Gamma-band entrainment abnormalities in schizophrenia: Modality-specific or cortex-wide impairment?

A growing body of literature suggests that cognitive impairment in people with schizophrenia (PSZ) results from disrupted cortical excitatory/inhibitory (E-I) balance, which may be linked to gamma entrainment and can be measured noninvasively using electroencephalography (EEG). However, it is not yet known the degree to which these entrainment abnormalities covary within subjects across sensory modalities. Furthermore, the degree to which cross-modal gamma entrainment reflects variation in biological processes associated with cognitive performance remains unclear. We used EEG to measure entrainment to repetitive auditory and visual stimulation at beta (20 Hz) and gamma (30 and 40 Hz) frequencies in PSZ (n = 78) and healthy control subjects (HCS; n = 80). Three indices were measured for each frequency and modality: event-related spectral perturbation (ERSP), intertrial coherence (ITC), and phase-lag angle (PLA). Cognition and symptom severity were also assessed. We found little evidence that gamma entrainment covaried across sensory modalities. PSZ exhibited a modest correlation between modalities at 40 Hz for ERSP and ITC measures (r = 0.23-0.24); however, no other significant correlations between modalities emerged for either HCS or PSZ. Both univariate and multivariate analyses revealed that (a) the pattern of entrainment abnormalities in PSZ differed across modalities, and (b) modality rather than frequency band was the main source of variance. Finally, we observed a significant association between cognition and gamma entrainment in the auditory domain only in HCS. Gamma-band EEG entrainment does not reflect a unitary transcortical mechanism but is instead modality specific. To the extent that entrainment reflects the integrity of cortical E-I balance, the deficits observed in PSZ appear to be modality specific and not consistently associated with cognitive impairment. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Access to Pediatric Eye Care Following Vision Screening.

PURPOSE: To quantify the accessibility of eye care providers from photoscreening centers within the vision screening region in relation to population density and median household income. METHODS: Driving times between vision screening locations and eye care centers were mapped and analyzed using OpenStreetMap software (Open Street Map Foundation). U.S. Census Bureau data of population density and median household income were linked with screening centers using ArcGIS Online (Esri) to determine correlations with driving times. RESULTS: A total of 290 driving times for 145 photo-screening centers, 147 optometrists, and 7 pediatric ophthalmologists were calculated and mapped. Median driving times from a photoscreening center to the nearest optometrist and ophthalmologist were 4.74 and 25.10 minutes, respectively, with 90% of the screening centers residing within 12.46 and 67.19 minutes of the nearest optometrist and ophthalmologist, respectively. Driving times to optometrists are far less than times to pediatric ophthalmologists due to the greater number of optometrists. Decreasing driving times with increasing population and median household income indicate the concentration of optometrists and pediatric ophthalmologists within urbanized areas. CONCLUSIONS: Most photoscreening centers reside within 5 and 70 minutes of the nearest optometrist and pediatric ophthalmologist, respectively. Driving times indicate the region's greater accessibility to optometrists than to pediatric ophthalmologists. Eye care centers tend to be localized within urbanized areas with higher population densities and higher median household incomes. [J Pediatr Ophthalmol Strabismus. 2022;59(6):369-374.].

Ultrafast transient absorption spectroelectrochemistry: femtosecond to nanosecond excited-state relaxation dynamics of the individual components of an anthraquinone redox couple.

Many photoactivated processes involve a change in oxidation state during the reaction pathway and formation of highly reactive photoactivated species. Isolating these reactive species and studying their early-stage femtosecond to nanosecond (fs-ns) photodynamics can be challenging. Here we introduce a combined ultrafast transient absorption-spectroelectrochemistry (TA-SEC) approach using freestanding boron doped diamond (BDD) mesh electrodes, which also extends the time domain of conventional spectrochemical measurements. The BDD electrodes offer a wide solvent window, low background currents, and a tuneable mesh size which minimises light scattering from the electrode itself. Importantly, reactive intermediates are generated electrochemically, via oxidation/reduction of the starting stable species, enabling their dynamic interrogation using ultrafast TA-SEC, through which the early stages of the photoinduced relaxation mechanisms are elucidated. As a model system, we investigate the ultrafast spectroscopy of both anthraquinone-2-sulfonate (AQS) and its less stable counterpart, anthrahydroquinone-2-sulfonate (AH2QS). This is achieved by generating AH2QS in situ from AQS via electrochemical means, whilst simultaneously probing the associated early-stage photoinduced dynamical processes. Using this approach we unravel the relaxation mechanisms occurring in the first 2.5 ns, following absorption of ultraviolet radiation; for AQS as an extension to previous studies, and for the first time for AH2QS. AQS relaxation occurs via formation of triplet states, with some of these states interacting with the buffered solution to form a transient species within approximately 600 ps. In contrast, all AH2QS undergoes excited-state single proton transfer with the buffered solution, resulting in formation of ground state AHQS- within approximately 150 ps.

The minority or the misunderstood? A young man's journey with anorexia nervosa.

INTRODUCTION: Despite findings that 1 in 4 eating disorder sufferers are male (Beat, 2017), they continue to be known as "female" disorders, an association which delays diagnosis in males and prevents them from seeking the help that they need to recover. AIM: The current paper aimed to challenge this misconception by enabling and supporting Ben, a young male diagnosed with Anorexia Nervosa aged 16, to share his experience of seeking and receiving treatment for the disorder. METHOD: It achieved this by exploring how his disorder developed, his experience of a child and adolescent inpatient service and the events leading up to this, and his life post-discharge, all in collaboration with Ben himself and using his own words. DISCUSSION: The paper concludes with some implications for future practice, including that eating disorders should not be skewed towards any gender, treatment programmes need to ensure full inclusivity of males, and more gender sensitive information is required to raise awareness of this population and thus reduce the stigma and isolation they experience at present. It is hoped that these, along with the rest of the paper, will be accessible to and utilized by both professionals and non-professionals alike. ACCESSIBLE SUMMARY: ● Around one quarter of people diagnosed with an eating disorder are male, yet they continue to be known as "female" disorders. Because of this, young males are often missed by the system and as a result, receive treatment later than they should. They are currently underrepresented in services. ● This paper challenges the association above by supporting a young man who suffered with a type of eating disorder known as Anorexia Nervosa to share his journey from his personal perspective. It provides great insight into what it is like to be a male with an eating disorder, including how it felt to be the only male in an inpatient facility surrounded by females with the same disorder. ● The paper also provides important information for professionals working in the area. For example, eating disorders, including Anorexia Nervosa, should not be associated with one specific gender, and treatment programmes for young people with eating disorders should ensure they are appropriate for both females and males. As a society, we need to challenge the stigma which exists for males in admitting when they are struggling and asking for help, and we need to do everything we can to ensure that young men are picked up earlier in the system, in order to give them the best chance of recovery. ● It is hoped that Ben's story and the recommendations from it can go on to help other males who might be struggling.

Disturbance, dispersal and marine assemblage structure: A case study from the nearshore Southern Ocean.

Disturbance is a key factor in most natural environments and, globally, disturbance regimes are changing, driven by increased anthropogenic influences, including climate change. There is, however, still a lack of understanding about how disturbance interacts with species dispersal capacity to shape marine assemblage structure. We examined the impact of ice scour disturbance history (2009-2016) on the nearshore seafloor in a highly disturbed region of the Western Antarctic Peninsula by contrasting the response of two groups with different dispersal capacities: one consisting of high-dispersal species (mobile with pelagic larvae) and one of low-dispersal species (sessile with benthic larvae). Piecewise Structural Equation Models were constructed to test multi-factorial predictions of the underlying mechanisms, based on hypothesised responses to disturbance for the two groups. At least two or three disturbance factors, acting at different spatial scales, drove assemblage composition. A comparison between both high- and low-dispersal models demonstrated that these mechanisms are dispersal dependent. Disturbance should not be treated as a single metric, but should incorporate remote and direct disturbance events with consideration of taxa-dispersal and disturbance legacy. These modelling approaches can provide insights into how disturbance shapes assemblages in other disturbance regimes, such as fire-prone forests and trawl fisheries.

Definition and Validation of a Novel Metric of Erythropoiesis-Stimulating Agent Response in Hemodialysis Patients.

Erythropoiesis-stimulating agents (eg, epoetin alfa) are the primary treatment for anemia in patients with end-stage renal disease. Hemoglobin variability in and out of a narrow target range is common and associated with higher morbidity and mortality risk. More robust erythropoiesis-stimulating agent response metrics are needed to define optimal dosing and their association with clinical outcomes. In this cross-sectional, single-center, retrospective study, 49 patients with end-stage renal disease on hemodialysis were followed over 12 months. To quantify hemoglobin deviations outside the target range (10-12 g/dL), the area under the curve of hemoglobin versus time over a 12-month period (AUC-HGB) was calculated using the trapezoidal rule. Patients were categorized into 4 responder groups based on AUC-HGB quartiles. Comparative analyses of demographic and clinical characteristics between responder groups were performed. Correlations between AUC-HGB, erythropoietin resistance index, and time within therapeutic range were calculated. There were no significant differences in laboratory and dialysis parameters between responder groups except hemoglobin concentration and epoetin alfa dose. There was a negative correlation between AUC-HGB and time within therapeutic range (r = -.92; P < .001) and hemoglobin concentration (r = -.85; P < .01), indicating internal validity of the metric. There was a positive correlation between AUC-HGB and erythropoietin resistance index (r = .70; P < .001) indicating external validity. The poor response group received a higher median epoetin alfa dose (160 U/kg/week) compared to the excellent response group (68.8 U/kg/week; P < .001) with a similar number of dose changes between the groups. AUC-HGB is a valid marker of epoetin alfa response and should be considered in future analyses of larger populations.

Preoperative High-Resolution Manometry Criteria are Associated with Dysphagia After Nissen Fundoplication.

BACKGROUND: Dysphagia after Nissen fundoplication is challenging for patients. High-resolution manometry (HRM) has rarely been studied preoperatively to determine whether manometry values correlated with postoperative dysphagia after fundoplication. We aim to determine whether HRM criteria could predict dysphagia after Nissen fundoplication. METHODS: A retrospective review of single-institution laparoscopic Nissen fundoplications (LNF) from 2013 to 2015 was completed. Dysphagia was graded using a standard scale. Four groups were: those with new postoperative dysphagia (ND), never had dysphagia (NV), continued dysphagia (CD), and resolved dysphagia (RD). Manometry criteria included distal contractile integral (DCI), contraction front velocity (CFV), distal latency (DL), integrated relaxation pressure (IRP), percent peristalsis (PP), and distal esophageal contraction amplitude (DECA). Statistical bootstrapping was used to power sample sizes for ANOVA analysis. RESULTS: Ninety-four patients were included in the original cohort. Statistical bootstrapping sample size was 2992 patients. Among patients who did not have dysphagia prior to LNF, no HRM metric was associated with developing new dysphagia. Among those with dysphagia prior to LNF, a higher DCI, CFV, DL, PP, and DECA were associated with resolution of dysphagia. The RD group was 2.77 times more likely to have a DCI ≥ 1000 mmHg-s-cm compared with the CD group. CONCLUSIONS: HRM criteria could not predict the development of postoperative dysphagia. However, in those with preoperative dysphagia and strong manometry criteria, dysphagia is more likely to resolve after Nissen fundoplication. Meanwhile, in those with preoperative dysphagia and weak manometry, dysphagia may persist and these patients may be better served with a partial fundoplication.

A Statewide Strategy for Expanding Graduate Medical Education by Establishing New Teaching Hospitals and Residency Programs.

The graduate medical education (GME) system in the United States is in need of reform to ensure that the physician workforce being trained is able to meet the current and future health care needs of the population. However, GME funding to existing teaching hospitals and programs relies heavily on support from Medicare, which was capped in 1997. Thus, new, innovative models to expand GME are needed. To address physician shortages, especially in primary care and general surgery and in rural areas, the state of Georgia implemented a statewide initiative. They increased medical school enrollment by 600 students from 2000 to 2010 and committed to establishing new GME programs at new teaching hospitals to train 400 additional residents by 2018. As increasing the capacity of GME programs likely increases the number of physicians practicing in the state, these efforts aim to encourage trainees to practice in Georgia. Although new teaching hospitals, like these, are eligible for new Medicare funding, this approach to expanding GME also incorporates state funding to cover the start-up costs associated with establishing a new teaching hospital and GME program.In this article, the authors provide background on the current state of GME funding in the United States and on the physician workforce and medical education system in Georgia. They then outline the steps taken to expand GME by establishing new teaching hospitals and programs. They conclude by sharing outcomes to date as well as challenges faced and lessons learned so that others can follow this novel model.

Analysis of the genetic phylogeny of multifocal prostate cancer identifies multiple independent clonal expansions in neoplastic and morphologically normal prostate tissue.

Genome-wide DNA sequencing was used to decrypt the phylogeny of multiple samples from distinct areas of cancer and morphologically normal tissue taken from the prostates of three men. Mutations were present at high levels in morphologically normal tissue distant from the cancer, reflecting clonal expansions, and the underlying mutational processes at work in morphologically normal tissue were also at work in cancer. Our observations demonstrate the existence of ongoing abnormal mutational processes, consistent with field effects, underlying carcinogenesis. This mechanism gives rise to extensive branching evolution and cancer clone mixing, as exemplified by the coexistence of multiple cancer lineages harboring distinct ERG fusions within a single cancer nodule. Subsets of mutations were shared either by morphologically normal and malignant tissues or between different ERG lineages, indicating earlier or separate clonal cell expansions. Our observations inform on the origin of multifocal disease and have implications for prostate cancer therapy in individual cases.

20 years later: laparoscopic fundoplication durability.

BACKGROUND: Laparoscopic surgery for gastrointestinal reflux disease was introduced in 1991. Early safety, efficacy, and 5-10-year durability have been amply documented, but long-term patient outcomes have been criticized. This study presents 20-year outcomes after laparoscopic fundoplication (LF) in a consecutive patient cohort. METHODS: Patients who underwent primary LF procedures for gastroesophageal reflux disease (GERD) were identified from a prospectively collected IRB-approved database (1991-1995). A phone symptom questionnaire was administered using a 5-point validated GERD scoring system (heartburn, regurgitation, and dysphagia). Symptomatic success was defined by a lack of surgical re-intervention and a low symptom score. RESULTS: One-hundred and ninety-three patients were identified during the time period. Fifty-one patients completed the survey (100 lost to follow-up, 40 deceased, 2 declined to answer). Respondents had a median follow-up of 19.7 years. Overall, 38/51 (74.5%) of patients reported complete control of heartburn and regurgitation. Ten patients reported only occasional heartburn. Eight of fifty-one (16%) reported daily dysphagia, and 22/51 (43%) of respondents were using proton pump inhibitors at the time of telephone interview. Nine of fifty-one (18%) underwent revision of the original surgery which did not negatively impact the satisfaction rating, with 8/9 (89%) of these patients reporting the highest satisfaction rating. Overall, 46/51 (90%) were satisfied with their choice of surgery. CONCLUSION: Long-term results from the early experience with LF are excellent with 94% of patients reporting only occasional or fewer reflux symptoms at 20-year follow-up. However, 18% required surgical revision surgery to maintain their results. There is a relatively high rate of daily dysphagia but 90% of patients are happy to have had LF.

Genome sequencing of normal cells reveals developmental lineages and mutational processes.

The somatic mutations present in the genome of a cell accumulate over the lifetime of a multicellular organism. These mutations can provide insights into the developmental lineage tree, the number of divisions that each cell has undergone and the mutational processes that have been operative. Here we describe whole genomes of clonal lines derived from multiple tissues of healthy mice. Using somatic base substitutions, we reconstructed the early cell divisions of each animal, demonstrating the contributions of embryonic cells to adult tissues. Differences were observed between tissues in the numbers and types of mutations accumulated by each cell, which likely reflect differences in the number of cell divisions they have undergone and varying contributions of different mutational processes. If somatic mutation rates are similar to those in mice, the results indicate that precise insights into development and mutagenesis of normal human cells will be possible.

Constitutional and somatic rearrangement of chromosome 21 in acute lymphoblastic leukaemia.

Changes in gene dosage are a major driver of cancer, known to be caused by a finite, but increasingly well annotated, repertoire of mutational mechanisms. This can potentially generate correlated copy-number alterations across hundreds of linked genes, as exemplified by the 2% of childhood acute lymphoblastic leukaemia (ALL) with recurrent amplification of megabase regions of chromosome 21 (iAMP21). We used genomic, cytogenetic and transcriptional analysis, coupled with novel bioinformatic approaches, to reconstruct the evolution of iAMP21 ALL. Here we show that individuals born with the rare constitutional Robertsonian translocation between chromosomes 15 and 21, rob(15;21)(q10;q10)c, have approximately 2,700-fold increased risk of developing iAMP21 ALL compared to the general population. In such cases, amplification is initiated by a chromothripsis event involving both sister chromatids of the Robertsonian chromosome, a novel mechanism for cancer predisposition. In sporadic iAMP21, breakage-fusion-bridge cycles are typically the initiating event, often followed by chromothripsis. In both sporadic and rob(15;21)c-associated iAMP21, the final stages frequently involve duplications of the entire abnormal chromosome. The end-product is a derivative of chromosome 21 or the rob(15;21)c chromosome with gene dosage optimized for leukaemic potential, showing constrained copy-number levels over multiple linked genes. Thus, dicentric chromosomes may be an important precipitant of chromothripsis, as we show rob(15;21)c to be constitutionally dicentric and breakage-fusion-bridge cycles generate dicentric chromosomes somatically. Furthermore, our data illustrate that several cancer-specific mutational processes, applied sequentially, can coordinate to fashion copy-number profiles over large genomic scales, incrementally refining the fitness benefits of aggregated gene dosage changes.

RAG-mediated recombination is the predominant driver of oncogenic rearrangement in ETV6-RUNX1 acute lymphoblastic leukemia.

The ETV6-RUNX1 fusion gene, found in 25% of childhood acute lymphoblastic leukemia (ALL) cases, is acquired in utero but requires additional somatic mutations for overt leukemia. We used exome and low-coverage whole-genome sequencing to characterize secondary events associated with leukemic transformation. RAG-mediated deletions emerge as the dominant mutational process, characterized by recombination signal sequence motifs near breakpoints, incorporation of non-templated sequence at junctions, ∼30-fold enrichment at promoters and enhancers of genes actively transcribed in B cell development and an unexpectedly high ratio of recurrent to non-recurrent structural variants. Single-cell tracking shows that this mechanism is active throughout leukemic evolution, with evidence of localized clustering and reiterated deletions. Integration of data on point mutations and rearrangements identifies ATF7IP and MGA as two new tumor-suppressor genes in ALL. Thus, a remarkably parsimonious mutational process transforms ETV6-RUNX1-positive lymphoblasts, targeting the promoters, enhancers and first exons of genes that normally regulate B cell differentiation.

Distinct H3F3A and H3F3B driver mutations define chondroblastoma and giant cell tumor of bone.

It is recognized that some mutated cancer genes contribute to the development of many cancer types, whereas others are cancer type specific. For genes that are mutated in multiple cancer classes, mutations are usually similar in the different affected cancer types. Here, however, we report exquisite tumor type specificity for different histone H3.3 driver alterations. In 73 of 77 cases of chondroblastoma (95%), we found p.Lys36Met alterations predominantly encoded in H3F3B, which is one of two genes for histone H3.3. In contrast, in 92% (49/53) of giant cell tumors of bone, we found histone H3.3 alterations exclusively in H3F3A, leading to p.Gly34Trp or, in one case, p.Gly34Leu alterations. The mutations were restricted to the stromal cell population and were not detected in osteoclasts or their precursors. In the context of previously reported H3F3A mutations encoding p.Lys27Met and p.Gly34Arg or p.Gly34Val alterations in childhood brain tumors, a remarkable picture of tumor type specificity for histone H3.3 driver alterations emerges, indicating that histone H3.3 residues, mutations and genes have distinct functions.

Correlation of altitude and compartment pressures in porcine hind limbs.

Recent wartime contingencies have demanded frequent aeromedical evacuation of polytrauma patients, all with risk factors for the development of compartment syndrome. This study investigated the effect of altitude on the pressure in uninjured myofascial compartments of 10 pigs as part of a program with the ultimate goal of determining the behavior of an injured extremity in a changing altitude environment. The data showed a trend toward a small increase in pressure with increase in altitude--an average maximal delta of 2.7 mm Hg from the opening pressure. A small increase in compartment pressure, such as seen in this study, in a normal, uninjured compartment would likely go clinically unnoticed. However, aeromedical evacuation missions fly patients with fractures that can affect the physiology of compartments. Potentially, even a small change in pressure can lead to a compartment syndrome. Further study involving a fracture model will be required to further elucidate this clinical question.

Classification and imaging of proximal humerus fractures.

The decision to operate and the selection of the appropriate surgical modality for proximal humerus fractures are largely based on the fracture pattern. Understanding the particular fracture pattern in each case is complicated. Most well-accepted classification systems were developed based on radiographs complemented by intraoperative findings. Three-dimensional reconstructions based on CT currently available in most institutions allow a much better understanding of complex fractures. Modern thinking about fracture classification probably should be revisited in the light of improved imaging techniques.

Rapid neural adaptation to sound level statistics.

Auditory neurons must represent accurately a wide range of sound levels using firing rates that vary over a far narrower range of levels. Recently, we demonstrated that this "dynamic range problem" is lessened by neural adaptation, whereby neurons adjust their input-output functions for sound level according to the prevailing distribution of levels. These adjustments in input-output functions increase the accuracy with which levels around those occurring most commonly are coded by the neural population. Here, we examine how quickly this adaptation occurs. We recorded from single neurons in the auditory midbrain during a stimulus that switched repeatedly between two distributions of sound levels differing in mean level. The high-resolution analysis afforded by this stimulus showed that a prominent component of the adaptation occurs rapidly, with an average time constant across neurons of 160 ms after an increase in mean level, much faster than our previous experiments were able to assess. This time course appears to be independent of both the timescale over which sound levels varied and that over which sound level distributions varied, but is related to neural characteristic frequency. We find that adaptation to an increase in mean level occurs more rapidly than to a decrease. Finally, we observe an additional, slow adaptation in some neurons, which occurs over a timescale of tens of seconds. Our findings provide constraints in the search for mechanisms underlying adaptation to sound level. They also have functional implications for the role of adaptation in the representation of natural sounds.

Pneumothorax in pediatric patients after urological laparoscopic surgery: experience with 4 patients.

PURPOSE: Pneumothorax is a rare but known complication of adult urological laparoscopic surgery and has been described occasionally in children as well. The etiologies for pneumothorax during such procedures are discussed as is the management of pneumothorax in this setting. We investigate the occurrence of pneumothorax during laparoscopic pediatric urological procedures in children. MATERIALS AND METHODS: Pneumothorax developed during urological laparoscopic procedures in 4 pediatric patients (3 females, 1 male). Patient age ranged from 8 months to 11 years (mean 5.4 years). Laparoscopic surgical procedures performed included right upper pole partial nephrectomy, left upper pole partial nephroureterectomy, removal of left multicystic dysplastic kidney and bilateral Cohen reimplantation of ureters. Procedures were performed with a maximum insufflation pressure of 15 mm Hg. During the same time period as these four cases, a total of 285 laparoscopic urologic procedures were performed at our institution. RESULTS: Pneumothorax was suspected due to decreased oxygen saturations, subcutaneous emphysema, increased respiratory effort and decreased chest lung sounds unilaterally. Pneumothorax was confirmed with chest x-rays. Operative time ranged from 171 to 249 minutes (mean 199.5). Duration of surgery before pneumothorax developed ranged from 75 to 239 minutes (mean 176, median 168). Conservative management of pneumothorax was used in 3 patients and a pigtail chest tube was used in 1. In all cases the estimated blood loss was minimal. CONCLUSIONS: Urologists performing laparoscopy in children should be aware of the possibility of a pneumothorax developing during the procedure. Evaluation for decrease in O2 saturation should include a search for pneumothorax in these patients. Close observation generally suffices for management.