and viral factors in the control of vector-borne diseases.

Assessment of the impact of shared brain imaging data on the scientific literature.

Data sharing is increasingly recommended as a means of accelerating science by facilitating collaboration, transparency, and reproducibility. While few oppose data sharing philosophically, a range of barriers deter most researchers from implementing it in practice. To justify the significant effort required for sharing data, funding agencies, institutions, and investigators need clear evidence of benefit. Here, using the International Neuroimaging Data-sharing Initiative, we present a case study that provides direct evidence of the impact of open sharing on brain imaging data use and resulting peer-reviewed publications. We demonstrate that openly shared data can increase the scale of scientific studies conducted by data contributors, and can recruit scientists from a broader range of disciplines. These findings dispel the myth that scientific findings using shared data cannot be published in high-impact journals, suggest the transformative power of data sharing for accelerating science, and underscore the need for implementing data sharing universally.