bluuebunny/crossref_metadata_2025 huggingface dataset:
Dimensional reduction by conformal bootstrap
Authors: Hikami Shinobu
Published: August 2019

Dimensional reductions in the branched polymer model and the random field Ising model (RFIM) are discussed by a conformal bootstrap method. Small minors are applied for the evaluations of the scale dimensions of these two models and the results are compared to the $D'=D-2$D Yang–Lee edge singularity and to the pure $D'=D-2$D Ising model, respectively. For the former case, the dimensional reduction is shown to be valid for $3 \le D \le 8$ and, for the latter case, the deviation from the dimensional reduction can be seen below five dimensions.
Longitudinal evidence of the impact of dog ownership and dog walking on mental health
Authors: Cui Y , Russell M , Davern M , Christian H
Published: August 2019

Background

Emerging evidence supports the physical health and social benefits of dog ownership. This study examined the longitudinal effect of dog ownership and dog walking on mental health.

Methods

Data from a cohort of 1023 participants taking part in the RESIDential Environments project, in Perth, Western Australia were collected over a 2 year period (baseline and follow-up). Self-report survey items measured mental health (stress and depression), dog ownership status and weekly minutes of dog walking. Logistic regression models accounted for potential confounding factors including socio–demographic, self-rated health and baseline mental health.

Results

Overall, no statistically significant effects were observed over time between dog ownership and stress (adjusted OR: 1.20; 95% CI: 0.79, 1.81) or depression (adjusted OR: 1.51; 95% CI: 0.72, 3.16). There was a small inverse but non-significant association between weekly minutes of dog walking and stress over time (adjusted OR: 0.85; 95% CI: 0.60, 1.22).

Conclusion

There was little evidence of prospective associations between dog ownership or dog walking and mental health. Further research is required to confirm longitudinal relationships between dog ownership and dog walking and mental health and investigate dog-related factors, such as a person’s attachment to their dog.
Quantifying the Range of Signal Modification in Clinically Fit Hearing Aids
Authors: Rallapalli Varsha , Anderson Melinda , Kates James , Balmert Lauren , Sirow Lynn , Arehart Kathryn , Souza Pamela
Published: August 2019

Objectives:

Hearing aids provide various signal processing techniques with a range of parameters to improve the listening experience for a hearing-impaired individual. In previous studies, we reported significant differences in signal modification for mild versus strong signal processing in commercially available hearing aids. In this study, the authors extend this work to clinically prescribed hearing aid fittings based on best-practice guidelines. The goals of this project are to determine the range of cumulative signal modification in clinically fit hearing aids across manufacturers and technology levels and the effects of listening conditions including signal to noise ratio (SNR) and presentation level on these signal modifications.

Design:

We identified a subset of hearing aids that were representative of a typical clinical setting. Deidentified hearing aid fitting data were obtained from three audiology clinics for adult hearing aid users with sensorineural hearing loss for a range of hearing sensitivities. Matching laboratory hearing aids were programmed with the deidentified fitting data. Output from these hearing aids was recorded at four SNRs and three presentation levels. The resulting signal modification was quantified using the cepstral correlation component of the Hearing Aid Speech Quality Index which measures the speech envelope changes in the context of a model of the listener’s hearing loss. These metric values represent the hearing aid processed signal as it is heard by the hearing aid user. Audiometric information was used to determine the nature of any possible association with the distribution of signal modification in these clinically fit hearing aids.

Results:

In general, signal modification increased as SNR decreased and presentation level increased. Differences across manufacturers were significant such that the effect of presentation level varied differently at each SNR, for each manufacturer. This result suggests that there may be variations across manufacturers in processing various listening conditions. There was no significant effect of technology level. There was a small effect of pure-tone average on signal modification for one manufacturer, but no effect of audiogram slope. Finally, there was a broad range of measured signal modification for a given hearing loss, for the same manufacturer and listening condition.

Conclusions:

The signal modification values in this study are representative of commonly fit hearing aids in clinics today. The results of this study provide insights into how the range of signal modifications obtained in real clinical fittings compares with a previous study. Future studies will focus on the behavioral implications of signal modifications in clinically fit hearing aids.
Sleep-related symptoms of midlife women with and without type 2 diabetes mellitus
Authors: Im Eun-Ok , Yang You Lee , Liu Jianghong , Chee Wonshik
Published: August 2019

Objectives:

The purpose of this study was to determine the associations between type 2 diabetes mellitus and sleep-related symptoms among midlife women from four major racial/ethnic groups in the United States.

Methods:

The data from 164 participants of two larger Internet survey studies (62 women diagnosed with type 2 diabetes and 102 women without diabetes) were included. In the original studies, multiple instruments including the questions on background characteristics, health status, and menopause status and the Sleep Index for Midlife Women were used. The data were analyzed using χ2 tests, independent t tests, Mann–Whitney U tests, and hierarchical multiple regression analyses.

Results:

The mean total number of sleep-related symptoms was significantly higher in those with type 2 diabetes (9.95 ± 5.83) than those without diabetes (7.25 ± 6.08) (t = 2.81, P = 0.006). The mean total severity score of sleep-related symptoms was also significantly higher in those with type 2 diabetes (33.42 ± 22.41) than those without diabetes (21.87 ± 21.40) (t = 3.29, P = 0.001). Among postmenopausal women and Asian women, there were significant differences in total numbers and total severity scores between those with type 2 diabetes and those without diabetes (all P < 0.05). When background characteristics, health status, and menopause status were controlled, having a diagnosis of type 2 diabetes was positively associated with total numbers (β=0.143, P = 0.047) and total severity scores (β=0.176, P = 0.014) of sleep-related symptoms.

Conclusions:

This secondary analysis supported significant associations of type 2 diabetes to sleep-related symptoms of midlife women from four major racial/ethnic groups in the United States.
Injectable Tissue Replacement and Regeneration: Anatomic Fat Grafting to Restore Decayed Facial Tissues
Authors: Cohen Steven R. , Womack Hayley
Published: August 2019

Aging is a dynamic process that can be modeled and understood tissue by tissue and cell by cell. Numerous authors have helped us understand the anatomy of facial fat compartments and the effects of aging on our facial tissues such as skin, fat, bone and fibrous ligaments. Injectable tissue replacement and regeneration (ITR2) is a method to replace decayed tissues of the face using “like tissues” in an effort to delay or slow the rate of tissue decay seen in facial aging. Facial topography and proportion analysis are performed to diagnose individual-specific losses of facial fat. The degree of sun damage and skin thinning is noted as is the degree of loss in the superficial fat compartment. Deep compartment fat loss is evaluated as is pyriform aperture, orbital, mandibular ramus, mandibular body, and chin resorption. From this analysis, a detailed treatment plan is formulated. Using a mechanical device, 3 different fat grafts are created: 2 mm (millifat), 1 mm (microfat), and 500 microns (cell optimized, matrix rich nanofat); anatomic replacement of all areas of tissue loss is carried out. Millifat is used for deep compartment and bone losses, microfat for superficial fat losses above the facial musculature and nanofat is used intradermally and as a biological cream for topical application. The rationale behind this standardized approach is explained and the scientific foundations for the idea are presented. Reduction in tissue decay appears to be a valid observation, but awaits others confirmation.
Mittens and Booties Syndrome
Authors: Ristagno Elizabeth H. , Marshall Gary S.
Published: August 2019

We describe the first 2 cases from the United States, of human parechovirus infection in infants manifesting a distinct rash of the hands and feet. We propose the term “Mittens and Booties Syndrome” and provide a review of the literature of all published cases.
Dynamic functional connectivity of the migraine brain: a resting-state functional magnetic resonance imaging study
Authors: Lee Mi Ji , Park Bo-Yong , Cho Soohyun , Park Hyunjin , Kim Sung-Tae , Chung Chin-Sang
Published: August 2019

Migraine headache is an episodic phenomenon, and patients with episodic migraine have ictal (headache), peri-ictal (premonitory, aura, and postdrome), and interictal (asymptomatic) phases. We aimed to find the functional characteristics of the migraine brain regardless of headache phase using dynamic functional connectivity analysis. We prospectively recruited 50 patients with migraine and 50 age- and sex-matched controls. All subjects underwent a resting-state functional magnetic resonance imaging. Significant networks were defined in a data-driven fashion from the interictal (>48 hours apart from headache phases) patients and matched controls (interictal data set) and tested to ictal or peri-ictal patients and controls (ictal/peri-ictal data set). Both static and dynamic analyses were used for the between-group comparison. A false discovery rate correction was performed. As a result, the static analysis did not reveal a network which was significant in both interictal and ictal/peri-ictal data sets. Dynamic analysis revealed significant between-group differences in 7 brain networks in the interictal data set, among which a frontoparietal network (controls > patients, P = 0.0467), 2 brainstem networks (patients > controls, P = 0.0467 and <0.001), and a cerebellar network (controls > patients, P = 0.0408 and <0.001 in 2 states) remained significant in the ictal/peri-ictal data set. Using these networks, migraine was classified with a sensitivity of 0.70 and specificity of 0.76 in the ictal/peri-ictal data set. In conclusion, the dynamic connectivity analysis revealed more functional networks related to migraine than the conventional static analysis, suggesting a substantial temporal fluctuation in functional characteristics. Our data also revealed migraine-related networks which show significant difference regardless of headache phases between patients and controls.
Itch sensitization? A systematic review of studies using quantitative sensory testing in patients with chronic itch
Authors: van Laarhoven Antoinette I.M. , Marker Jens B. , Elberling Jesper , Yosipovitch Gil , Arendt-Nielsen Lars , Andersen Hjalte H.
Published: August 2019

As well established for patients with chronic pain, patients suffering from chronic itch also exhibit signs of peripheral and central sensitization. This has been linked to parallel neuroplastic sensitization processes. However, for chronic itch, sensitization has not yet been systematically assessed, studied, and hence validated. This review (Prospero CRD42016043002) summarizes and meta-analytically evaluates whether sensory aberrations including sensitization for itch occur in chronic itch. Databases PubMed, Embase, and Cochrane Library were searched for studies investigating somatosensory sensitivity assessment by quantitative sensory testing stimuli, including experimental cutaneous chemical pruritic provocations, in patients with chronic itch from skin/neurological conditions and compared with healthy controls. Outcomes were extracted for lesional and nonlesional skin, and risk of biases were assessed. Meta-analyses were performed when sufficient quantitative data were available. Of 4667 identified articles, 46 were included and 25 were eligible for meta-analyses. Patients (66% atopic dermatitis [AD]) were found more sensitive than the controls to histamine-evoked itch in lesional skin (standardized mean difference [SMD]: 0.66 confidence interval [CI]: 0.16-1.15), but not nonlesionally (SMD: −0.26 [CI: −0.58 to 0.06]). Cowhage did not evoke more itch in nonlesional skin of patients as compared to the controls (SMD: 0.38 [CI: −0.04 to 0.81]). For numerous other chemical provocations as well as for mechanical, thermal, and electrical stimulation paradigms, results were ambiguous or based on few studies. Patients with chronic itch are only robustly sensitized to various chemical pruritic stimuli when applied lesionally. More studies on somatosensory aberrations in chronic itch conditions other than AD are needed to establish whether sensitization is robustly present across chronic itch conditions.
Recurrent low back pain patients demonstrate facilitated pronociceptive mechanisms when in pain, and impaired antinociceptive mechanisms with and without pain
Authors: McPhee Megan E. , Graven-Nielsen Thomas
Published: August 2019

Low back pain (LBP) has been inconsistently associated with enhanced pronociceptive and impaired antinociceptive mechanisms. It remains unknown whether alterations are causal, consequential, or coincidental to pain presence. This study investigated pronociceptive and antinociceptive mechanisms in recurrent LBP (RLBP) patients across painful and pain-free periods, compared with age/sex-matched asymptomatic controls. During a painful episode (day 0) and when pain-free (day 28), 30 RLBP patients were assessed and compared with 30 controls over the same timeframe. Pressure pain thresholds were recorded bilaterally on the arm, back, and leg. Cuff algometry was used to assess cuff pressure pain detection threshold and cuff pain tolerance threshold on the lower legs, as well as temporal summation of pain (10 repeated painful cuff test stimuli on the dominant leg scored on a visual analogue scale) and conditioned pain modulation ([CPM]: cuff pain detection/tolerance threshold on dominant leg, before vs during painful cuff conditioning on the contralateral leg). Recurrent LBP patients displayed reduced pressure pain thresholds at the arm and back on day 0 compared with day 28 (P < 0.047) and with controls on day 0 (P < 0.049). Cuff pain detection threshold was reduced, and ratings of suprathreshold test stimuli were increased in RLBP patients on day 0 compared with day 28 (P < 0.02). Temporal summation of pain magnitude (increase in visual analogue scale scores) was enhanced in RLBP participants on day 0 compared with day 28 (P = 0.027) and with controls on day 0 (P = 0.039). Conditioned pain modulation magnitude (increased threshold during conditioning) was lower overall in RLBP participants than in controls (P = 0.021). Enhanced pronociceptive mechanisms were observed in RLBP patients. When pain-free, measures returned to similar levels as controls, except for CPM, which remained impaired.
Anti-alarmin approaches entering clinical trials
Authors: Gauvreau Gail M. , White Lucie , Davis Beth E.
Published: August 2019

Purpose of review

The alarmins, thymic stromal lymphopoietin (TSLP), interleukin (IL)-25 and IL-33, are upstream regulators of T2 (type 2) inflammation and found to be expressed at high levels in airway epithelium of patients with T2 asthma. This review will summarize how alarmins regulate the inflamed asthmatic airways through previously described and newly identified mechanisms.

Recent findings

Alarmins drive allergic and nonallergic asthma through activation of innate lymphoid cell 2 (ILC2), which are a rich source of cytokines such as IL-5 and IL-13, with resulting effects on eosinophilopoeisis and remodelling, respectively. Findings from bronchial allergen challenges have illustrated widespread expression of alarmins and their receptors across many effector cells in airways, and recent studies have emphasized alarmin regulation of CD4+ T lymphocytes, eosinophils and basophils, and their progenitors. Furthermore, a link between alarmins and lipid mediators is being uncovered.

Alarmins can drive well defined inflammatory pathways through activation of dendritic cells and polarizing T cells to produce type 2 cytokines, as well as they can directly activate many other effector cells that play a central role in allergic and nonallergic asthma. Clinical trials support a central role for TSLP in driving airway inflammation and asthma exacerbations, while ongoing trials blocking IL-33 and IL-25 will help to define their respective role in asthma.
Brief Report: High Programmatic Isoniazid Preventive Therapy (IPT) Use in Pregnancy Among HIV-Infected Women
Authors: LaCourse Sylvia M. , Wagner Anjuli D. , Cranmer Lisa M. , Copeland Audrey , Maleche-Obimbo Elizabeth , Richardson Barbra A. , Matemo Daniel , Kinuthia John , John-Stewart Grace
Published: August 2019

Background:

The World Health Organization recommends isoniazid preventive therapy (IPT) for people living with HIV (PLHIV) to prevent tuberculosis (TB), including pregnant women. Recent trial results suggest increased adverse pregnancy outcomes associated with IPT during pregnancy. Data are limited regarding programmatic IPT use in pregnant PLHIV.

Methods:

We assessed previous programmatic IPT during pregnancy among HIV-infected mothers on enrollment to an infant TB prevention trial in Kenya. Pregnancy IPT use was assessed by the estimated conception date assuming 38 weeks of gestation. Correlates of initiation and completion were analyzed by relative risk regression, using generalized linear models with log link and Poisson family adjusted for IPT initiation year.

Results:

Between August 15, 2016, to June 6, 2018, 300 HIV-infected women enrolled at 6 weeks postpartum. Two hundred twenty-four (74.7%) women reported previous IPT, of whom 155/224 (69.2%) had any pregnancy IPT use. Forty-five (29.0%) initiated preconception extending into early pregnancy, 41 (26.5%) initiated and completed during pregnancy, and 69 (44.5%) initiated in pregnancy and extended into early postpartum. The median gestational age at IPT pregnancy initiation was 15.1 weeks (interquartile range 8.3–28.4). Pregnancy/early postpartum IPT initiation was associated with new pregnancy HIV diagnosis [adjusted relative risk 1.9 95% confidence interval (CI): 1.6 to 2.2, P < 0.001]. Six-month IPT completion rates were high [147/160 (91.9%)] among women with sufficient time to complete before trial enrollment and similar among preconception or during pregnancy initiators [adjusted relative risk 0.93 (95% confidence interval: 0.83 to 1.04, P = 0.19)].

Conclusions:

Programmatic IPT use was high in pregnant PLHIV, with frequent periconception and early pregnancy initiation. Programmatic surveillance could provide further insights on pregnancy IPT implementation and maternal and infant safety outcomes.
Efficacy of a spatial repellent for control of malaria in Indonesia: a cluster-randomized controlled trial
Authors: Syafruddin Din , Asih Puji BS , Rozi Ismail Ekoprayitno , Permana Dendi Hadi , Hidayati Anggi Puspa Nur , Syahrani Lepa , Zubaidah Siti , Sidik Dian , Bangs Michael J. , Bøgh Claus , Liu Fang , Eugenio Evercita C. , Hendrickson Jared , Burton Timothy , Baird J. Kevin , Collins Frank , Grieco John P. , Lobo Neil F. , Achee Nicole L.
Published: August 2019

A cluster randomized, double-blinded, placebo-controlled trial was conducted to estimate protective efficacy of a spatial repellent against malaria infection at Sumba, Indonesia. Following radical cure in 1,341 children aged ≥ 6 months - ≤5 years in 24 clusters, households were given transfluthrin or placebo passive emanators (devices designed to release vaporized chemical). Monthly blood screening and biweekly human-landing mosquito catches were performed during 10-months baseline (June 2015 to March 2016) and a 24-month intervention period (April 2016 to April 2018). Screening detected 164 first-time infections and an accumulative total of 459 infections in 667 subjects in placebo-control households; and 134 first-time and 253 accumulative total infections among 665 subjects in active intervention households. The 24-cluster protective effect of 27.7% and 31.3%, for time to first-event and overall (total new) infections, respectively, was not statistically significant. Purportedly, this was due in part to zero to low incidence in some clusters, undermining the ability to detect a protective effect. Subgroup analysis of 19 clusters where at least one infection occurred during baseline showed 33.3% (p-value = 0.083) and 40.9% (p-value = 0.0236, statistically significant at the 1-sided 5% significance level) protective effect to first-infection and overall infections, respectively. Among 12 moderate-to high-risk clusters, a statistically significant decrease on infection by intervention was detected (60% protective efficacy). Primary entomological analysis of impact was inconclusive. While this study suggests spatial repellents prevent malaria, additional evidence is required to demonstrate the product class provides an operationally feasible and effective means of reducing malaria transmission.
Prospective Trial Registration and Publication Rates of Randomized Clinical Trials in Digital Health: A Cross Sectional Analysis of Global Trial Registries
Authors: Al-Durra Mustafa , Nolan Robert P. , Seto Emily , Cafazzo Joseph A.
Published: August 2019

Registration of clinical trials was introduced to mitigate the risk of publication and selective reporting bias in the realm of clinical research. The prevalence of publication and selective reporting bias in trial results has been evidenced through scientific research. This bias may compromise the ethical and methodological conduct in the design, implementation and dissemination of evidence-based healthcare interventions. Principal investigators of digital health trials may be overwhelmed with challenges that are unique to digital health research, such as the usability of the intervention under test, participant recruitment, and retention challenges that may contribute to non-publication rate and prospective trial registration. Our primary research objective was to examine the prevalence of prospective registration and publication rates in digital health trials. We included 417 trials that enrolled participants in 2012 and were registered in any of the seventeen WHO registries. The prospective registration and publication rates were at (38.4%) and (65.5%) respectively. We identified a statistically significant (P<.001) “Selective Registration Bias” with 95.7% of trials published within a year after registration, were registered retrospectively. We reported a statistically significant relationship (P=.003) between prospective registration and funding sources, with industry-funded trials having the lowest compliance with prospective registration at (14.3%). The lowest non-publication rates were in the Middle East (26.7%) and Europe (28%), and the highest were in Asia (56.5%) and the U.S. (42.5%). We found statistically significant differences (P<.001) between trial location and funding sources with the highest percentage of industry funded trials in Asia (17.3%) and the U.S. (3.3%).
Accuracy of Medical Billing Data Against the Electronic Health Record in the Measurement of Colorectal Cancer Screening Rates
Authors: Rudrapatna Vivek A. , Glicksberg Benjamin S. , Avila Patrick , Harding-Theobald Emily , Wang Connie , J. Butte Atul
Published: August 2019

Objective

Administrative healthcare data are an attractive source of secondary analysis because of their potential to answer population-health questions. Although these datasets have known susceptibilities to biases, the degree to which they can distort measurements like cancer screening rates are not widely appreciated, nor are their causes and possible solutions.

Methods

Using a billing code database derived from our institution’s electronic health records (EHR), we estimated the colorectal cancer screening rate of average-risk patients aged 50-74 seen in primary care or gastroenterology clinic in 2016-2017. 200 records (150 unscreened, 50 screened) were sampled to quantify the accuracy against manual review.

Results

Out of 4,611 patients, an analysis of billing data suggested a 61% screening rate. Manual review revealed a positive predictive value of 96% (86-100%), negative predictive value of 21% (15-29%), and a corrected screening rate of 85% (81-90%). Most false negatives occurred due to exams performed outside the scope of the database – both within and outside of our institution – but 21% of false negatives fell within the database’s scope. False positives occurred due to incomplete exams and inadequate bowel preparation. Reasons for screening failure include ordered but incomplete exams (48%), lack of or incorrect documentation by primary care (29%) including incorrect screening intervals (13%), and patients declining screening (13%).

Conclusions

Although analytics on administrative data are commonly ‘validated’ by comparison to independent datasets, comparing our naïve estimate to the CDC estimate (∼60%) would have been misleading. Therefore, regular data audits using the complete EHR are critical to improve screening rates and measure improvement.

Study Highlights

WHAT IS KNOWN

Medical billing data might be useful for measuring colon cancer screening rates but are bias-prone and difficult to validate

The degree to which these biases may skew the results of simple population-level analytics is not widely appreciated, nor are their causes and possible solutions.

WHAT IS NEW HERE

Billing data from the health record does not accurately capture unscreened patients. Some reasons were predictable (screening outside the system or prior to software implementation) but others were not.

The common practice of external validation would have been falsely reassuring for these data. The naïve estimate of screening rates matches the CDC estimate (61%); the true rate was 85%.

Periodic data audits using the full EHR is critical to continue to improve screening rates and monitor improvements accurately and at scale.
Generalisability of Results from UK Biobank: Comparison With a Pooling of 18 Cohort Studies
Authors: Batty G. David , Gale Catharine R. , Kivimäki Mika , Deary Ian J. , Bell Steven
Published: August 2019

Background

The UK Biobank cohort study has become a much-utilised and influential scientific resource. With a primary goal of understanding disease aetiology, the low response to the original survey of 5.5% has, however, led to debate as to the generalisability of these findings. We therefore compared risk factor–disease estimations in UK Biobank with those from 18 nationally representative studies with conventional response rates.

Methods

We used individual-level baseline data from UK Biobank (N=502,655) and a pooling of data from the Health Surveys for England (HSE) and the Scottish Health Surveys (SHS), comprising 18 studies and 89,895 individuals (mean response rate 68%). Both study populations were aged 40-69 years at study induction and linked to national cause-specific mortality registries.

Findings

Despite a typically more favourable risk factor profile and lower mortality rates in UK Biobank participants relative to the HSE-SHS consortium, risk factors–endpoints associations were directionally consistent between studies, albeit with some heterogeneity in magnitude. For instance, for cardiovascular disease mortality, the age- and sex-adjusted hazard ratio (95% confidence interval) for ever having smoked cigarettes (versus never) was 2.04 (1.87, 2.24) in UK Biobank and 1.99 (1.78, 2.23) in HSE-SHS, yielding a ratio of hazard ratios close to unity (1.02, 0.88, 1.19; p-value 0.76). For hypertension (versus none), corresponding results were again in same direction but with a lower effect size in UK Biobank (1.89; 1.69, 2.11) than in HSE-SHS (2.56; 2.20, 2.98), producing a ratio of hazard ratios below unity (0.74; 0.62, 0.89; p-value 0.001). A similar pattern of observations were made for risk factors (smoking, obesity, educational attainment, and physical stature) in relation to different cancer presentations and suicide whereby the ratios of hazard ratios ranged from 0.57 (0.40, 0.81) and 1.07 (0.42, 2.74).

Interpretation

Despite a low response rate, aetiological findings from UK Biobank appear to be generalisable to England and Scotland.
Laser capture microdissection coupled mass spectrometry (LCM-MS) for spatially resolved analysis of formalin-fixed and stained human lung tissues
Authors: Herrera Jeremy A. , Mallikarjun Venkatesh , Rosini Silvia , Montero Maria Angeles , Warwood Stacey , O’Caulian Ronan , Knight David , Schwartz Martin A. , Swift Joe
Published: August 2019

Haematoxylin and eosin (H&E) – which respectively stain nuclei blue and other cellular and stromal material pink – are routinely used for clinical diagnosis based on the identification of morphological features. A richer characterization can be achieved by laser capture microdissection coupled to mass spectrometry (LCM-MS), giving an unbiased assay of the proteins that make up the tissue. However, the process of fixing, and H&E staining of tissues is poorly compatible with standard sample preparation methods for mass spectrometry, resulting in low protein yield. Here we describe a microproteomics technique optimized to analyze H&E-stained, formalin-fixed paraffin-embedded (FFPE) tissues. We advance our methodology by combining 3 techniques shown to individually enhance protein yields (heat extraction, physical disruption, and in column digestion) into one optimized pipeline for the analysis of H&E stained FFPE tissues. Micro-dissected morphologically normal human lung alveoli (0.082 mm3) and human lung blood vessels (0.094 mm3) from FFPE fixed section from Idiopathic Pulmonary Fibrosis (IPF) specimens were then subject to comparative proteomics using this methodology. This approach yielded 1252 differentially expressed proteins including 137 extracellular matrix (ECM) proteins. In addition, we offer proof of principal that MS can identify distinct, characteristic proteomic compositions of anatomical features within complex tissues.
Probability of Change in Life: amino acid changes in single nucleotide substitutions
Authors: Chan Kwok-Fong , Koukouravas Stelios , Yeo Joshua Yi , Koh Darius Wen-Shuo , Gan Samuel Ken-En
Published: August 2019

Mutations underpin the processes in life, be it beneficial or detrimental. While mutations are assumed to be random in the bereft of selection pressures, the genetic code has underlying computable probabilities in amino acid phenotypic changes. With a wide range of implications including drug resistance, understanding amino acid changes is important. In this study, we calculated the probabilities of substitutions mutations in the genetic code leading to the 20 amino acids and stop codons. Our calculations reveal an enigmatic in-built self-preserving organization of the genetic code that averts disruptive changes at the physicochemical properties level. These changes include changes to start, aromatic, negative charged amino acids and stop codons. Our findings thus reveal a statistical mechanism governing the relationship between amino acids and the universal genetic code.
Peculiar cases of a “sleeping” brain in alert cancer patients
Authors: Benveniste Helene , Vaska Paul , Franceschi Dinko , Salerno Michael , Rizwan Sabeen , Lee Hedok , Logan Jean , Rothman Douglas , Lazebnik Yuri , Volkow Nora D. , Bilfinger Thomas V.
Published: August 2019

Cognitive and constitutional symptomatology is common in cancer patients but the causes are not well understood. To investigate whether cancers cause these symptoms by changing cerebral metabolism, we measured the cerebral rate of glucose consumption (CMRglc) in patients diagnosed with a lung lesion.

Methods

The CMRglc was quantified in 20 patients undergoing 18F-FDG PET for lesion staging. The cognitive status was assessed by neuropsychological testing.

Results

Paradoxically, despite being alert three of the patients had CMRglc typical of people who are in deep sleep or anesthetized. All three had cancers, two died within 2 months of scanning. Remaining patients including four with early stage cancer had CMRglc within normal range.

Conclusions

We speculate that the low CMRglc reflects a switch to an alternative energy source that is mediated by cancers remotely. Identifying the underlying mechanism and the alternative energy sources may help to understand how cancers can change body metabolism.
Demographic history shaped geographical patterns of deleterious mutation load in a broadly distributed Pacific Salmon
Authors: Rougemont Quentin , Moore Jean-Sébastien , Leroy Thibault , Normandeau Eric , Rondeau Eric B. , Withler Ruth E. , Van Doornik Donald M. , Crane Penelope A. , Naish Kerry A. , Garza John Carlos , Beacham Terry D. , Koop Ben F. , Bernatchez Louis
Published: August 2019

A thorough reconstruction of historical processes is essential for a comprehensive understanding the mechanisms shaping patterns of genetic diversity. Indeed, past and current conditions influencing effective population size have important evolutionary implications for the efficacy of selection, increased accumulation of deleterious mutations, and loss of adaptive potential. Here, we gather extensive genome-wide data that represent the extant diversity of the Coho salmon (Oncorhynchus kisutch) to address two objectives. We demonstrate that a single glacial refugium is the source of most of the present-day genetic diversity, with detectable inputs from a putative secondary micro-refugium. We found statistical support for a scenario whereby ancestral populations located south of the ice sheets expanded in postglacial time, swamping out most of the diversity from other putative micro-refugia. Demographic inferences revealed that genetic diversity was also affected by linked selection in large parts of the genome. Moreover, we demonstrate that the recent demographic history of this species generated regional differences in the load of deleterious mutations among populations, a finding that mirrors recent results from human populations and provides increased support for models of expansion load. We propose that insights from these historical inferences should be better integrated in conservation planning of wild organisms, which currently focuses largely on neutral genetic diversity and local adaptation, with the role of potentially maladaptive variation being generally ignored.
The quorum sensing transcription factor AphA directly regulates natural competence inVibrio cholerae
Authors: Haycocks James R. J. , Warren Gemma Z. L. , Walker Lucas M. , Chlebek Jennifer L. , Dalia Triana N. , Dalia Ankur B. , Grainger David C.
Published: August 2019

Many bacteria use population density to control gene expression via quorum sensing. InVibrio cholerae, quorum sensing coordinates virulence, biofilm formation, and DNA uptake by natural competence. The transcription factors AphA and HapR, expressed at low- and high-cell density respectively, play a key role. In particular, AphA triggers the entire virulence cascade upon host colonisation. In this work we have mapped genome-wide DNA binding by AphA. We show that AphA is versatile, exhibiting distinct modes of DNA binding and promoter regulation. Unexpectedly, whilst HapR is known to induce natural competence, we demonstrate that AphA also intervenes. Most notably, AphA is a direct repressor oftfoX, the master activator of competence. Hence, production of AphA markedly suppressed DNA uptake; an effect largely circumvented by ectopic expression oftfoX. Our observations suggest dual regulation of competence. At low cell density AphA is a master repressor whilst HapR activates the process at high cell density. Thus, we provide deep mechanistic insight into the role of AphA and highlight howV. choleraeutilises this regulator for diverse purposes.

AUTHOR SUMMARY

Cholera remains a devastating diarrhoeal disease responsible for millions of cases, thousands of deaths, and a $3 billion financial burden every year. Although notorious for causing human disease, the microorganism responsible for cholera is predominantly a resident of aquatic environments. Here, the organism survives in densely packed communities on the surfaces of crustaceans. Remarkably, in this situation, the microbe can feast on neighbouring cells and acquire their DNA. This provides a useful food source and an opportunity to obtain new genetic information. In this paper, we have investigated how acquisition of DNA from the local environment is regulated. We show that a “switch” within the microbial cell, known to activate disease processes in the human host, also controls DNA uptake. Our results explain why DNA scavenging only occurs in suitable environments and illustrates how interactions between common regulatory switches affords precise control of microbial behaviours.
Stimulus-specific adaptation to behaviorally-relevant sounds in awake rats
Authors: Yaron A. , Jankowski M. M. , Badrieh R. , Nelken I.
Published: August 2019

Stimulus-specific adaptation (SSA) is the reduction in responses to a common stimulus that does not generalize, or only partially generalizes, to other stimuli. SSA has been studied mainly with sounds that bear no behavioral meaning. We hypothesized that the acquisition of behavioral meaning by a sound should modify the amount of SSA evoked by that sound. To test this hypothesis, we used fear conditioning in rats, using two word-like stimuli, derived from the English words “danger” and “safety”, as well as pure tones. One stimulus (CS+) was associated with a foot shock whereas the other stimulus (CS-) was presented without a concomitant foot shock. We recorded neural responses to the auditory stimuli using chronically implanted multi-electrode arrays, recording responses telemetrically in freely moving animals before and after conditioning. Consistent with our hypothesis, SSA changed in a way that depended on the behavioral role of the sound: the contrast between standard and deviant responses remained the same or decreased for CS+ stimuli but increased for CS- stimuli, showing that SSA is shaped by experience. In most cases the sensory responses underlying these changes in SSA increased following conditioning. Unexpectedly, the responses to CS+ word-like stimuli showed a specific, substantial decrease, which we interpret as evidence for substantial inhibitory plasticity.
Assignment of frost tolerant coast redwood trees of unknown origin to populations within their natural range using nuclear and chloroplast microsatellite genetic markers
Authors: Breidenbach Natalie , Gailing Oliver , Krutovsky Konstantin V.
Published: August 2019

Considering climate change and expected changes in temperature and precipitation, some introduced timber species are prospective for growing in Germany or Europe to produce valuable wood products and support sustainable forestry. The Californian tree, coast redwood (Sequoia sempervirens[D. Don] Endl.) is one of such species due to its excellent wood properties and high growth rate. It is sensitive to the freezing temperatures, but several trees of unknown origin introduced to Germany decades ago demonstrated high frost tolerance, and their propagated cuttings were planted all over German botanic gardens and arboreta. The knowledge of their origin within the natural distribution range could help us identify the potential genetic resources of frost resistant coast redwood genotypes. Therefore, both trees of unknown origin in Germany (G) and two reference data sets representing the “Kuser provenance test” established in 1990 in France (F) and samples collected in California (C) with known origin were genotyped using 18 microsatellite markers including 12 nuclear and six chloroplast simple sequence repeat (cpSSR) markers. The number of haplotypes found in the data sets based on six cpSSR markers was surprisingly very high. These markers were used to assign the German frost resistant trees (G) to the two reference data sets (F and C). The genetic structure among California samples (C) based on nSSR and cpSSR markers was very weak and mainly due to northern and southern clusters separated by the San Francisco Bay as a geographic barrier between coast redwood populations confirming previously published data. It was impossible to confidently assign frost tolerant trees (G) to single native populations, but rather to either the northern or southern cluster. However, the existing frost tolerant genotypes can already be used to establish commercial coast redwood plantation for future German forestry.
Pseudolesion in the right parafissural liver parenchyma on CT: the base is found in embryology and collagen content
Authors: Klein Willemijn M , Sonnemans Lianne JP , Franckenberg Sabine , Fliss Barbara , Gascho Dominic , Prokop Mathias , Lamers Wouter H , Hikspoors Jill PJM , Thali Michael J , Flach Patricia M
Published: August 2019

Background

Computed tomography (CT) images of livers may show a hypo-attenuated structure alongside the falciform ligament, which can be a focal fatty pseudolesion and can mimic a malignancy. The preferred location is on the right parafissural site, ventral in segment IVa/b. The etiology is not clear, nor is it known how the histology of this location develops. These are evaluated in this study.

Methods

40 adult cadavers with autopsy and / or postmortem CT in a university hospital and a forensic center were included. Liver biopsies were taken at the left side of the falciform ligament as control, and at the right side as the possible precursor of a pseudolesion; these were examined for collagen and fat content. Cadavers with steatotic (>5% fat) or fibrotic (>2% collagen) control samples were excluded.

Results

Significantly more collagen was present in the right parafissural liver parenchyma: median 0.68% (IQR: 0.32 – 1.17%), compared to the left side 0.48% (IQR: 0.21 – 0.75%) (p 0.008), with equal fat content and CT attenuation values. The etiophysiology goes back to the demise of the umbilical venes in the early embryonic and neonatal period.

Conclusions

The right parafissural area contains more collagen and an equal amount of fat compared to the control left side. This supports the hypothesis of delayed, ‘third’ inflow: the postnatal change in blood supply from umbilical to portal leaves the downstream parafissural area hypoperfused leading to hypoxia which in turn results in collagen accumulation and the persistence of paraumbilical veins of Sappey.

Key points

The typical location for a parafissural hepatic pseudolesion contains increased collagen.

A change in histology is caused by physiological demise of the umbilical venes.

The suboptimal blood supply of the right parafissural side leads to hypoxia and collagen deposition.

Embryologic knowledge and postmortem histology can help resolve issues in radiology.
TRiC activates the unfolded protein response and protects starved stem cells by modulating energy and lipid metabolism during planarian regeneration
Authors: Gutiérrez-Gutiérrez Óscar , Felix Daniel A. , Salvetti Alessandra , Thems Anne , Pietsch Stefan , Koeberle Andreas , Rudolph K. Lenhard , González-Estévez Cristina
Published: August 2019

Fasting protects stem cells and increases stem cell functionality through mechanisms which are not fully understood. Planarians are not only able to regenerate their bodies, but also to stand long periods of starvation by shrinking in size. This adaptation is possible because of a large population of adult stem cells which indefinitely self-renew even under starved conditions and thus confer planarians with immortality. How starved planarians are able to maintain healthy stem cells and to fuel stem cell proliferation allowing regeneration is unknown. Here we found the TCP-1 ring complex (TRiC) to be upregulated in starved stem cells. Down-regulation of TRiC impairs planarian regenerative response by inducing stem cell genome instability, mitotic defects and stem cell death which translates into stem cell exhaustion. This regulation is specific of starvation since feeding planarians prevents the phenotype. Importantly we found that TRiC activates the unfolded protein response (UPR) which allows a convergent regulation of cellular energy and lipid metabolism in starved planarians thus permitting the high energy demanding regenerative mitotic response. We identified a novel mechanism through which starvation protects the somatic stem cell genome allowing for unlimited stem cell proliferation and regeneration.
Altered auditory feedback induces coupled changes in formant frequencies during speech production
Authors: Tang Ding-lan , Lametti Daniel R. , Watkins Kate E.
Published: August 2019

Speaking is one of the most complicated motor behaviours, involving a large number of articulatory muscles which can move independently to command precise changes in speech acoustics. Here, we used real-time manipulations of speech feedback to test whether the acoustics of speech production (e.g. the formants) reflect independently controlled articulatory movements or combinations of movements. During repetitive productions of “head, bed, dead”, either the first (F1) or the second formant (F2) of vowels was shifted and fed back to participants. We then examined whether changes in production in response to these alterations occurred for only the perturbed formant or both formants. In Experiment 1, our results showed that participants who received increased F1 feedback significantly decreased their F1 productions in compensation, but also significantly increased the frequency of their F2 productions. The combined F1-F2 change moved the utterances closer to a known pattern of speech production (i.e. the vowel category “hid, bid, did”). In Experiment 2, we further showed that a downshift in frequency of F2 feedback also induced significant compensatory changes in both the perturbed (F2) and the unperturbed formant (F1) that were in opposite directions. Taken together, the results demonstrate that a shift in auditory feedback of a single formant drives combined changes in related formants. The results suggest that, although formants can be controlled independently, the speech motor system may favour a strategy in which changes in formant production are coupled to maintain speech production within specific regions of the vowel space corresponding to existing speech-sound categories.

New & Noteworthy

Findings from previous studies examining responses to altered auditory feedback are inconsistent with respect to the changes speakers make to their production. Speakers can compensate by specifically altering their production to offset the acoustic error in feedback. Alternatively, they may compensate by changing their speech production more globally to produce a speech sound closer to an existing category in their repertoire. Our study shows support for the latter strategy.