Integrated information theory (IIT) 4.0: Formulating the properties of phenomenal existence in physical terms.

This paper presents Integrated Information Theory (IIT) 4.0. IIT aims to account for the properties of experience in physical (operational) terms. It identifies the essential properties of experience (axioms), infers the necessary and sufficient properties that its substrate must satisfy (postulates), and expresses them in mathematical terms. In principle, the postulates can be applied to any system of units in a state to determine whether it is conscious, to what degree, and in what way. IIT offers a parsimonious explanation of empirical evidence, makes testable predictions concerning both the presence and the quality of experience, and permits inferences and extrapolations. IIT 4.0 incorporates several developments of the past ten years, including a more accurate formulation of the axioms as postulates and mathematical expressions, the introduction of a unique measure of intrinsic information that is consistent with the postulates, and an explicit assessment of causal relations. By fully unfolding a system's irreducible cause-effect power, the distinctions and relations specified by a substrate can account for the quality of experience.

A versatile X-ray phase retarder for lock-in XMCD measurements.

X-ray magnetic circular dichroism (XMCD) is a technique commonly used to probe magnetic properties of materials with element and orbital selectivity, which requires the use of circularly polarized (CP) X-rays. It is possible to accomplish XMCD experiments with fixed CP and alternating the magnetic field orientation, but most reliable data are obtained when alternating the magnetization orientation and the polarization between right and left helicities. A versatile strategy has been developed to perform XMCD experiments using a hard X-ray quarter-wave plate, at both polychromatic dispersive and conventional monochromatic optics, in combination with synchronous data acquisition. The switching frequency waveform is fed into a lock-in amplifier to detect and amplify the XMCD signal. The results on a reference sample demonstrate an improvement in data quality and acquisition time. The instrumentation successfully generated 98% of CP X-rays switching the beam helicity at 13 Hz, with the possibility of faster helicity switching once it is installed at the new Brazilian fourth-generation source, SIRIUS.

Barriers to Care of Sexual Health Concerns in Men Following Traumatic Pelvic Fractures.

INTRODUCTION: Traumatic pelvic fractures are associated with sexual dysfunction in men. However, how men are counseled and access care for sexual health following injury remains unknown. AIM: The purpose of this study was to identify factors associated with accessing and obtaining care for sexual health concerns following traumatic pelvic fracture in men. METHODS: Men treated for traumatic pelvic fractures at a level 1 trauma center were invited to participate in an online cross-sectional survey. The survey addressed multiple demographic and sexual function domains, as well as the postinjury sexual health care experience. De novo sexual dysfunction following injury was ascertained and reasons for not seeking care examined. Inverse probability weighting was utilized to adjust for nonresponse. Multivariable logistic regression was performed to identify factors associated with discussion of sexual health with providers after injury. OUTCOMES: The primary outcome was discussion of sexual health with health care providers after injury. Secondary outcomes included prevalence of self-reported sexual dysfunction, classification of sexual dysfunction experienced, and perceived barriers to accessing or obtaining care for sexual health concerns. RESULTS: 277 men completed the survey. After adjustment, 46.3% (95% CI = 39.4%-53.0%) reported de novo sexual dysfunction after injury, with erectile dysfunction the most common symptom (27.9%). Only 20.4% (95% CI = 15.1%-26.0%) recalled having discussions or being asked about their sexual health following injury, and of these conversations 70.7% were patient-initiated. The most common perceived barriers to discussing sexual health with providers were the belief that sexual dysfunction would resolve with time (26.1%), and a lack of knowledge about their condition and treatment options (21.5%). On multivariate analysis, the presence of postinjury sexual dysfunction (adjusted odds ratio [aOR] = 3.42), private insurance (aOR = 2.17), and being married or in a partnership (aOR = 3.10) were independently associated with likelihood of having had sexual health discussions. CLINICAL IMPLICATIONS: Despite the high prevalence of sexual dysfunction in men following pelvic trauma, sexual health concerns are inadequately addressed due to both patient and provider factors. STRENGTHS & LIMITATIONS: The major strengths include large sample size, detailed reporting of subject experience, and new information in a previously understudied area of pelvic trauma survivorship. The primary limitations are low survey response rate, lack of representativeness of survey participants to whole pelvic fracture cohort, single-center experience, and cross-sectional study design. CONCLUSION: Sexual health concerns after pelvic fracture are common but inadequately addressed by health care providers. Improved postinjury, survivorship-model care pathways need to be designed to better address sexual health after injury. Johnsen NV, Lang J, Wessells H, et al. Barriers to Care of Sexual Health Concerns in Men Following Traumatic Pelvic Fractures. J Sex Med 2019;16:1557-1566.

Temporal restriction of Cas9 expression improves CRISPR-mediated deletion efficacy and fidelity.

Clinical application of CRISPR-Cas9 technology for large deletions of somatic mutations is inefficient, and methods to improve utility suffer from our inability to rapidly assess mono- vs. biallelic deletions. Here we establish a model system for investigating allelic heterogeneity at the single-cell level and identify indel scarring from non-simultaneous nuclease activity at gRNA cut sites as a major barrier to CRISPR-del efficacy both in vitro and in vivo. We show that non-simultaneous nuclease activity is partially prevented via restriction of CRISPR-Cas9 expression via inducible adeno-associated viruses (AAVs) or lipid nanoparticles (LNPs). Inducible AAV-based expression of CRISPR-del machinery significantly improved mono- and biallelic deletion frequency in vivo, supporting the use of the Xon cassette over traditional constitutively expressing AAV approaches. These data depicting improvements to deletions and insight into allelic heterogeneity after CRISPR-del will inform therapeutic approaches for phenotypes that require either large mono- or biallelic deletions, such as autosomal recessive diseases or where mutant allele-specific gRNAs are not readily available, or in situations where the targeted sequence for excision is located multiple times in a genome.

CRISPR screen for rAAV production implicates genes associated with infection.

Recombinant adeno-associated virus (rAAV) vectors are an effective and well-established tool in the growing gene therapy field, with five FDA-approved AAV-mediated gene therapies already on the market and numerous more in clinical trials. However, manufacturing rAAV vectors is an expensive, timely, and labor-intensive process that limits the commercial use of AAV-mediated gene therapies. To address this limitation, we screened producer cells for genes that could be targeted to increase rAAV yield. Specifically, we performed a CRISPR-based genome-wide knockout screen in HEK 293 cells using an antibody specific to intact AAV2 capsids coupled with flow cytometry to identify genes that modulate rAAV production. We discovered that the knockout of a group of heparan sulfate biosynthesis genes previously implicated in rAAV infectivity decreased rAAV production. Additionally, we identified several vesicular trafficking proteins for which knockout in HEK 293 cells increased rAAV yields. Our findings provide evidence that host proteins associated with viral infection may have also been co-opted for viral assembly and that the genetic makeup of viral producer cells can be manipulated to increase particle yield.

Understanding Patient Perspectives Regarding Remote Monitoring Devices Following Total Joint Replacement.

Background: Advances in smart technology have expanded into the field of orthopedic surgery to deliver enhanced patient care. Smart technology has also raised important issues regarding protected patient information. The purpose of this study is to determine patient preferences regarding smart technology in their postarthroplasty care. Methods: Patient surveys were administered in the office setting of 2 adult reconstructive orthopedic surgeons during a 4-week period. Surveys queried patient demographics, twelve yes/no questions, five continuous agree/disagree statements, and a single free-text question. Logistic regression and statistical significance testing were performed. Results: Of the study patients, 83.6% were willing to wear a device. Women were more likely to consent to a monitoring device and have activity data collected than men (P < .05). Younger patients were more likely to consent to a device and have data collected than octogenarians. Nearly 90% of respondents indicated peace of mind with data being constantly tracked. However, 64% of respondents had hesitations about a surgically implanted device that was independent of a previous arthroplasty surgery (P < .05). Conclusions: Patients are comfortable with smart technology being involved in their postoperative care, especially younger patients and women. Older individuals, possibly with less experience using smart technology in their lives, were not as willing to wear smart devices or have their data collected. Nearly two-thirds of patients had hesitations about surgically implanted smart devices. Further investigation is needed to understand hesitations concerning smart implants as the orthopedic community enters an era of commercially available smart implants in total joint arthroplasty.

Retention of entry-level faculty members in obstetrics and gynecology.

OBJECTIVE: The purpose of this study was to examine retention rates of entry-level physician faculty members in obstetrics and gynecology. STUDY DESIGN: Ongoing data were collected by the Association of American Medical Colleges between 1981 and 2009 for full-time, entry-level assistant professors to determine whether they remained at their original departments, switched to another school, or left academia. Retention curves and 5- and 10-year retention rates at their original department and for academia were determined. RESULTS: The number of entry-level faculty members per year increased significantly for women and those faculty members in general obstetrics and gynecology. Retention rates at the original departments improved for all disciplines in recent years (2000-09), regardless of sex. Among those faculty members who left their original department, faculty members in general obstetrics/gynecology were more likely than subspecialists to leave academia. CONCLUSION: Growth in the number of entry-level physician faculty members was accompanied by higher retention rates at their original departments only in recent years.

Causal reductionism and causal structures.

Causal reductionism is the widespread assumption that there is no room for additional causes once we have accounted for all elementary mechanisms within a system. Due to its intuitive appeal, causal reductionism is prevalent in neuroscience: once all neurons have been caused to fire or not to fire, it seems that causally there is nothing left to be accounted for. Here, we argue that these reductionist intuitions are based on an implicit, unexamined notion of causation that conflates causation with prediction. By means of a simple model organism, we demonstrate that causal reductionism cannot provide a complete and coherent account of 'what caused what'. To that end, we outline an explicit, operational approach to analyzing causal structures.

Consciousness and the fallacy of misplaced objectivity.

Objective correlates-behavioral, functional, and neural-provide essential tools for the scientific study of consciousness. But reliance on these correlates should not lead to the 'fallacy of misplaced objectivity': the assumption that only objective properties should and can be accounted for objectively through science. Instead, what needs to be explained scientifically is what experience is intrinsically-its subjective properties-not just what we can do with it extrinsically. And it must be explained; otherwise the way experience feels would turn out to be magical rather than physical. We argue that it is possible to account for subjective properties objectively once we move beyond cognitive functions and realize what experience is and how it is structured. Drawing on integrated information theory, we show how an objective science of the subjective can account, in strictly physical terms, for both the essential properties of every experience and the specific properties that make particular experiences feel the way they do.

Machine learning approach to predict postoperative opioid requirements in ambulatory surgery patients.

Opioids play a critical role in acute postoperative pain management. Our objective was to develop machine learning models to predict postoperative opioid requirements in patients undergoing ambulatory surgery. To develop the models, we used a perioperative dataset of 13,700 patients (≥ 18 years) undergoing ambulatory surgery between the years 2016-2018. The data, comprising of patient, procedure and provider factors that could influence postoperative pain and opioid requirements, was randomly split into training (80%) and validation (20%) datasets. Machine learning models of different classes were developed to predict categorized levels of postoperative opioid requirements using the training dataset and then evaluated on the validation dataset. Prediction accuracy was used to differentiate model performances. The five types of models that were developed returned the following accuracies at two different stages of surgery: 1) Prior to surgery-Multinomial Logistic Regression: 71%, Naïve Bayes: 67%, Neural Network: 30%, Random Forest: 72%, Extreme Gradient Boost: 71% and 2) End of surgery-Multinomial Logistic Regression: 71%, Naïve Bayes: 63%, Neural Network: 32%, Random Forest: 72%, Extreme Gradient Boost: 70%. Analyzing the sensitivities of the best performing Random Forest model showed that the lower opioid requirements are predicted with better accuracy (89%) as compared with higher opioid requirements (43%). Feature importance (% relative importance) of model predictions showed that the type of procedure (15.4%), medical history (12.9%) and procedure duration (12.0%) were the top three features contributing to model predictions. Overall, the contribution of patient and procedure features towards model predictions were 65% and 35% respectively. Machine learning models could be used to predict postoperative opioid requirements in ambulatory surgery patients and could potentially assist in better management of their postoperative acute pain.

Evidence for ligand-induced paramagnetism in CdSe quantum dots.

We report evidence that paramagnetism in CdSe QDs can be induced via manipulation of the surface chemistry. Using SQUID magnetometry and X-ray absorption spectroscopy, we demonstrate that the paramagnetic behavior of the CdSe QDs can be varied by changing the ligand end-group functionality of the passivating layer. Contrary to previous reports, no evidence for ferromagnetism was observed. The results suggest that the paramagnetism is induced via pi back-bonding between Cd 4d orbtials and ligands with empty pi* orbitals.

Retention of chairs in obstetrics and gynecology: a comparison with other clinical departments.

OBJECTIVE: To compare the retention of chairs in academic obstetrics and gynecology with other core clinical departments. METHODS: Ongoing data were collected from each medical school for the Association of American Medical Colleges Faculty Roster between 1979 and 2007. Primary outcome measures included 5-year and 10-year retention rates and survival curves of first-time chairs. Comparisons were made between first-time chairs in obstetrics and gynecology and other core clinical departments: internal medicine, family medicine, pediatrics, psychiatry, and surgery. RESULTS: Five-year retention rates of obstetrics and gynecology chairs declined from 80% for those who began in 1979-1982 to 53% for those who began in 1998-2002. Ten-year retention in obstetrics and gynecology declined from 54% for those beginning in 1979-1982 to 26% for those beginning in 1993-1997. Other clinical departments experienced more stable 5-year and 10-year retention rates. Although substantially longer than other clinical departments in the 1979-1982 cohort, the median tenure of obstetrics and gynecology chairs who began in 1993-1997 was comparable with or less than that of other clinical departments. Discrete-time survival analysis revealed this decline in obstetrics and gynecology chair retention to be significant (P<.001) and more consistent than in other departments. CONCLUSION: Compared with other core clinical departments, retention of first-time chairs in obstetrics and gynecology declined more consistently from the highest to among the lowest. Chairs were inclined to not remain in office for a prolonged period. LEVEL OF EVIDENCE: II.

Standard screening methods underreport AAV-mediated transduction and gene editing.

Conventional methods to discern adeno-associated virus (AAV) vector transduction patterns are based on high, stable expression of a reporter gene. As a consequence, conventionally described tropisms omit cell types that undergo transient transduction, or have low but undetectable levels of reporter expression. This creates a blind spot for AAV-based genome editing applications because only minimal transgene expression is required for activity. Here, we use editing-reporter mice to fill this void. Our approach sensitively captures both high and low transgene expression from AAV vectors. Using AAV8 and other serotypes, we demonstrate the superiority of the approach in a side-by-side comparison with traditional methods, demonstrate numerous, previously unknown sites of AAV targeting, and better predict the gene editing footprint after AAV-CRISPR delivery. We anticipate that this system, which captures the full spectrum of transduction patterns from AAV vectors in vivo, will be foundational to current and emerging AAV technologies.

Kinetic Trapping of Folded Proteins Relative to Aggregates under Physiologically Relevant Conditions.

Anfinsen's thermodynamic hypothesis does not explicitly take into account the possibility of protein aggregation. Here, we introduce a cyclic-perturbation approach to prove that not only the native state but also soluble aggregates of most proteins can be highly populated under mild, physiologically relevant conditions, even at very low concentration. Surprisingly, these aggregates are not necessarily amyloid in nature and are usually not observed in bioactive proteins due to the extremely low kinetic flux from the native state toward a region of the chemical-potential landscape encoding aggregates. We first illustrate this concept for the representative model protein apomyoglobin-at room temperature and no denaturant-and demonstrate kinetic trapping of the native state relative to at least two different types of soluble, predominantly nonamyloid aggregates. The concentration and temperature dependence of aggregation confirm the above scenario. Extension of our analysis to the Escherichia coli proteome shows that the majority of the soluble bacterial proteome is also kinetically trapped in the nonaggregated state. Hence, the existence and low kinetic accessibility of large aggregates at room temperature and pH 6-7 is a general phenomenon. We also show that the average critical protein concentration for aggregation of most of the bacterial proteome is extremely small, much lower than the typical cellular protein concentration. Hence, the thermodynamic driving force for protein aggregation is large even if aggregation does not usually occur in healthy cells due to kinetic trapping. A broader view of Anfinsen's thermodynamic hypothesis encompassing all protein states, including aggregates, is necessary to understand the behavior of proteins in their natural environment.

Fit for genomic and proteomic purposes: Sampling the fitness of nucleic acid and protein derivatives from formalin fixed paraffin embedded tissue.

The demand for nucleic acid and protein derivatives from formalin-fixed paraffin-embedded (FFPE) tissue has greatly increased due to advances in extraction and purification methods, making these derivatives available for numerous genomic and proteomic platforms. Previously, DNA, RNA, microRNA (miRNA), or protein derived from FFPE tissue blocks were considered "unfit" for such platforms, as the process of tissue immobilization by FFPE resulted in cross-linked, fragmented, and chemically modified macromolecules. We conducted a systematic examination of nucleic acids and proteins co-extracted from 118 FFPE blocks sampled from the AIDS and Cancer Specimen Resource (ACSR) at The George Washington University after stratification by storage duration and the three most common tumor tissue types at the ACSR (adenocarcinoma, squamous cell carcinoma, and papillary carcinoma). DNA, RNA, miRNA, and protein could be co-extracted from 98% of the FFPE blocks sampled, with DNA and miRNA "fit" for diverse genomic purposes including sequencing. While RNA was the most labile of the FFPE derivatives, especially when assessed by RNA integrity number (RIN), it was still "fit" for genomic methods that use smaller sequence lengths, e.g., quantitative PCR. While more than half of the protein derivatives were fit for proteomic purposes, our analyses indicated a significant interaction effect on the absorbance values for proteins derived from FFPE, implying that storage duration may affect protein derivatives differently by tumor tissue type. The mean absorbance value for proteins derived from more recently stored FFPE was greater than protein derived from older FFPE, with the exception of adenocarcinoma tissue. Finally, the fitness of one type of derivative was weakly associated with the fitness of derivatives co-extracted from the same FFPE block. The current study used several novel quality assurance approaches and metrics to show that archival FFPE tissue blocks are a valuable resource for contemporary genomic and proteomic platforms.

Johan Turi's animal, mineral, vegetable cures and healing practices: an in-depth analysis of Sami (Saami) folk healing one hundred years ago.

BACKGROUND: The healing knowledge of a Sami (Saami) hunter and reindeer herder was surveyed as a window into the concepts of health, healing, and disease in early twentieth-century Sapmi (Northern Sweden). The two books of Johan Turi (1854-1936)--An Account of the Sami (1910) and Lappish Texts (1918-19) were examined to determine the varieties of recorded zootherapeutic, mineral, chemical, and ethnobotanical lore, as well as the therapeutic acts, identified conditions, and veterinary knowledge included. METHODS: Tabulation of the materials and species mentioned in Turi's descriptions (n = 137) permitted analysis of the relative frequency of differing types of healing in Turi's overall therapeutic repertoire, his relative attention to chronic vs. acute ailments, and the frequency of magic as a component of healing. A qualitative appraisal was made of the degree to which outside influences affected Sami healing of the period. A further assessment of the possible clinical efficacy of the recorded remedies was undertaken. RESULTS: Turi's remedies consist most often of zootherapeutics (31%), followed by physical acts such as massage, moxibustion, or manipulation (22%). Ethnobotanical cures make up a significantly smaller portion of his repertoire (17%), followed by mineral and chemical cures (12%). Magic rituals (including incantations and ritual acts) make up a significant portion of Turi's repertoire, and could be used alone (17%) or in conjunction with other types of healing (38%). Turi's healing aimed primarily at acute ailments (65%), with chronic conditions addressed less often (35%). A literature review revealed that Turi's remedies held a marked frequency of likely efficacy, at least in cases in which it was possible to ascertain the precise species, conditions, or substances described. Although it is possible at times to recognize foreign sources in Turi's repertoire, it is clear that Turi understood all his healing methods as distinctively Sami. CONCLUSION: The research illustrates the variety and depth of a single informant's healing knowledge, and demonstrates the value of both historical sources and in-depth data collection with single experts as useful means of assessing and characterizing an indigenous population's healing traditions.

Can semi-supervised learning explain incorrect beliefs about categories?

Three experiments with 88 college-aged participants explored how unlabeled experiences-learning episodes in which people encounter objects without information about their category membership-influence beliefs about category structure. Participants performed a simple one-dimensional categorization task in a brief supervised learning phase, then made a large number of unsupervised categorization decisions about new items. In all three experiments, the unsupervised experience altered participants' implicit and explicit mental category boundaries, their explicit beliefs about the most representative members of each category, and even their memory for the items encountered during the supervised learning phase. These changes were influenced by both the range and frequency distribution of the unlabeled stimuli: mental category boundaries shifted toward the middle of the range and toward the trough of the bimodal distribution of unlabeled items, whereas beliefs about the most representative category members shifted toward the modes of the unlabeled distribution. One consequence of this shift in representations is a false-consensus effect (Experiment 3) where participants, despite receiving very disparate training experiences, show strong agreement in judgments about representativeness and boundary location following unsupervised category judgments.

First-time department chairs at U.S. medical schools: a 29-year perspective on recruitment and retention.

PURPOSE: Given the resources that medical schools expend to recruit and develop department chairs, the authors carried out the investigation reported here to address the scarcity of national information on the recruitment and retention of first-time chairs. METHOD: The authors used data from the Association of American Medical Colleges (AAMC) Faculty Roster. The data included first-time chairs at all Liaison Committee on Medical Education accredited medical schools from July 1978 through June 2007 (a total of 125 schools). Primary outcome measures were the annual percentages of new chairs, retention rates of chairs, and retention curves of chairs. RESULTS: The annual frequencies of first-time chairs to recruit were remarkably similar between clinical and basic science departments, yet recruitment was more frequent for larger clinical departments. On average, 8.2% of all chair positions were filled each year by new chairs. Today's first-time chairs tend to be older, with there being a gradual emergence of more women. Retention curves revealed the median tenure to be 8.0 years for the most recent cohort of chairs (starting 1994 through 1998), which was down from 9.9 years for the earliest cohort analyzed (chairs starting 1979 through 1983). Chairs with longer tenures were more likely to be less than 50 years old, hold a professor rank, and be external candidates. CONCLUSIONS: Retention of academic chairs in both clinical and basic science departments is cyclic but has declined in more recent years. The methodology presented here may serve as a template for calculating recruiting and retention rates of chairs in individual disciplines and at individual medical schools, to compare rates between schools.

A portable high-field pulsed-magnet system for single-crystal x-ray scattering studies.

We present a portable pulsed-magnet system for x-ray studies of materials in high magnetic fields (up to 30 T). The apparatus consists of a split-pair of minicoils cooled on a closed-cycle cryostat, which is used for x-ray diffraction studies with applied field normal to the scattering plane. A second independent closed-cycle cryostat is used for cooling the sample to near liquid helium temperatures. Pulsed magnetic fields (approximately 1 ms in total duration) are generated by discharging a configurable capacitor bank into the magnet coils. Time-resolved scattering data are collected using a combination of a fast single-photon counting detector, a multichannel scaler, and a high-resolution digital storage oscilloscope. The capabilities of this instrument are used to study a geometrically frustrated system revealing strong magnetostrictive effects in the spin-liquid state.

Novel pressure-induced magnetic transition in magnetite (Fe3O4).

Fe K-edge x-ray magnetic circular dichroism of magnetite (Fe3O4) powders was measured with synchrotron radiation under variable pressure and temperature conditions in diamond anvil cell. The magnetic dichroism was observed to decrease discontinuously by approximately 50% between 12 and 16 GPa, independent of temperature. The magnetic transition is attributed to a high-spin to intermediate-spin transition of Fe2+ ions in the octahedral sites and could account for previously observed structural and electrical anomalies in magnetite at this pressure range. The interpretation of x-ray magnetic circular dichroism data is supported by x-ray emission spectroscopy and theoretical cluster calculations.