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Purpose To describe the initial experience with the Assia Pupil Expander 200 (APX-200, APX Ophthalmology) in eyes that underwent phacoemulsification or intraocular lens repositioning surgery that required mechanical pupil expansion. Setting Department of Ophthalmology, Meir Medical Center, Kfar-Saba, and Ein-Tal Eye Center, Tel Aviv, Israel. Design Retrospective case series. Methods The APX-200 is a single-use device, intended for mechanical expansion of the pupil during intraocular surgery. Two devices are inserted through 2 opposite 19-gauge incisions using designated forceps. The surgical course and early postoperative follow-up was recorded in 50 eyes. Results The study included 50 consecutive eyes, with mean preoperative pupil diameter was 3.7 mm. The APX effectively dilated the pupils in all cases. No complication related to the use of the APX such as hyphema, iridodialysis, or Descemet membrane detachment were noted in this series. A central and round pupil was restored in all eyes at 1-month postoperatively, with 14 eyes (28%) having mild sphincter tears. Pupilloplasty was not required in any of the cases. Conclusions The APX-200 was an effective and safe device for pupil expansion during intraocular surgery.

The recognition of the immune system as a key component of the tumor microenvironment (TME) led to promising therapeutics. Because such therapies benefit only subsets of patients, understanding the activities of immune cells in the TME is required. Eosinophils are an integral part of the TME especially in mucosal tumors. Nonetheless, their role in the TME and the environmental cues that direct their activities are largely unknown. We report that breast cancer lung metastases are characterized by resident and recruited eosinophils. Eosinophil recruitment to the metastatic sites in the lung was regulated by G protein–coupled receptor signaling but independent of CCR3. Functionally, eosinophils promoted lymphocyte-mediated antitumor immunity. Transcriptome and proteomic analyses identified the TME rather than intrinsic differences between eosinophil subsets as a key instructing factor directing antitumorigenic eosinophil activities. Specifically, TNFα/IFNγ–activated eosinophils facilitated CD4+ and CD8+ T-cell infiltration and promoted antitumor immunity. Collectively, we identify a mechanism by which the TME trains eosinophils to adopt antitumorigenic properties, which may lead to the development of eosinophil-targeted therapeutics. Significance: These findings demonstrate antitumor activities of eosinophils in the metastatic tumor microenvironment, suggesting that harnessing eosinophil activity may be a viable clinical strategy in patients with cancer.

ObjectiveTo compare the measured bone conduction threshold at 3 kHz with the calculated threshold in newly diagnosed sudden sensorineural hearing loss.MethodsA retrospective chart review was conducted of pure tone audiograms in confirmed sudden sensorineural hearing loss cases.ResultsOf 157 patients with sudden sensorineural hearing loss, 144 had idiopathic hearing loss, 8 had vestibular schwannoma and 5 had Ménière's disease. The r value for the correlation between the two methods of 3 kHz assessment for all patients was 0.887 (p < 0.001). The mean difference between the measured and calculated 3 kHz thresholds was 0.76 ± 7.96 dB, 0.4 ± 8.08 dB and 1.5 ± 1.8 dB in the sudden sensorineural hearing loss, idiopathic and Ménière's disease groups, respectively. The mean difference between the measured and calculated 3 kHz thresholds was significantly greater in the vestibular schwannoma group (6.86 ± 4.38 dB) than in the idiopathic group (p = 0.013).ConclusionThe 3 kHz frequency may encompass important audiometric information. A discrepancy between the measured and calculated bone conduction 3 kHz thresholds raises suspicion of an underlying vestibular schwannoma as an aetiology for sudden sensorineural hearing loss, and these thresholds should therefore be measured independently and routinely.

Background Preoperative planning of open laryngotracheal surgery is important for achieving good results. This study examines the surgeon’s perception of the importance of using life size 3D printed models of the pediatric airway on surgical decision making. Methods Life-size three-dimensional models of the upper airway were created based on CT images of children scheduled for laryngotracheal-reconstruction and cricotracheal resection with anastomosis. Five pediatric airway surgeons evaluated the three-dimensional models for determining the surgical approach, incision location and length, graft length, and need for single or double-stage surgery of seven children (median age 4.4 years, M:F ratio 4:3). They rated the importance of the three-dimensional model findings compared to the direct laryngoscopy videos and CT findings for each domain on a validated Likert scale of 1–5. Results The mean rating for all domains was 3.6 ± 0.63 (“moderately important” to “very important”), and the median rating was 4 (“very important”). There was full agreement between raters for length of incision and length of graft. The between-rater agreement was 0.608 (“good”) for surgical approach, 0.585 (“moderate”) for incision location, and 0.429 (“moderate”) for need for single- or two-stage surgery. Conclusion Patient-specific three-dimensional printed models of children’s upper airways were scored by pediatric airway surgeons as being moderately to very important for preoperative planning of open laryngotracheal surgery. Large–scale, objective outcome studies are warranted to establish the reliability and efficiency of these models. Graphical abstract

BACKGROUND Respiratory syncytial virus (RSV) bronchiolitis is the most common lower respiratory tract disorder causing hospitalization in infants. Due to decreased hospitalization rates of premature infants following Palivizumab immune prophylaxis, the proportion of infants with chronic diseases not eligible for Palivizumab has increased. AIM To characterize infants hospitalized during 2014-2018 with RSV bronchiolitis, to compare between those with and without chronic conditions, and to identify risk factors for severe disease. METHODS This retrospective study analyzed demographic and clinical data of patients younger than 2 years admitted with bronchiolitis during four consecutive RSV seasons. RESULTS Of 1124 hospitalizations due to RSV bronchiolitis, 244 (22%) were in infants with chronic diseases. Although 20/1124 qualified for RSV prophylaxis, only eight received immune prophylaxis. Compared to otherwise healthy infants, children with chronic diseases had longer hospitalizations, median 4.8 days (interquartile range [IQR]: 3.4-8.3) versus 3.7 days (IQR: 2.7-5.1), p

Classifications of scaphoid fractures associate the angle of the fracture with its stability. To examine this assumption, we measured acute scaphoid fracture angles and inclinations in relation to different scaphoid axes, using fracture displacement as an indicator of instability. We examined the effect of using different axes on the measurements of angles. CT scans of 133 scaphoid fractures were classified according to the location of the fractures. Using a three-dimensional computer model, we computed four scaphoid axes. For each fracture, we then measured the fracture angle and the direction of the fracture inclination in relation to each one of the axes. We found a correlation between displacement and the angles of proximal fractures using one of these axes (the surface principal component analysis axis). No such correlations were found for waist fractures, which were the majority of fractures. There were significant differences between the measurements made with different axes. The findings indicate that the angle of the fracture and the direction of the fracture inclination are minor factors in the displacement of most scaphoid fractures.Level of evidence: III

Objective To describe the effect of sinusitis on Weber test lateralization which normally lateralizes toward the ear of a conductive hearing loss and away from the ear of a sensorineural hearing loss; to investigate whether the presence of an extra-aural condition might affect Weber test results. Study design Descriptive study. Setting Tertiary referral center. Subjects and methods Consecutive adult patients with maxillary and/or frontal sinusitis were included (study group), as well as patients with normal sinus structure and function (control group) were enrolled between February and September 2019. Presence or absence of paranasal disease and middle ear aeration was confirmed by computerized tomography. Subjects with otologic condition were excluded. The physical examinations, tympanograms, and audiograms were unremarkable. The Weber test consisted of 512, 1024, and 2048 Hz tuning forks that were applied on the central incisors and frontal midline, and lateralization patterns were compared with the extent of paranasal pathology. Results There were 44 participants (M:F=26:18), age 19 to 63 years (average 51). The cohort included 39 patients with sinusitis, affecting the frontal and/or maxillary sinus(es), as well as 5 controls without evidence of paranasal disease. There was a match between the extent of paranasal disease and the results of all 3 Weber test frequencies in 35 patients (80%). Omission of the 2048 and 1024 Hz tuning forks from the analysis yielded a match in 40 (91%) and 43 (98%) patients, respectively. No Weber test lateralized to the nondiseased sinus in any subject. Weber test lateralization was observed in 11% of patients, after the sinonasal pathology was successfully addressed. Conclusion Weber test lateralization in the absence of aural pathology may be explained by asymmetry related to paranasal disease and may alert to its presence.

Objective To investigate the success rate of intramuscular (IM) glucagon in preventing need for IV glucose and describe its glycemic effect. Methods Retrospective study of 158 consecutive term neonates with feeding-resistant hypoglycemia treated with glucagon. Results After glucagon, blood glucose (BG) increased in all but 1 infant by 25.9 ± 17.1, 42.1 ± 21.1, and 39.2 ± 28.3 mg/dL (1.4 ± 0.9, 2.3 ± 1.2, 2.2 ± 1.6 mmol/L) at 30, 60 and 120 mins respectively. In multivariable logistic regression, glucagon success was dependent upon gender (increased male risk) (P = 0.021), meeting American Academy of Pediatrics (AAP) criteria for immediate IV glucose (P = 0.004), birth weight, (P = 0.018) and delta glucose concentration at 60 min (P = 0.013). After IM glucagon, 24 out of 49 infants that met AAP criteria for immediate IV glucose (49%) ended up not requiring any additional intervention. Conclusions Glucagon increases BG nearly universally in hypoglycemic infants and allowed reducing the number of infants that needed immediate IV glucose infusion therapy by ≈half.

Objective To validate a smartphone-based Rinne test employing the vibration application of mobile telephones. Study design Prospective controlled clinical study. Setting Tertiary referral medical center. Methods Twenty consecutive patients hospitalized in the otolaryngology department of a tertiary medical center due to unilateral hearing loss (HL study group), and 30 consecutive inpatients on the same ward who had no otological history (controls) were enrolled. Each participant underwent the traditional 512 Hz tuning fork-based Rinne test, as well as a smartphone-based Rinne test by means of a single uncovered smartphone with a vibration application. The test results were compared to those of formal audiometry. Results The overall agreement between the traditional Rinne test and the smartphone-based test was 98%. The Sensitivity was 85% for both tests, specificity was 90% and 93% for smartphone and tuning fork tests, respectively. The smartphone-based Rinne test could correctly discriminate between patients with an air–bone gap ≥ 25 dB at 512 Hz from patients with a lower or no air–bone gap at 512 Hz. The smartphone-based Rinne could not evaluate two patients with a moderately severe/severe sensorineural hearing loss due to their inability to detect the vibrations. Conclusion A smartphone-based Rinne test was validated for the detection of an air–bone gap ≥ 25 dB at 512 Hz in the clinical setting. The validity of patient-operated smartphone-based Rinne test awaits further study. Level of evidence 2B.

BACKGROUND: Susac syndrome (retino-cochleo-cerebral vasculopathy, SuS) is an autoimmune endotheliopathy characterized by the clinical triad of encephalopathy, branch retinal artery occlusions and sensorineural hearing loss. In contrast to data regarding auditory function, data measuring vestibular function is sparse and the cervical vestibular-evoked myogenic potentials (cVEMPs). OBJECTIVE: To determine whether the video head impulse test (vHIT) can serve as a confirmatory assessment of vestibulocochlear dysfunction in cases of suspected SuS. METHODS: Seven patients diagnosed with SuS underwent pure tone audiometry, a word recognition test, cVEMPs and the vHIT. RESULTS: Five patients were diagnosed with definite SuS, and two with probable SuS. Two patients were asymptomatic for hearing loss or tinnitus, and no sensorineural hearing loss was detected by audiograms. Four patients complained of tinnitus, and three patients reported experiencing vertigo. Three patients had abnormal cVEMPs results. All seven patients’ vHIT results were normal, except for patient #2, who was one of the three who complained of vertigo. The calculated gain of her left anterior semicircular canal was 0.5, without saccades. CONCLUSIONS: This is the first study to describe the results of the vHIT and cVEMPs among a group of patients with SuS. The results suggest that the vHIT should not be the only exam used to assess the function of the vestibular system of SuS patients.

The most common site of breast cancer metastasis is the bone, occurring in approximately 70% of patients with advanced disease. Bone metastasis is associated with severe morbidities and high mortality. Therefore, deeper understanding of the mechanisms that enable bone-metastatic relapse are urgently needed. We report the establishment and characterization of a bone-seeking variant of breast cancer cells that spontaneously forms aggressive bone metastases following surgical resection of primary tumor. We characterized the modifications in the immune milieu during early and late stages of metastatic relapse and found that the formation of bone metastases is associated with systemic changes, as well as modifications of the bone microenvironment towards an immune suppressive milieu. Furthermore, we characterized the intrinsic changes in breast cancer cells that facilitate bone-tropism and found that they acquire mesenchymal and osteomimetic features. This model provides a clinically relevant platform to study the functional interactions between breast cancer cells and the bone microenvironment, in an effort to identify novel targets for intervention.

In this study, we combine a theoretical mathematical model with machine learning (ML) to predict tumour sizes in breast cancer. Our study is based on clinical data from 1869 women of various ages w...

OBJECTIVE To review insights gained from a 21-year experience with gentamicin-induced vestibulotoxicity including differences in vestibulotoxicity between single daily dosing (SDD) and multiple daily dosing (MDD) regimens. STUDY DESIGN Retrospective case series. SETTING Tertiary care center. PATIENTS Patients with gentamicin vestibulotoxicity referred to the Hertz Multidisciplinary Neurotology Clinic between January 1993 and September 2014. INTERVENTION None. MAIN OUTCOME MEASURES Spectrum of vestibular dysfunction measured using videonystagmography, vestibular evoked myogenic potentials, video head impulse testing, and magnetic scleral search coil testing. RESULTS Of 53 patients with gentamicin-induced vestibulotoxicity, 24 received SDD and 29 received MDD treatment. The most common indications for treatment were sepsis, endocarditis, and osteomyelitis. Angular acceleration receptor function (semicircular canals) was more commonly affected than linear acceleration receptor function (otolithic organ of the saccule; 100% vs. 62%). A significant proportion of patients (53%) developed vestibulotoxicity in the absence of nephrotoxicity and 40% experienced vestibulotoxicity in a delayed fashion up to 10 days posttreatment cessation (mean 3.9 ± 0.7). Therapeutic monitoring did not necessarily prevent delayed vestibulotoxicity. Nephrotoxicity was less common for SDD compared with MDD (60% vs. 35%, p = 0.01). However, the SDD group experienced vestibulotoxicity at a lower cumulative dose (6.3 vs. 7.0 g, p = 0.04) and shorter duration of therapy (20.7 vs 29.4 d, p = 0.02). CONCLUSIONS Our study further highlights important insights regarding gentamicin-induced vestibulotoxicity. While SDD is associated with decreased risk for nephrotoxicity compared with MDD, it confers a higher risk for vestibulotoxicity.

To report our experience of a sequence of events that resulted in an iatrogenic cholesteatoma originating from the external auditory canal (EAC) years after tympanoplasty that had included a tympanomeatal flap. Data on the presentation and pathogenesis of iatrogenic cholesteatomas arising from misplaced tympanomeatal flaps during tympanoplasty without mastoidectomy were retrieved from the patients’ medical records and analyzed. Five patients were identified with cholesteatomas involving the EAC. They all had recurrent ear infections and varying degrees of conductive hearing loss. Each patient’s past surgical history included one or more tympanoplasties in which an ipsilateral tympanomeatal flap had been raised. None had undergone a mastoidectomy. Two patients presented with small cholesteatomas that had developed over an average of 6.5 years after surgery. Three patients had large cholesteatomas that had developed over an average of 33.7 years after surgery. Clinical presentations and imaging studies suggested a misplaced tympanomeatal flap as the most likely source of cholesteatoma. Tympanomeatal flap misplacement may cause iatrogenic cholesteatoma formation originating from the EAC during tympanoplasty even without mastoidectomy. These cholesteatomas can grow substantially before becoming symptomatic as they extend to and through the mastoid. They may not affect the sound conduction system until late in the course of the disease. Meticulous replacement of tympanomeatal flaps and exercising a high index of suspicion postoperatively can reduce the incidence of this complication.

Purpose To establish whether toric intraocular lens (IOL) calculation on the basis of anterior corneal measurements alone, in corneas with oblique anterior astigmatism, will result in a systematic overcorrection or undercorrection of postoperative refractive astigmatism, and to establish whether adjustment of oblique anterior corneal astigmatism to allow for the likely effect of posterior corneal astigmatism is needed in such eyes. Setting The Queen Elizabeth Hospital, Department of Ophthalmology, Adelaide, South Australia. Design Retrospective case series. Methods Data were collected from consecutive eyes with oblique anterior corneal astigmatism undergoing cataract surgery or refractive lens exchange. Toric IOL calculations were made using unadjusted anterior corneal astigmatism measurements and an astigmatically neutral technique. By comparison of targeted vs achieved astigmatic correction using vector analysis, the astigmatic power prediction error and angle of error were derived. Results In 50 eyes, the mean postoperatively measured refractive astigmatism was 0.42 diopters (D) (SD 0.33 D), the mean targeted refractive astigmatism was 0.15 (SD 0.18), and the vector-derived mean absolute prediction error was 0.23 D (SD 0.21). All 50 eyes (100%) fell at or within ±1.00 D of the target and 45 eyes (90%) at or within ±0.50 D. The geometric mean astigmatism correction index was 0.98, and the mean absolute angle of error was 8.63 degrees (SD 8.55). Conclusions There is no systematic error attributable to posterior corneal astigmatism in toric IOL calculation and no need for adjustment of anteriorly measured corneal keratometric values for toric IOL calculation in eyes with oblique anterior corneal astigmatism. To do so may introduce an error in astigmatic outcome.

Primary resistance to CD19-directed chimeric antigen receptor T-cell therapy (CART19) occurs in 10% to 20% of patients with acute lymphoblastic leukemia (ALL); however, the mechanisms of this resistance remain elusive. Using a genome-wide loss-of-function screen, we identified that impaired death receptor signaling in ALL led to rapidly progressive disease despite CART19 treatment. This was mediated by an inherent resistance to T-cell cytotoxicity that permitted antigen persistence and was subsequently magnified by the induction of CAR T-cell functional impairment. These findings were validated using samples from two CAR T-cell clinical trials in ALL, where we found that reduced expression of death receptor genes was associated with worse overall survival and reduced T-cell fitness. Our findings suggest that inherent dysregulation of death receptor signaling in ALL directly leads to CAR T-cell failure by impairing T-cell cytotoxicity and promoting progressive CAR T-cell dysfunction. Significance: Resistance to CART19 is a significant barrier to efficacy in the treatment of B-cell malignancies. This work demonstrates that impaired death receptor signaling in tumor cells causes failed CART19 cytotoxicity and drives CART19 dysfunction, identifying a novel mechanism of antigen-independent resistance to CAR therapy. See related commentary by Green and Neelapu, p. 492.

In X-linked hypohidrotic ectodermal dysplasia, the most frequent ectodermal dysplasia, an inherited deficiency of the signalling protein ectodysplasin A1 (EDA1) impairs the development of the skin and its appendages, various eccrine glands, and dentition. The severe hypohidrosis common to X-linked hypohidrotic ectodermal dysplasia patients may lead to life-threatening hyperthermia, especially during hot weather or febrile illness. Fc-EDA, an EDA1 replacement protein known to prevent the disease in newborn animals, was tested in 2 clinical trials (human adults and neonates) and additionally administered under compassionate use to 3 infants in utero. The data support the safety of Fc-EDA and efficacy if applied prenatally. Anti-drug antibodies were detected after intravenous administration in adult males and nonpregnant females, but not in pregnant women when Fc-EDA was delivered intra-amniotically. Most importantly, there was no detectable immune response to the investigational drug in neonates treated by intravenous infusions and in infants who had received Fc-EDA in utero. In conclusion, the safety profile of this drug encourages further development of prenatal EDA1 replacement therapy.

Anti-TNF antibodies are effective for treating patients with inflammatory bowel disease (IBD), but many patients fail to respond to anti-TNF therapy, highlighting the importance of TNF-independent disease. We previously demonstrated that acute deletion of two IBD susceptibility genes, A20 (Tnfaip3) and Abin-1 (Tnip1), in intestinal epithelial cells (IECs) sensitizes mice to both TNF-dependent and TNF-independent death. Here we show that TNF-independent IEC death after A20 and Abin-1 deletion is rescued by germ-free derivation or deletion of MyD88, while deletion of Trif provides only partial protection. Combined deletion of Ripk3 and Casp8, which inhibits both apoptotic and necroptotic death, completely protects against death after acute deletion of A20 and Abin-1 in IECs. A20 and Abin-1-deficient IECs are sensitized to TNF-independent, TNFR-1-mediated death in response to lymphotoxin alpha (LTα) homotrimers. Blockade of LTα in vivo reduces weight loss and improves survival when combined with partial deletion of MyD88. These data show that microbial signals, MyD88, and LTα all contribute to TNF-independent intestinal injury.SUMMARYHere we show that germ-free derivation, MyD88 deletion, combined Ripk3 and Casp8 deletion, or anti-LTα, all reduce TNF-independent intestinal injury after A20 and Abin-1 deletion.

Costello syndrome (CS) is a congenital disorder caused by heterozygous activating germline HRAS mutations in the canonical Ras/mitogen-activated protein kinase (Ras/MAPK) pathway. CS is one of the RASopathies, a large group of syndromes caused by mutations within various components of the Ras/MAPK pathway. An important part of the phenotype that greatly impacts quality of life is hypotonia. To gain a better understanding of the mechanisms underlying hypotonia in CS, a mouse model with an activating HrasG12V allele was utilized. We identified a skeletal myopathy that was due, in part, to inhibition of embryonic myogenesis and myofiber formation, resulting in a reduction in myofiber size and number that led to reduced muscle mass and strength. In addition to hyperactivation of the Ras/MAPK and PI3K/AKT pathways, there was a significant reduction in p38 signaling, as well as global transcriptional alterations consistent with the myopathic phenotype. Inhibition of Ras/MAPK pathway signaling using a MEK inhibitor rescued the HrasG12V myopathy phenotype both in vitro and in vivo, demonstrating that increased MAPK signaling is the main cause of the muscle phenotype in CS., Summary: A Costello syndrome (CS) mouse model carrying a heterozygous Hras p.G12V mutation was utilized to investigate Ras pathway dysregulation, revealing that increased MAPK signaling is the main cause of the muscle phenotype in CS.

Breath analysis holds great promise for rapid, noninvasive early cancer detection; however, clinical implementation is impeded by limited signal from nascent tumors and high background expression by non-malignant tissues. To address this issue, we developed a novel breath-based reporter system for early cancer detection using D-limonene, a volatile organic compound (VOC) from citrus fruit that is not produced in humans, in order to minimize background signal and maximize sensitivity and specificity for cancer detection. We metabolically engineered HeLa human cervical cancer cells to express limonene at levels detectable by mass spectrometry by introducing a single plant gene encoding limonene synthase. To improve limonene production and detection sensitivity twofold, we genetically co-expressed a modified form of a key enzyme in the cholesterol biosynthesis pathway. In a HeLa xenograft tumor mouse model, limonene is a sensitive and specific volatile reporter of tumor presence and growth, permitting detection of tumors as small as 5 mm. Moreover, tumor detection in mice improves proportionally with breath sampling time. By continuously collecting VOCs for 10 hours, we improve sensitivity for cancer detection 100-fold over static headspace sampling methods. Whole-body physiologically-based pharmacokinetic (PBPK) modeling and simulation of tumor-derived limonene predicts detection of tumors as small as 7 mm in humans, equivalent to the detection limit of clinical imaging modalities, such as PET, yet far more economical.Significance StatementWe developed a breath-based reporter system using the plant terpene, D-limonene – a volatile secondary metabolite that gives citrus fruit its characteristic scent but is not produced in human tissues – as a biomarker for early cancer detection. Results from this study could pave the way for in vivo gene delivery and tumor-specific expression of exogenous volatile cancer reporters with broad applicability to the early diagnosis of a wide variety of cancers.

Scientific research on neuro-cognitive mechanisms of autism often focuses on circuits that support social functioning. However, autism is a heterogeneous developmental variation in multiple domains, including social communication, but also language, cognition, and sensory-motor control. This suggests that the underlying mechanisms of autism share a domain-general foundation that impacts all of these processes. In this Perspective Review, we propose that autism is not a social deficit that results from an atypical “social brain”. Instead, typical social development relies on learning. In social animals, infants depend on their caregivers for survival, which makes social information vitally salient. The infant must learn to socially interact in order to survive and develop, and the most prominent learning in early life is crafted by social interactions. Therefore, the most prominent outcome of a learning variation is atypical social development. To support the hypothesis that autism results from a variation in learning, we first review evidence from neuroscience and developmental science, demonstrating that typical social development depends on two domain-general processes that determine learning: (a) motivation, guided by allostatic regulation of the internal milieu; and (b) multi-modal associations, determined by the statistical regularities of the external milieu. These two processes are basic ingredients of typical development because they determine allostasis-driven learning of the social environment. We then review evidence showing that allostasis and learning are affected among individuals with autism, both neurally and behaviorally. We conclude by proposing a novel domain-general framework that emphasizes allostasis-driven learning as a key process underlying autism. Guided by allostasis, humans learn to become social, therefore, the atypical social profile seen in autism can reflect a domain-general variation in allostasis-driven learning. This domain-general view raises novel research questions in both basic and clinical research and points to targets for clinical intervention that can lower the age of diagnosis and improve the well-being of individuals with autism.

The accumulation of circulating low-density neutrophils (LDN) has been described in cancer patients and associated with tumor-supportive properties, as opposed to the high-density neutrophils (HDN). Here we aimed to evaluate the clinical significance of circulating LDN in lung cancer patients, and further assessed its diagnostic vs prognostic value. Using mass cytometry (CyTOF), we identified major subpopulations within the circulating LDN/HDN subsets and determined phenotypic modulations of these subsets along tumor progression. LDN were highly enriched in the low-density (LD) fraction of advanced lung cancer patients (median 7.0%; range 0.2%-80%, n = 64), but not in early stage patients (0.7%; 0.05%-6%; n = 35), healthy individuals (0.8%; 0%-3.5%; n = 15), or stable chronic obstructive pulmonary disease (COPD) patients (1.2%; 0.3%-7.4%, n = 13). Elevated LDN (>10%) remarkably related with poorer prognosis in late stage patients. We identified three main neutrophil subsets which proportions are markedly modified in cancer patients, with CD66b+ /CD10low /CXCR4+ /PDL1inter subset almost exclusively found in advanced lung cancer patients. We found substantial variability in subsets between patients, and demonstrated that HDN and LDN retain a degree of inherent spontaneous plasticity. Deep phenotypic characterization of cancer-related circulating neutrophils and their modulation along tumor progression is an important advancement in understanding the role of myeloid cells in lung cancer.

Objectives Describe the histopathology of the temporal bones in MELAS (myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) syndrome. The syndrome results from a known point mutation in mitochondrial DNA. Methods Histopathology analysis of a pair of temporal bones from the oldest surviving MELAS syndrome temporal bone donor. Histopathologic findings were correlated with known premortem clinical data. Results The inner ears showed severe but incomplete atrophy of the stria vascularis for the length of the cochleae. In contrast, the organ of Corti and inner hair cells appeared intact with some loss of outer hair cells. Other than moderate loss at the basal turn, spiral ganglion cells numbers were normal. The vestibular neuroepithelium was mostly normal with the exception of moderate degeneration of the macula sacculi and partial collapse of the saccular wall on the right. The cerebral cortex had infarct-like lesions with adjacent gliosis. Conclusion This is an analysis of the oldest patient with MELAS syndrome to date, an addition to only two previously published patients. It supports the notion that hearing loss is a result of dysfunction of the stria vascularis and not loss of hair cells or neurons. Patterns of vestibular pathology are in agreement to in-vivo measurements. These findings support auditory rehabilitation with cochlear implants and may be relevant to hearing loss due to other mitochondrial mutations. Level of evidence 4.

Introduction: Sudden sensorineural hearing loss (SSNHL) can be the presenting symptom of vestibular schwannoma (VS). Usually, steroidal treatment is given before magnetic resonance imaging (MRI) is performed. Objectives: The aim of this study was to investigate whether there is a different pattern of steroidal treatment response after SSNHL in patients with and without a VS, in order to determine whether rapid hearing improvement can serve as a predictor of the presence of VS. Methods: Charts of patients with SSNHLs were reviewed. Analysis of the presenting symptoms of patients with an SSNHL with and without a coexisting VS and comparison of the response to steroids of the two groups of patients was performed. Results: A total of 420 patients were treated for SSNHLs during the study period. Treatment consisted of intraoral prednisone 1 mg/kg/day. The male-to-female ratio was 1.00:1.17, and the median age at diagnosis was 38 years (range 18–82); neither parameter correlated with the presence of VS. MRI scans demonstrated a VS in 20 patients (4.76%). Audiometric testing 7 days after steroidal treatment initiation revealed that the pure-tone average of 240 patients (60%) without VS improved, and that of the 16 (80%) patients with VS improved by the same audiometric criteria (p = 0.0007). Conclusions:Improvement of hearing within 1 week after steroidal treatment initiation in patients with SSNHLs may suggest the presence of a VS.

BACKGROUND Balance is a complex process involving the coordinated activities of multiple sensory, motor and biomechanical components. Balance function may be disturbed in subjects suffering from hearing loss but the impairment has been attributed to the pathology underlying the hearing loss. AIM The purpose of the study was to investigate the possible interference of simulated conductive hearing loss with the ability to maintain postural balance. METHODS Twenty normal-hearing subjects, 20-30 years old, underwent the computerised dynamic posturography test battery before and after plugging their external ear canals with earplugs, thus simulating a 40dB conductive hearing loss. RESULTS Eighteen females and two males were tested before and after plugging their ear canals. Average CHL was 40 ± 4.9dB. The composite equilibrium score was significantly diminished after plugging the ears with an average sway score of 73.5% (P

The major cause of melanoma mortality is metastasis to distant organs, including lungs and brain. Reciprocal interactions of metastasizing tumor cells with stromal cells in secondary sites play a critical role in all stages of tumorigenesis and metastasis. Changes in the metastatic microenvironment were shown to precede clinically relevant metastases, and may occur prior to the arrival of disseminated tumor cells to the distant organ, thus creating a hospitable "premetastatic niche." Exosomes secreted by tumor cells were demonstrated to play an important role in the preparation of a hospitable metastatic niche. However, the functional role of melanoma-derived exosomes on metastatic niche formation, and the downstream pathways activated in stromal cells at the metastatic niche are largely unresolved. Here we show that extracellular vesicles (EVs) secreted by metastatic melanoma cells that spontaneously metastasize to lungs and to brain, activate proinflammatory signaling in lung fibroblasts and in astrocytes. Interestingly, unlike paracrine signaling by melanoma cells, EVs secreted by metastatic melanoma cells instigated a proinflammatory gene signature in lung fibroblasts but did not activate wound-healing functions, suggesting that tumor cell-secreted EVs activate distinct CAF characteristics and tumor-promoting functions. Moreover, melanoma-secreted EVs also activated proinflammatory signaling in astrocytes, indicating that EV-mediated reprogramming of stromal cells is a general mechanism of modulating the metastatic niche in multiple distant organs. Thus, our study demonstrates that melanoma-derived EVs reprogram tumor-promoting functions in stromal cells in a distinct manner, implicating a central role for tumor-derived EV signaling in promoting the formation of an inflammatory metastatic niche.

ObjectiveArtificial stone dust (ASD) contains high levels of ultrafine particles (UFP Methods68 workers with up to 20 years of ASD exposure at the workplace were recruited from small enterprises throughout the country and compared with 48 non-exposed individuals. Pulmonary function test (PFT), CT, induced sputum (IS) and cytokine analyses were performed by conventional methods. The CT scans were evaluated for features indicative of silicosis in three zones of each lung. UFP were quantitated by the NanoSight LM20 system (NanoSight, Salisbury) using the Nanoparticle Tracking Analysis. Interleukin (IL)-6, IL-8 and tumour necrosis factor alpha (TNF-α) levels were measured by Luminex (R&D Systems).ResultsThirty-four patients had CT scores between 0 and 42, and 29 of them were diagnosed with silicosis. Content of the UFP retrieved from IS supernatants correlated negatively with the PFT results (total lung capacity r=−0.347, p=0.011; forced expiratory volume in 1 s r=−0.299, p=0.046; diffusion lung carbon monoxide in a single breath r=−0.425, p=0.004) and with the CT score (r=0.378, p=0.023), and with the inflammatory cytokines IL-8 (r=0.336, p=0.024), IL-6 (r=0.294, p=0.065) and TNF-α (r=0.409, p=0.007). Raw material of ASD was left to sedimentate in water for 6 UFP/mL in IS samples had a sensitivity of 77% to predict pulmonary disease.ConclusionsThis is the first demonstration of an association between UFP-related decreased PFT results, worsening of CT findings and elevation of inflammatory cytokines, which may be attributed to high-dose inhalation of UFP of ASD at the workplace.

To study optimal head position after intratympanic steroid injections to enhance drug bioavailability.Application of virtual and in vitro models of the intratympanic anatomy.The surgical 3-dimensional printing laboratory of a tertiary academic medical center.A high-resolution computerized tomographic scan of healthy temporal bone and surrounding soft tissue was segmented and reconstructed to a 3-dimensional model. The tympanic membrane was perforated in the posterior-inferior quadrant. Methylene blue-stained 10-mg/mL dexamethasone was administered to the middle ear cleft, after which a 3-dimensional rotation in space was performed to hypothesize the optimal position in relation to gravity. The same stereolithography file used for the actual model was used for a digital virtual liquid flow simulation. The optimal head position was defined as the one with the maximum vertical distance between the round window membrane and the plane of the aditus ad antrum and eustachian tube orifice.The virtual model yielded the following position of the head as optimal: 53º rotation away from the injected ear in the vertical axis (yaw), 27º rotation toward the noninjected ear in the longitudinal axis (roll), and 10º neck extension in the transverse axis (pitch).Virtual imaging determined that 53º and 27º yaw and roll, respectively, away and 10º pitch were the optimal position for drug delivery after intratympanic injection to the middle ear and that an erect head position provided optimal passage of steroids from the middle ear to the inner ear.

Summary: Melanoma is the deadliest skin cancer due to its high rate of metastasis, frequently to the brain. Brain metastases are incurable; therefore, understanding melanoma brain metastasis is of great clinical importance. We used a mouse model of spontaneous melanoma brain metastasis to study the interactions of melanomas with the brain microenvironment. We find that CXCL10 is upregulated in metastasis-associated astrocytes in mice and humans and is functionally important for the chemoattraction of melanoma cells. Moreover, CXCR3, the receptor for CXCL10, is upregulated in brain-tropic melanoma cells. Targeting melanoma expression of CXCR3 by nanoparticle-mediated siRNA delivery or by shRNA transduction inhibits melanoma cell migration and attenuates brain metastasis in vivo. These findings suggest that the instigation of pro-inflammatory signaling in astrocytes is hijacked by brain-metastasizing tumor cells to promote their metastatic capacity and that the CXCL10-CXCR3 axis may be a potential therapeutic target for the prevention of melanoma brain metastasis. : Melanoma brain metastases are incurable. Doron et al. find that astrocyte-secreted CXCL10 is functional in melanoma chemoattraction to the brain. CXCR3, the CXCL10 receptor, is upregulated in brain-seeking melanoma cells. Silencing CXCR3 expression attenuates brain metastasis, suggesting that the CXCL10-CXCR3 axis may be a therapeutic target for melanoma brain metastasis. Keywords: melanoma, brain metastasis, astrocytes, CXCL10, CXCR3, brain tropism

Objectives: To characterize blast-induced cholesteatomas (BIC) in terms of symptoms, presentation, and location within the middle ear cleft (MEC). Design: A search for all English language articles in “MEDLINE” via “PubMed” and “Google Scholar” was conducted. Results: A total of 67 ears with BIC were included. Fifty-eight ears in which the traumatic perforation failed to spontaneously close were excluded, leaving seven case reports (eight patients, nine ears) for statistical analysis. Time between blast exposure to spontaneous tympanic membrane (TM) closure was 16 days to 10 months. Time between blast exposure and cholesteatoma diagnosis was 5 months to 4 years. The cholesteatomas were diagnosed due to symptoms in two ears, as asymptomatic finding on physical examination in one ear and as asymptomatic finding in axial imaging in three ears. Conclusions: BICs can develop behind intact tympanic membrane or along with TM perforation. Based on the current review, when a TM perforation and spontaneous healing were documented, after blast exposure, MRI scan is an integral component of the follow-up. The optimal timing for MRI performance after blast exposure, is yet to be identified.

Introduction Hamartomatous polyposis syndromes (HPS) are rare autosomal-dominant inherited disorders associated with gastrointestinal (GI) tract and other cancers. HPS include Peutz-Jeghers syndrome (PJS), juvenile polyposis syndrome (JPS), and phosphatase and tensin homolog hamartomatous tumor syndromes (PHTS). Diagnosis, management, and outcome prediction of HPS pose a clinical challenge. To characterize genotype, phenotype, histology and outcomes of individuals with HPS. Methods A retrospective cohort study (2004-2017) of consecutive patients that were clinically diagnosed with HPS that visited a specialized GI oncology clinic. Demographic, clinicopathological, and genetic data were obtained from medical records. Results Fifty-two individuals from 34 families were included. Common clinical manifestations were GI bleeding (40% JPS, 23% PJS, and 25% PHTS) and bowel obstruction (46.15% PJS and 11.4% JPS). Twenty patients (38.4%) underwent surgery, 5 of whom required multiple procedures. Higher polyp burden was associated with the need for surgery (P = 0.007). Polyp histology varied widely with 69.2% of patients exhibiting histology different from the syndrome hallmark. GI cancer history was positive in 65%, 40%, and 50% of JPS, PJS, and PHTS families, respectively. Five (9.6%) patients developed cancers (one patient each had small bowel-1, colon-1, and thyroid-1, one patient had both small bowel adenocarcinoma and breast cancer, and one had both breast cancer and liposarcoma). Twenty (38.4%) patients tested positive for STK11, PTEN, SMAD4, BMPR1A, or AKT1 mutations: Sanger sequencing and multi-gene next generation sequencing panels detected mutations in 40.9% and 100% of tested cases, respectively. Discussion HPS patients present versatile phenotypes with overlapping clinical and histological characteristics. Polyp burden is associated with the need for surgery. Next-generation sequencing increases mutation detection.

Background Marfan syndrome (MFS) is a genetic disorder affecting connective tissue. The composition of the dura can change. Consequently, lumbo-sacral dural herniations and cerebrospinal fluid (CSF) leaks are encountered, however, they have yet to been described in the temporal bone. Aims/objectives To define the prevalence of temporal bone meningocele or encephalocele among patients with MFS. Materials and methods Reviewed medical records of all adult patients, diagnosed with MFS, who were treated between 1993 and 2018 at a single academic referral institute. Head targeted CT scans were analyzed. The presence of an anterior or lateral skull base defect was recorded. Results One-hundred and one patients diagnosed with MFS were identified. Twelve of which had suitable CT scans and were enrolled in the study. The median age of patients with defects was 65 years (range 41-71). Five of the twelve patients (41.6%) had tegmen defect. Of the seven defects found, the median size of the defects was 3 mm (range 2-5 mm). All defects were in the temporal bone, none in the anterior skull base. Conclusions and significance The prevalence of radiological evidence of a temporal bone defect among patients with MFS is high. This is a new, important, and potentially life-threatening association with the syndrome.

Background Tophi develop in untreated or uncontrolled gout. This is an update of a Cochrane Review first published in 2014. OBJECTIVES: To assess the benefits and harms of non-surgical and surgical treatments for the management of tophi in gout. Search methods We updated the search of Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and Embase databases to 28 August 2020. Selection criteria We included all published randomised controlled trials (RCTs) or controlled clinical trials examining interventions for tophi in gout in adults. Data collection and analysis We used standard methodological procedures expected by Cochrane. Main results We included one trial in our original review. We added four more trials (1796 participants) in this update. One had three arms; pegloticase infusion every two weeks (biweekly), monthly pegloticase infusion (pegloticase infusion alternating with placebo infusion every two weeks) and placebo. Two studies looked at lesinurad 200 mg or 400 mg in combination with allopurinol. One trial studied lesinurad 200 mg or 400 mg in combination with febuxostat. One trial compared febuxostat 80 mg and 120 mg to allopurinol. Two trials were at unclear risk of performance and detection bias due to lack of information on blinding of participants and personnel. All other trials were at low risk of bias. Moderate-certainty evidence (downgraded for imprecision; one study; 79 participants) showed that biweekly pegloticase resolved tophi in 21/52 participants compared with 2/27 on placebo (risk ratio (RR) 5.45, 95% confidence interval (CI) 1.38 to 21.54; number needed to treat for a benefit (NNTB) 3, 95% CI 2 to 6). Similar proportions of participants receiving biweekly pegloticase (80/85) had an adverse event compared to placebo (41/43) (RR 0.99, 95% CI 0.91 to 1.07). However, more participants on biweekly pegloticase (15/85) withdrew due to an adverse event compared to placebo (1/43) (RR 7.59, 95% CI 1.04 to 55.55; number needed to treat for a harm (NNTH) 7, 95% CI 4 to 16). More participants on monthly pegloticase (11/52) showed complete resolution of tophi compared with placebo (2/27) (RR 2.86, 95% CI 0.68 to 11.97; NNTB 8, 95% CI 4 to 91). Similar numbers of participants on monthly pegloticase (84/84) had an adverse event compared to placebo (41/43) (RR 1.05, 95% CI 0.98 to 1.14). More participants on monthly pegloticase (16/84) withdrew due to adverse events compared to placebo (1/43) (RR 8.19, 95% CI 1.12 to 59.71; NNTH 6, 95% CI 4 to 14). Infusion reaction was the most common reason for withdrawal. Moderate-certainty evidence (2 studies; 103 participants; downgraded for imprecision) showed no clinically significant difference for complete resolution of target tophus in the lesinurad 200 mg plus allopurinol arm (11/53) compared to the placebo plus allopurinol arm (16/50) (RR 0.40, 95% CI 0.04 to 4.57), or in the lesinurad 400 mg plus allopurinol arm (12/48) compared to the placebo plus allopurinol arm (16/50) (RR 0.79, 95% CI 0.42 to 1.49). An extension study examined lesinurad 200 mg or 400 mg in combination with febuxostat, or placebo (low-certainty evidence, downgraded for indirectness and imprecision). Participants on lesinurad in the original study continued (CONT) on the same dose. Lesinurad 400 mg plus febuxostat may be beneficial for tophi resolution; 43/65 in the lesinurad 400 mg CONT arm compared to 38/64 in the lesinurad 200 mg CONT arm had tophi resolution (RR 1.11, 95% CI 0.85 to 1.46). Lesinurad 400 mg plus febuxostat may result in no difference in adverse events; 57/65 in the lesinurad 400 mg CONT arm had an adverse event compared to 50/64 in lesinurad 200 mg CONT arm (RR 1.12, 95% CI 0.96 to 1.32). Lesinurad 400 mg plus febuxostat may result in no difference in withdrawals due to adverse events; 10/65 participants in the lesinurad 400 mg CONT arm withdrew due to an adverse event compared to 10/64 participants in the lesinurad 200 mg CONT arm (RR 0.98, 95% CI 0.44 to 2.20). Lesinurad 400 mg plus febuxostat may result in no difference in mean serum uric acid (sUA), which was 3 mg/dl in the lesinurad 400 mg CONT group compared to 3.9 mg/dl in the lesinurad 200 mg CONT group (mean difference -0.90, 95% CI -1.51 to -0.29). Participants who were not on lesinurad in the original study were randomised (CROSS) to lesinurad 200 mg or 400 mg, both in combination with febuxostat. Low-certainty evidence downgraded for indirectness and imprecision showed that lesinurad 400 mg (CROSS) may result in tophi resolution (17/34) compared to lesinurad 200 mg (CROSS) (14/33) (RR 1.18, 95% CI 0.70 to 1.98). Lesinurad 400 mg in combination with febuxostat may result in no difference in adverse events (33/34 in the lesinurad 400 mg CROSS arm compared to 27/33 in the lesinurad 200 mg (CROSS); RR 1.19, 95% CI 1.00 to 1.41). Lesinurad 400 mg plus febuxostat may result in no difference in withdrawals due to adverse events, 5/34 in the lesinurad 400 mg CROSS arm withdrew compared to 2/33 in the lesinurad 200 mg CROSS arm (RR 2.43, 95% CI 0.51 to 11.64). Lesinurad 400 mg plus febuxostat results in no difference in sUA (4.2 mg/dl in lesinurad 400 mg CROSS) compared to lesinurad 200 mg (3.8 mg/dl in lesinurad 200 mg CROSS), mean difference 0.40 mg/dl, 95% CI -0.75 to 1.55. Authors' conclusions Moderate-certainty evidence showed that pegloticase is probably beneficial for resolution of tophi in gout. Although there was little difference in adverse events when compared to placebo, participants on pegloticase had more withdrawals due to adverse events. Lesinurad 400 mg plus febuxostat may be beneficial for tophi resolution compared with lesinurad 200 mg plus febuxostat; there was no difference in adverse events between these groups. We were unable to determine whether lesinurad plus febuxostat is more effective than placebo. Lesinurad (400 mg or 200 mg) plus allopurinol is probably not beneficial for tophi resolution, and there was no difference in adverse events between these groups. RCTs on interventions for managing tophi in gout are needed, and the lack of trial data is surprising given that allopurinol is a well-established treatment for gout.

Many oncology centers provide integrative oncology (IO) care, many within palliative care settings. The primary study objective was to examine the impact of IO-palliative patient-tailored program on quality of life (QoL) among patients with advanced cancer. In this pragmatic prospective controlled study, patients with advanced cancer undergoing chemotherapy/palliative care were referred by their oncology healthcare providers to an integrative physician (IP) consultation and weekly IO treatments. Patients with high adherence to integrative care (AIC; ≥ 4 IO sessions/6 weeks) were compared with moderate (2–3 sessions) or low AIC patients (regarded as control group). Outcomes were assessed at 6- and 12-week follow-up with Edmonton Symptom Assessment Scale (ESAS) and EORTC QLQ-C30 (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire) tools. Change in QoL scores (ESAS fatigue in particular) was considered a primary study outcome. Of 225 eligible patients, 153 underwent baseline and 6-week optimal assessment (high AIC, 100; moderate AIC, 22; low AIC, 31). High AIC patients reported greater improvement on ESAS scores for fatigue (vs. low–moderate AIC, P

Spectrophotometric techniques provide qualitative but not quantitative data on lung particles. We aimed to quantitate silica content in biopsies of lung-transplanted silicosis patients by applying X-ray fluorescence (XRF) spectrometry. Lung biopsies of 17 lung-transplanted artificial patients were quantitated for silica and other minerals particles by Niton XL3 XRF spectrometry. Occupational and clinical history data were assessed. Lung biopsies of artificial stone-induced silicosis (ASIS) patients contained significantly higher levels of silica compared to those of idiopathic pulmonary fibrosis (IPF) patients (7284.29 ± 4693.75 ppm vs. 898.88 ± 365.66 ppm, p &lt, 0.0001). Silica content correlated negatively with age, body mass index, and pulmonary function test results. A 1128 ppm silica cut-off value yielded 100% sensitivity and 94% specificity for predicting ASIS (AUC = 0.94, p &lt, 0.0001). In conclusion, XRF measurements in lung biopsies can differentiate between silica and mineral particles in ASIS and IPF.

Mortality from breast cancer is almost exclusively a result of tumor metastasis, and lungs are one of the main metastatic sites. Cancer-associated fibroblasts are prominent players in the microenvironment of breast cancer. However, their role in the metastatic niche is largely unknown. In this study, we profiled the transcriptional co-evolution of lung fibroblasts isolated from transgenic mice at defined stage-specific time points of metastases formation. Employing multiple knowledge-based platforms of data analysis provided powerful insights on functional and temporal regulation of the transcriptome of fibroblasts. We demonstrate that fibroblasts in lung metastases are transcriptionally dynamic and plastic, and reveal stage-specific gene signatures that imply functional tasks, including extracellular matrix remodeling, stress response, and shaping the inflammatory microenvironment. Furthermore, we identified Myc as a central regulator of fibroblast rewiring and found that stromal upregulation of Myc transcriptional networks is associated with disease progression in human breast cancer.

Objective To calculate the incidence of sensorineural hearing loss (SNHL; pure or as part of a mixed hearing loss, MHL) among bullous myringitis (BM) patients with a coexisting HL to assess whether steroidal treatment should be initiated even before the findings of a formal audiogram are available. Methods Retrospective medical record review in a tertiary referral center and systematic review of the English literature. Results The medical records of 81 patients with BM were retrieved among whom 50 patients (62%) had actually sustained a HL, although only 39/81 patients reported a HL when asked. Twenty-four patients had a MHL, 18 had a SNHL, and eight had a conductive HL (CHL). The systematic review included 106 ears: 17 had no HL, 53 had a MHL, 20 had a SNHL, and 16 had a CHL. The combined published and current results yielded a SNHL and MHL rates of 38/139 (27%) and 77/139 (55%), respectively of all BM patients with confirmed HL. Conclusion BM is intuitively associated with a CHL resulting from the impeded function of the affected middle ear. Medical history and physical examination are not sufficient to exclude a SNHL in BM patients, and formal audiometry is mandatory for exclusion/confirmation in this setting. Nevertheless, steroidal treatment should not be delayed until the performance of formal audiometry because the actual rate of pure CHL in this setting is very low.Level of Evidence: 2.

In patients with lumbar spinal stenosis, female gender has been associated with higher pain and functional disability. Sarcopenia and multifidus atrophy have also been associated with symptomatic severity.The purpose of this study was to determine if gender differences in sarcopenia and multifidus atrophy are associated with gender disparities in disease symptomatology.Prospectively collected medical records and imaging studies were retrospectively reviewed.We retrospectively reviewed medical records and imaging studies for 63 patients with clinically and radiologically defined lumbar spinal stenosis at L3/4 or L4/5 who underwent minimally invasive decompression.Pain and functional disability were measured using the Oswestry Disability Index (ODI) and visual analogue scores for back pain (VASB) and leg pain (VASL).Multifidus total cross sectional area (tCSA), multifidus functional cross sectional area (fnCSA), multifidus fatty infiltration (FI), psoas tCSA, and psoas relative cross sectional area (rCSA) were evaluated by univariable and multivariable regression to identify gender linked and gender independent predictors of higher ODI, VASB, and VASL.Female gender was significantly associated with lower multifidus fnCSA (p.001), higher multifidus FI (p.001), lower psoas tCSA (p.001), lower psoas rCSA (p = .002), and higher preoperative ODI (p = .008). Lower psoas rCSA (p = .044) and psoas tCSA in the lowest sex specific quartile (p = .034) were significantly associated with higher preoperative VASB and psoas rCSA less than the sex specific median (p = .050) was significantly associated with higher preoperative VASL after controlling for age and gender. Multifidus FI was significantly associated with preoperative ODI after adjusting for age (p = .048) but not after controlling additionally for gender (p = .651).Female patients with lumbar spinal stenosis may develop more severe and functionally significant multifidus atrophy, resulting in a more severe clinical course with higher functional disability. Sarcopenia was significantly associated with higher preoperative back pain and leg pain in both male and female patients with lumbar spinal stenosis.

Patients with progressive neurological disorders such as Parkinson's disease, Huntington's disease, and Amyotrophic Lateral Sclerosis (ALS) suffer both chronic and episodic difficulties with locomotion. Real-time assessment and visualization of sensor data can be valuable to physicians monitoring the progression of these conditions. We present a system that utilizes the attention based bi-directional recurrent neural network (RNN) presented in [2] to evaluate foot pressure sensor data streamed directly from a pair of sensors attached to a patient. The demonstration also supports indirect streaming from recorded sessions, such as those stored in a FHIR [1] enabled electronic medical records repository, for post-hoc evaluation and comparison of a patient's gait over time. The system evaluates and visualizes the streamed gait in a real time web interface to provide a personalized normality rating that highlights the strengths and weaknesses of a patient's gait.

Key Points Question Can widely available measures of atrophy on magnetic resonance imaging increase diagnostic certainty of underlying frontotemporal lobar degeneration (FTLD) and estimate clinical deterioration in the behavioral variant of frontotemporal dementia (bvFTD)? Findings This diagnostic/prognostic study investigated the clinical utility of 5 validated visual atrophy scales (VAS) and the Magnetic Resonance Parkinsonism Index. When combined, VAS showed excellent diagnostic performance for differentiating between bvFTD with high and low confidence of FTLD and for the estimation of longitudinal clinical deterioration, whereas the Magnetic Resonance Parkinsonism Index was increased in bvFTD with underlying 4-repeat tauopathies. Meaning These findings suggest that, in bvFTD, VAS can be used to increase diagnostic certainty of underlying FTLD and estimate longitudinal clinical deterioration., This diagnostic/prognostic study assesses the utility of 6 visual atrophy scales and the Magnetic Resonance Parkinsonism Index in patients with behavioral variant frontotemporal dementia to distinguish those with high vs low confidence of frontotemporal lobar degeneration., Importance The presence of atrophy on magnetic resonance imaging can support the diagnosis of the behavioral variant of frontotemporal dementia (bvFTD), but reproducible measurements are lacking. Objective To assess the diagnostic and prognostic utility of 6 visual atrophy scales (VAS) and the Magnetic Resonance Parkinsonism Index (MRPI). Design, Setting, and Participants In this diagnostic/prognostic study, data from 235 patients with bvFTD and 225 age- and magnetic resonance imaging–matched control individuals from 3 centers were collected from December 1, 1998, to September 30, 2019. One hundred twenty-one participants with bvFTD had high confidence of frontotemporal lobar degeneration (FTLD) (bvFTD-HC), and 19 had low confidence of FTLD (bvFTD-LC). Blinded clinicians applied 6 previously validated VAS, and the MRPI was calculated with a fully automated approach. Cortical thickness and subcortical volumes were also measured for comparison. Data were analyzed from February 1 to June 30, 2020. Main Outcomes and Measures The main outcomes of this study were bvFTD-HC or a neuropathological diagnosis of 4-repeat (4R) tauopathy and the clinical deterioration rate (assessed by longitudinal measurements of Clinical Dementia Rating Sum of Boxes). Measures of cerebral atrophy included VAS scores, the bvFTD atrophy score (sum of VAS scores in orbitofrontal, anterior cingulate, anterior temporal, medial temporal lobe, and frontal insula regions), the MRPI, and other computerized quantifications of cortical and subcortical volumes. The areas under the receiver operating characteristic curve (AUROC) were calculated for the differentiation of participants with bvFTD-HC and bvFTD-LC and controls. Linear mixed models were used to evaluate the ability of atrophy measures to estimate longitudinal clinical deterioration. Results Of the 460 included participants, 296 (64.3%) were men, and the mean (SD) age was 62.6 (11.4) years. The accuracy of the bvFTD atrophy score for the differentiation of bvFTD-HC from controls (AUROC, 0.930; 95% CI, 0.903-0.957) and bvFTD-HC from bvFTD-LC (AUROC, 0.880; 95% CI, 0.787-0.972) was comparable to computerized measures (AUROC, 0.973 [95% CI, 0.954-0.993] and 0.898 [95% CI, 0.834-0.962], respectively). The MRPI was increased in patients with bvFTD and underlying 4R tauopathies compared with other FTLD subtypes (14.1 [2.0] vs 11.2 [2.6] points; P

Author(s): Keret, Ophir; Staffaroni, Adam M; Ringman, John M; Cobigo, Yann; Goh, Sheng-Yang M; Wolf, Amy; Allen, Isabel Elaine; Salloway, Stephen; Chhatwal, Jasmeer; Brickman, Adam M; Reyes-Dumeyer, Dolly; Bateman, Randal J; Benzinger, Tammie LS; Morris, John C; Ances, Beau M; Joseph-Mathurin, Nelly; Perrin, Richard J; Gordon, Brian A; Levin, Johannes; Voglein, Jonathan; Jucker, Mathias; la Fougere, Christian; Martins, Ralph N; Sohrabi, Hamid R; Taddei, Kevin; Villemagne, Victor L; Schofield, Peter R; Brooks, William S; Fulham, Michael; Masters, Colin L; Ghetti, Bernardino; Saykin, Andrew J; Jack, Clifford R; Graff-Radford, Neill R; Weiner, Michael; Cash, David M; Allegri, Ricardo F; Chrem, Patricio; Yi, Su; Miller, Bruce L; Rabinovici, Gil D; Rosen, Howard J; Dominantly Inherited Alzheimer Network | Abstract: IntroductionAsymptomatic and mildly symptomatic dominantly inherited Alzheimer's disease mutation carriers (DIAD-MC) are ideal candidates for preventative treatment trials aimed at delaying or preventing dementia onset. Brain atrophy is an early feature of DIAD-MC and could help predict risk for dementia during trial enrollment.MethodsWe created a dementia risk score by entering standardized gray-matter volumes from 231 DIAD-MC into a logistic regression to classify participants with and without dementia. The score's predictive utility was assessed using Cox models and receiver operating curves on a separate group of 65 DIAD-MC followed longitudinally.ResultsOur risk score separated asymptomatic versus demented DIAD-MC with 96.4% (standard errorn=n0.02) and predicted conversion to dementia at next visit (hazard ration=n1.32, 95% confidence interval [CI: 1.15, 1.49]) and within 2 years (area under the curven=n90.3%, 95% CI [82.3%-98.2%]) and improved prediction beyond established methods based on familial age of onset.DiscussionIndividualized risk scores based on brain atrophy could be useful for establishing enrollment criteria and stratifying DIAD-MC participants for prevention trials.

The AAA+ protein disaggregase, Hsp104, increases fitness under stress by reversing stress-induced protein aggregation. Natural Hsp104 variants might exist with enhanced, selective activity against neurodegenerative disease substrates. However, natural Hsp104 variation remains largely unexplored. Here, we screened a cross-kingdom collection of Hsp104 homologs in yeast proteotoxicity models. Prokaryotic ClpG reduced TDP-43, FUS, and α-synuclein toxicity, whereas prokaryotic ClpB and hyperactive variants were ineffective. We uncovered therapeutic genetic variation among eukaryotic Hsp104 homologs that specifically antagonized TDP-43 condensation and toxicity in yeast and TDP-43 aggregation in human cells. We also uncovered distinct eukaryotic Hsp104 homologs that selectively antagonized α-synuclein condensation and toxicity in yeast and dopaminergic neurodegeneration inC. elegans. Surprisingly, this therapeutic variation did not manifest as enhanced disaggregase activity, but rather as increased passive inhibition of aggregation of specific substrates. By exploring natural tuning of this passive Hsp104 activity, we elucidated enhanced, substrate-specific agents that counter proteotoxicity underlying neurodegeneration.

OBJECTIVE Auricular pseudocyst (AP: intracartilaginous cyst, endochondral AP, cystic chondromalacia, and benign idiopathic cystic chondromalacia) is a benign condition of unknown etiology. This report systematically reviews the published demographics, treatment protocols, and outcomes of AP between the various medical disciplines, and compares the findings to a theretofore-unreported 12-patient cohort. Primary outcome measure was AP complete resolution without recurrence. DATA SOURCE A systematic literature search of "MEDLINE" via "PubMed" and "Google Scholar" was performed in June, 2020. The 12 new patients were enrolled between January 2016 and December 2020. STUDY SELECTION Seventy-four papers met the study inclusion criteria and provided data on sex distribution, surgical approach and outcome, performance of approaches according to medical specialty, and recurrence rates of the reported AP populations. DATA EXTRACTION The appropriateness and study design quality were independently assessed by two reviewers. DATA SYNTHESIS The primary outcome was therapeutic success. A comparative analysis was also performed on the same extracted information that was retrieved from the medical files of the 12 new patients (10 men, 2 women, average age 24 yrs, range, 17-38). CONCLUSIONS AP is not uncommon. In line with the published literature, incision and curettage with excision of the anterior pseudocystic wall (deroofing) resulted in a recurrence rate of less than 17% with good cosmetic outcome among all 12 patients. Aspiration alone was associated with increased recurrence rates. Deroofing emerged as the preferred modality, with good cosmetic outcome and reduced recurrence rate. It was usually performed by otolaryngologists, while dermatologists used more conservative approach more frequently. Incision and drainage combined with compression reduces risk of recurrence.

Hannu Laaksovirta konsortion jäsenenä. The Genomics England Research Consortium, The International ALS/FTD Genomics Consortium (iAFGC), The International FTD Genetics Consortium (IFGC), The International LBD Genomics Consortium (iLBDGC), The NYGC ALS Consortium, The PROSPECT Consortium,17 James B. Rowe,17 Luisa Benussi,18 Giuliano Binetti,18,19 Roberta Ghidoni,18 Edwin Jabbari,20,21 Coralie Viollet,22 Jonathan D. Glass,23 Andrew B. Singleton,24 Vincenzo Silani,25,26 Owen A. Ross,27 Mina Ryten,8,28,29 Ali Torkamani,30 Toshiko Tanaka,31 Luigi Ferrucci,31 Susan M. Resnick,32 We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40?64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington?s disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered. We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40?64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington?s disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered.

Background: Respiratory syncytial virus (RSV) bronchiolitis is the most common lower respiratory tract disorder causing hospitalization in infants. Palivizumab has shifted the profile of the hospitalized population away from premature infants and towards those with chronic morbidities who are not eligible for prophylaxis. Aim: To characterize RSV bronchiolitis hospitalizations in infants with chronic diseases, compared to otherwise healthy infants. Methods: A four consecutive RSV season retrospective analysis of patients younger than two years admitted with bronchiolitis. Background demographic and clinical data, including vital sign measurements, laboratory tests, and pediatric intensive care unit (PICU) admissions during hospitalization, were analyzed. Results: Of 1124 hospitalizations due to RSV bronchiolitis, 244 (22%) were in infants with chronic diseases. Although 20/1124 qualified for RSV prophylaxis, only 8 had been vaccinated. Compared to otherwise healthy infants, children with chronic diseases had longer hospitalizations, median 4 days (IQR 4-7) vs 3 days (2-5), p

We here propose a new method of combining a mathematical model that describes a chemotherapy treatment for breast cancer with a machine-learning (ML) algorithm to increase performance in predicting tumor size using a five-step procedure. The first step involves modeling the chemotherapy treatment protocol using an analytical function. In the second step, the ML algorithm is trained to predict the tumor size based on clinico-pathological data and data obtained from magnetic resonance imaging results at different time points of treatment. In the third step, the model is solved according to adjustments made at the individual patient level based on the initial tumor size. In the fourth step, the important variables are extracted from the mathematical model solutions and inserted as added features. In the final step, we applied various ML algorithms on the merged data. Performance comparison among algorithms showed that the root mean square error of the linear regression decreased with the addition of the mathematical results, and the accuracy of prediction as well as the F1-scores increased with the addition of the mathematical model to the neural network. We established these results for four different cohorts of women at different ages with breast cancer who received chemotherapy treatment.

INTRODUCTION: Total proctocolectomy with ileal pouch anal anastomosis (IPAA) is performed in patients with adenomatous polyposis syndromes (APSs). Data regarding pouch outcomes in APS are scarce. The purposes of this study were to determine the prevalence of pouch-related symptoms in patients with APS and to identify the contributing factors. METHODS: This is a prospective cohort study. Demographic, surgical, and clinical data were collected. Endoscopy was performed, and biopsies from the terminal ileum, pouch, and cuff were obtained in all patients and reviewed by a dedicated pathologist. RESULTS: Fifty-one patients with APS after IPAA were followed. Twenty patients (39.2%) had pouch-related symptoms. Single-stage IPAA had better outcomes than 2-stage IPAA: fewer daily bowel movements (42.9% vs 13.8% with ≤5 daily bowel movement, P = 0.02), more solid consistency (52.4% vs 6.9%, P < 0.001), and less abdominal pain (19% vs 48.3%, P = 0.034). Younger age at IPAA (

The initial events of viral infection at the primary mucosal entry site following horizontal person-to-person transmission have remained ill defined. Our limited understanding is further underscored by the absence of animal models in the case of human-restricted viruses, such as human cytomegalovirus (HCMV), a leading cause of congenital infection and a major pathogen in immunocompromised individuals. Here, we established a novel ex vivo model of HCMV infection in native human nasal turbinate tissues. Nasal turbinate tissue viability and physiological functionality were preserved for at least 7 days in culture. We found that nasal mucosal tissues were susceptible to HCMV infection, with predominant infection of ciliated respiratory epithelial cells. A limited viral spread was demonstrated, involving mainly stromal and vascular endothelial cells within the tissue. Importantly, functional antiviral and proleukocyte chemotactic signaling pathways were significantly upregulated in the nasal mucosa in response to infection. Conversely, HCMV downregulated the expression of nasal epithelial cell-related genes. We further revealed tissue-specific innate immune response patterns to HCMV, comparing infected human nasal mucosal and placental tissues, representing the viral entry and the maternal-to-fetal transmission sites, respectively. Taken together, our studies provide insights into the earliest stages of HCMV infection. Studies in this model could help evaluate new interventions against the horizontal transmission of HCMV. IMPORTANCE HCMV is a ubiquitous human pathogen causing neurodevelopmental disabilities in congenitally infected children and severe disease in immunocompromised patients. The earliest stages of HCMV infection in the human host have remained elusive in the absence of a model for the viral entry site. Here, we describe the establishment and use of a novel nasal turbinate organ culture to study the initial steps of viral infection and the consequent innate immune responses within the natural complexity and the full cellular repertoire of human nasal mucosal tissues. This model can be applied to examine new antiviral interventions against the horizontal transmission of HCMV and potentially that of other viruses.

Therapeutic antibodies targeting the CTLA4/PD-1 pathways have revolutionized cancer immunotherapy by eliciting durable remission in patients with cancer. However, relapse following early response, attributable to primary and adaptive resistance, is frequently observed. Additional immunomodulatory pathways are being studied in patients with primary or acquired resistance to CTLA4 or PD-1 blockade. The DNAM1 axis is a potent coregulator of innate and adaptive immunity whose other components include the immunoglobulin receptors TIGIT, PVRIG, and CD96, and their nectin and nectin-like ligands. We review the basic biology and therapeutic relevance of this family, which has begun to show promise in cancer clinical trials.Significance:Recent studies have outlined the immuno-oncologic ascendancy of coinhibitory receptors in the DNAM1 axis such as TIGIT and PVRIG and, to a lesser extent, CD96. Biological elucidation backed by ongoing clinical trials of single-agent therapy directed against TIGIT or PVRIG is beginning to provide the rationale for testing combination regimens of DNAM1 axis blockers in conjunction with anti–PD-1/PD-L1 agents.

Recent epidemiological studies suggest late life onset epilepsy of unknown etiology (LOEU) is a risk factor for future dementia. These studies rely on inclusion and exclusion of multiple diagnostic codes rather than structured data and neuroimaging findings, and thus challenging to interpret clinically. We assessed the cumulative incidence of dementia in patients with LOEU diagnosed through admission data and neuroimaging over a 10-year follow-up and compared baseline characteristics that distinguish group level incident dementia. We screened our hospital records for patients aged 55–69 with new epilepsy, admitted between 2000 and 2008, and excluded patients diagnosed with epilepsy from an underlying cause on medical records or neuroimaging. We used retrospective hospital data to follow patients for incident dementia or mortality at 10 years and compared baseline (demographics, depression or anxiety, vascular risk factors, results of electroencephalogram (EEG) studies, antidepressant use and type of ant seizure medication) and follow up (seizure recurrence, incident cerebrovascular disease) characteristics for patients with and without incident dementia. Fifty-four LOEU cases were screened, age at first seizure was 61 ± 5. The 10-year cumulative incidence of dementia was 22.20% (95% Confidence Interval 22.08–23.10%) and time to dementia diagnosis was 5.4 ± 3.9 years. Patients with incident dementia were more likely to be women (83% vs 38%, p = 0.002), have interictal epileptic form discharges (IED) on baseline EEG (70% vs 29%, p = 0.011) and depression or anxiety (50% vs 18%, p = 0.026). No differences were found in other baseline or follow up characteristics. Our results support recent findings of dementia incidence in LOEU. Prospective studies on LOEU should evaluate phenotypic determinants of individuals with late life epilepsy and the rate of progression to dementia.