bluuebunny/crossref_metadata_2025 huggingface dataset:
Post-LASIK corneal epithelial irregularities October consultation #1
Authors: Moshirfar Majid , Bundogji Nour
Published: September 2021

A 55-year-old man with a history of bilateral laser-assisted in situ keratomileusis (LASIK) and subsequent enhancement over 15 years ago presented to our facility to investigate refractive surgery options. The patient reported progressive blurring and fluctuation of vision and desired independence from contact lenses and spectacles. Uncorrected distance visual acuity (UDVA) was 20/30 −2.0 in the right eye and 20/400 in the left eye, corrected to 20/60 in the left eye. Manifest refraction was +0.75 −1.75 × 180 diopters (D) in the right eye and −3.50 −3.50 × 64 D in the left eye. Keratometry readings were 43.9/41.1 @ 25 in the right eye and 49.3/46.8 @ 2 in the left eye. On slitlamp examination, the patient showed diffuse subepithelial fibrosis and confluent circumferential elevation, respecting the LASIK flap margin and extending centrally into the visual axis (Figure 1

JOURNAL/jcrs/04.03/02158034-202110000-00025/figure1/v/2023-08-19T002620Z/r/image-tiff

). Fluorescein pooling was also observed. Anterior segment ocular coherence tomography (OCT) demonstrated subepithelial hyperreflective density in the left eye (Figure 2

JOURNAL/jcrs/04.03/02158034-202110000-00025/figure2/v/2023-08-19T002620Z/r/image-tiff

). Pentacam showed irregularity and inferior steepening up to 52.0 D (Figure 3

JOURNAL/jcrs/04.03/02158034-202110000-00025/figure3/v/2023-08-19T002620Z/r/image-tiff

).

A review of the patient's records from 4 years ago revealed UDVA of 20/30 −2 in the right eye and 20/20 in the left eye with manifest refraction of +1.00 −1.50 × 30 D in the right eye and −0.25 D in the left eye. Keratometry then showed 39.52/40.91 @ 98 in the right eye and 39.85/40.42 @ 75 in the left eye. Patient's slitlamp examination revealed minimal subepithelial irregularity without endothelial changes in both eyes. At current presentation, the patient was not deemed a candidate for further refractive surgery given a low residual stromal bed after original LASIK with enhancement. The patient was seeking help and advice for his declining vision.

What is the most likely diagnosis, and what other conditions are on your differential? What would be your next step? Would you request additional diagnostic workup? What medical and surgical interventions would you recommend?
Intraindividual pain variability and phenotypes of pain in sickle cell disease: a secondary analysis from the Pain in Sickle Cell Epidemiology Study
Authors: Bakshi Nitya , Gillespie Scott , McClish Donna , McCracken Courtney , Smith Wally R. , Krishnamurti Lakshmanan
Published: September 2021

Mean pain intensity alone is insufficient to describe pain phenotypes in sickle cell disease (SCD). The objective of this study was to determine impact of day-to-day intraindividual pain variability on patient outcomes in SCD. We calculated metrics of pain variability and pain intensity for 139 participants with <10% missing data in the first 28 days of the Pain in Sickle Cell Epidemiology Study. We performed Spearman rank correlations between measures of intraindividual pain variability and outcomes. We then used k-means clustering to identify phenotypes of pain in SCD. We found that pain variability was inversely correlated with health-related quality of life, except in those with daily or near-daily pain. Pain variability was positively correlated with affective coping, catastrophizing, somatic symptom burden, sickle cell stress, health care utilization, and opioid use. We found 3 subgroups or clusters of pain phenotypes in SCD. Cluster 1 included individuals with the lowest mean pain, lowest temporal instability and dependency, lowest proportion of days with pain and opioid use, and highest physical function. Cluster 2 included individuals with the highest mean pain, highest temporal dependency, highest proportion of days with pain and opioid use, and lowest physical function. Cluster 3 included individuals with high levels of mean pain, highest temporal instability, but with lower temporal dependency, proportion of days with pain and opioid use, and physical function compared with cluster 2. We conclude that intraindividual pain variability is associated with patient outcomes and psychological characteristics in SCD and is useful in delineating phenotypes of pain in SCD.
Practical Strategies and Tools for Use by Occupational and Environmental Medicine Departments During COVID-19 Pandemic Surges
Authors: Guo Andrew H. , Diaz-Caturan Ma Visimee , Reis Cesar , Carritte Deborah , Smith Brad M.T. , Wester Yann O. , Hall Susan L.
Published: September 2021

Objectives:

Occupational and environmental medicine (OEM) departments in healthcare institutions can be quickly overwhelmed when COVID-19 infection rates rapidly and simultaneously increase in the workforce and the patients served. Our goal is to present a detailed toolkit of practical approaches for use by front-line OEM specialists to address workforce management tasks during pandemic surges.

Methods:

Specific focus is on tasks related to employee symptom triage, exposure risk assessment, workplace contact tracing, and work restrictions.

Results:

Tools include strategies used by customer call centers, two decision support algorithms (exposure due to cohabitation or non-cohabitation), a color-coded employee case tracking tool, a contact tracing protocol, and documentation templates that serve as memory aids for encounters.

Conclusions:

These tools are created with commonly used software. Implementation is feasible in most front-line OEM settings, including those with limited resources.
A Novel Physical Examination Test for Ischiofemoral Impingement: Validation With Magnetic Resonance Imaging Correlation
Authors: Maraş Özdemir Zeynep , Yıldırım Tülay , Karaca Leyla , Sağır Kahraman Ayşegül , Aydıngöz Üstün
Published: September 2021

Objective

The purpose of this study was to propose and validate a novel physical examination test for ischiofemoral impingement with magnetic resonance imaging (MRI) correlation.

Methods

We prospectively studied 24 women with buttock (deep gluteal) pain and 27 asymptomatic women. Each group underwent a 2-stage physical examination test that featured hip adduction–external rotation–extension and knee flexion. Visual analog scale pain scores were noted just before and during test stages on both sides. The MRI findings of the ischiofemoral impingement were evaluated quantitatively and qualitatively.

Results

Mean ages were 56.0 and 55.2 years (P = 0.797), and mean body mass indexes were 29.1 and 28.8 kg/m2 (P = 0.817) in symptomatic and asymptomatic groups, respectively. Ischiofemoral spaces were significantly narrower (P < 0.001), ischial angles were wider (P < 0.001, right; P = 0.002, left), and soft tissue edema at the ischiofemoral space was more common (P < 0.001) in the symptomatic group, which also had higher pretest visual analog scale scores (P < 0.001) that increased significantly during both upright standing (P = 0.003, right; P < 0.001, left) and recumbent (P < 0.001 for both sides) stages of the physical examination test.

Conclusions

A novel physical examination test significantly increases symptoms of ischiofemoral impingement with positive MRI correlation.
IgG4-Related Disease
Authors: Martín-Nares Eduardo , Hernández-Molina Gabriela , Baenas Diego Federico , Paira Sergio
Published: September 2021

Background

The tendency of IgG4-related disease (IgG4-RD) to form pseudotumors, as well as its multisystemic nature, makes it the perfect mimicker of many conditions. Moreover, some clinical, serological, radiological, or histological features of the disease might be shared with some mimickers.

Recently, 4 clinical phenotypes have been identified, and patients grouped in each phenotype have distinctive demographic, clinical, and serological features and outcomes, and, as expected, for each phenotype, a set of differential diagnoses should be considered.

Summary of the Literature

The main differential diagnoses for the pancreato-hepato-biliary phenotype are pancreatic adenocarcinoma and cholangiocarcinoma. Other differential diagnoses include type 2 autoimmune pancreatitis and primary sclerosing cholangitis. In patients with retroperitoneal/aortic phenotype, inflammatory conditions such as idiopathic retroperitoneal fibrosis and large vessel vasculitides should be ruled out, and most of the time, a biopsy will be needed to exclude malignancies. In head and neck limited phenotype, autoimmune conditions (eg, granulomatosis with polyangiitis, Graves orbitopathy, sarcoidosis), malignancies, and histiocytosis should be ruled out, whereas the main differential diagnoses of the Mikulicz/systemic phenotype are Sjögren syndrome, granulomatosis with polyangiitis, and multicentric Castleman disease.

Conclusions

Approaching a patient with probable IgG4-RD through a clinical phenotype framework will ease the diagnostic algorithm and facilitate the prompt recognition of the disease. There are certain clinical, serological, radiological, and histological features in each clinical phenotype that, if present, increase the likelihood that a patient may have IgG4-RD instead of the mimicker condition. Those clues that point toward IgG4-RD diagnosis should be actively sought in the workup of patients.
Human Papillomavirus and Oral Lesions: What is the Best Diagnostic Method?
Authors: Fiorillo Luca , Cervino Gabriele , Surace Giovanni , Fiorillo Maria Teresa , Meto Agron , Cicciu Marco
Published: September 2021

Oropharyngeal squamous cell carcinoma is the most common neoplasm of head and neck cancers related to the presence of human papillomavirus (HPV). in the dental, maxillofacial and ENT fields, the finding of mediated HPV lesions is quite common. The diagnostic techniques currently available are different and can be more or less invasive depending on the type of lesion and the need for the clinician. In this study, two clinical cases subjected to a double diagnostic technique were considered in order to exclude any possible risk of false negatives. The polymerase chain reaction (PCR) technique showed a lower sensitivity or in any case dictated by a limited number of HPV strains analyzed. Histological examination nowadays turns out to be the best diagnostic method despite requiring a surgical phase.
Surgical Result and Identification of FGFR2 Variants Using Whole-Exome Sequencing in a Chinese Family With Crouzon Syndrome
Authors: Lai Chenzhi , Pan Bo , Song Guodong , Zong Xianlei , Qi Zuoliang , Jin Xiaolei
Published: September 2021

Crouzon syndrome is considered as one of the most common craniosynostosis syndromes with a prevalence of 1 in 65,000 individuals, and has a close relationship with variants in fibroblast growth factor receptor 2. Here the authors described a Crouzon syndrome case, which was asked for surgery treatment for the symptom of multisuture craniosynostosis. Mild midfacial retrusion, larger head circumference, proptosis, pseudo-prognathism, and dental malposition could also be found obviously. Then fronto-orbital advancement and cranial cavity expansion were performed to the child. After whole-exome sequencing (WES) and Sanger sequencing, gene variants in the exons 2 and 3 of FGFR2 were detected. And protein tyrosine 105 replaced by cysteine in the extracellular region of FGFR2 was also detected. After operation, she presented a satisfactory anterior plagiocephaly and scaphocephaly correction, and the result was satisfied by surgeons and her parents. Variants detected using WES have further research prospect.
Evaluation of Zygomaticosphenoidal Angle in Patients With Unilateral Zygomaticomaxillary Complex Fracture
Authors: Khojastepour Leila , Razavi Nasim , Hasani Mahvash , Khaghaninejad Mohammad Saleh
Published: September 2021

This study aimed to assess the zygomaticosphenoidal (ZS) angle in patients with reducted unilateral zygomatico-maxillary complex (ZMC) fracture and compare it with the normal control group. This study was performed on CT images of 60 cases and 60 controls with a mean age of 35.1 ± 14.6. The ZS angle was measured on axial images containing the equator of the eyeball. Moreover, the mean absolute difference value and asymmetry index were calculated. Chi-square test, independent-sample t test, 1-way ANOVA, paired-sample t test, and ROC curve analysis were applied. The mean ZS angle in the control group was 46.6° ± 3.5°. Considering laterality, the mean of ZS was not significant in the control group. However, after reduction of unilateral ZMC fracture, there was a significant difference between the mean ZS angle in right and left sides. The mean absolute difference between right and left ZS angles was significantly higher in the case group. A threshold number of 0.9° is established in the mean absolute difference value which is the difference between the right and left ZS angles in an individual for detecting asymmetry. The ZS angle can be a useful anatomical aid to guide surgeons in achieving facial symmetry in ZMC fractures.
Intraoral Styloidectomy Using an Endoscope With Tissue Retractor
Authors: Iwai Toshinori , Iida Masaki , Sugiyama Satomi , Mitsudo Kenji
Published: September 2021

The extraoral approach with the risk of facial nerve injury and the visible scar is commonly performed for an elongated styloid process, because intraoral styloidectomy is challenging for the deep and limited surgical field. The authors report minimally invasive intraoral styloidectomy using an endoscope with tissue retractor. A 57-year-old female was referred to our department with a left pharyngeal foreign body sensation and pharyngeal pain after head turning and neck compression. Clinical and radiological diagnosis was an elongated styloid process (Eagle syndrome). Because the styloid process could be palpated intraorally, the patient underwent endoscopically-assisted intraoral styloidectomy without tonsillectomy under general anesthesia as minimally invasive surgery. The styloid process was resected safely with a piezoelectric surgical device under endoscopic guidance. The postoperative course was uneventful without complications.
Impact of Cleft Palate on Tongue-Based Upper Airway Obstruction in Pierre Robin Sequence: Implications for Mandibular Distraction Osteogenesis and Timing of Cleft Palate Repair
Authors: Prescher Hannes , Froimson Jill R. , Haravu Pranav N. , Reid Russell R.
Published: September 2021

Introduction:

The objectives of this study are to analyze the impact of cleft palate (CP) on upper airway obstruction using polysomnography in patients with Pierre Robin Sequence (PRS) undergoing mandibular distraction osteogenesis (MDO) and subsequent CP repair.

Methods:

A single-surgeon, retrospective chart review was performed of all patients with nonsyndromic PRS treated with MDO. Severity of upper airway obstruction was evaluated pre- and post-distraction via polysomnography. Details of MDO and CP repair were collected and any complications recorded.

Results:

Twenty-one nonsyndromic PRS patients with CP and 6 patients without CP met inclusion criteria. There was no significant difference in predistraction apnea-hypopnea index between the 2 groups (53.4 ± 42.1 versus 34.4 ± 18.9; P = 0.3). Patients with CP had significantly higher predistraction SpO2 saturation (94.5 ± 1.6% versus 91.0% ± 4.8%; P = 0.01), SpO2 nadir (74.5% ± 9.1% versus 63.6% ± 11.6%; P = 0.03) and lower percentage time spent below 90% SpO2 (6.0% ± 7.2% versus 23.6% ± 29.9%; P = 0.04). The rate of oronasal fistulas formation was 38%. The time between MDO and CP repair was shorter for patients with complications (250.8 ± 3.3 versus 370.8 ± 191.9 days; P = 0.08). Five patients experienced relapse of respiratory difficulties after CP repair.

Conclusions:

The presence of CP in nonsyndromic PRS patients decreases the severity of obstructive sleep apnea by oxygen parameters on PSG. Palatal fistulas and relapse of respiratory distress are common complications of CP repair following MDO. Delaying CP repair may help to decrease complication rates.
Photogrammetric Analysis of Nasal Dimensions in Indian Malaysian Adults
Authors: Packirisamy Vasanthakumar
Published: September 2021

In cosmetic rhinoplasty, knowledge of average nasal dimensions is important to create an aesthetic nose compatible with gender, ethnicity, and other facial feature. This study aimed to establish gender-specific nasal anthropometric data for Indian Malaysians (IMs) and to determine the interracial difference by comparing it with published data of three studies. Evaluation of nasal morphology was done on the standardized frontal, lateral, and basal photographs of 200 male and 200 female IM noses, aged 18–27 years. The measured variables were evaluated by using an independent t-test. Significant sexual dimorphism was found in 20 of 21 measurements, 5 nasal indices and 2 ratios. Significant racial features between IA and Saudi Arabian population were found in all 18 measurements and 5 nasal indexes. Seven of the 8 measurements and including the 2 ratios were significantly different between IM and Whites, but between IM and Chinese, all the 8 measurements and 2 ratios were significantly different. Compared to Saudi Arabian and Whites, IM had wider intercaantal distance, the nose was relatively shorter and wider, less projected radix, and prominent glabella with an increased backward slope of the forehead. Compared to the Chinese, the IM intercaantal distance and nose was narrower and the nasal root was slightly wider in the male group. The IM nasal tip was less projected and underrotated compared to all the 3 groups. In conclusion, the anthropometric analysis of IM noses revealed several unique nasal features, understanding these variations could be useful for the rhinoplasty surgeon to deliver ethnically congruent results.
Seasonal Variation of Nonsyndromic Orofacial Clefts in Northern Chinese Population
Authors: Hao Yanru , Zhuang Deshu , Jiao Xiaohui
Published: September 2021

Background:

Nonsyndromic orofacial clefts (NSOC) comprise a range of disorders affecting the lips and oral cavity. Various authors evaluated seasonal influence on the occurrence of NSOC differently. The aim of present study was to investigate seasonal variation in birth of individuals with orofacial cleft in northern China.

Methods:

A retrospective study comprised 499 cases and 452 controls were conducted. Children with NSOC operated in The First Affiliated Hospital of Harbin Medical University from 2009 to 2015 were investigated. Controls were children patients with trauma and bone fracture from the same hospital during the same period. Data on sex, birth time, area of residence was retrospectively collected from patients’ records. Chi-squared test was used for comparisons. P values less than or equal to 0.05 were considered to be significant.

Results:

Seasonal distribution was significantly different between cases and controls (P < 0.05). Birth time peaks of cases, especially males, occurred in winter. Furthermore, compared with controls, more cases with cleft lip/palate were born in winter (P < 0.05). There was no significant seasonal difference between female cases and controls (P > 0.05), and no statistical difference was found between cases with cleft palate and controls (P > 0.05).

Conclusions:

Our study revealed the presence of seasonal variation in individuals with orofacial cleft in northern Chinese population. We found a peak incidence of birth time for NSOC during winter.
The α-globin chain of hemoglobin potentiates tissue plasminogen activator induced hyperfibrinolysis in vitro
Authors: Morton Alexander P. , Hadley Jamie B. , Ghasabyan Arsen , Kelher Marguerite R. , Moore Ernest E. , Bevers Shaun , Dzieciatkowska Monika , Hansen Kirk C. , Cohen Mitchell S. , Banerjee Anirban , Silliman Christopher C.
Published: September 2021

BACKGROUND

Severe injury predisposes patients to trauma-induced coagulopathy, which may be subdivided by the state of fibrinolysis. Systemic hyperfibrinolysis (HF) occurs in approximately 25% of these patients with mortality as high as 70%. Severe injury also causes the release of numerous intracellular proteins, which may affect coagulation, one of which is hemoglobin, and hemoglobin substitutes induce HF in vitro. We hypothesize that the α-globin chain of hemoglobin potentiates HF in vitro by augmenting plasmin activity.

METHODS

Proteomic analysis was completed on a pilot study of 30 injured patients before blood component resuscitation, stratified by their state of fibrinolysis, plus 10 healthy controls. Different concentrations of intact hemoglobin A, the α- and β-globin chains, or normal saline (controls) were added to whole blood, and tissue plasminogen activator (tPA)–challenged thrombelastography was used to assess the degree of fibrinolysis. Interactions with plasminogen (PLG) were evaluated using surface plasmon resonance. Tissue plasminogen activator–induced plasmin activity was evaluated in the presence of the α-globin chain.

RESULTS

Only the α- and β-globin chains increased in HF patients (p < 0.01). The α-globin chain but not hemoglobin A or the β-globin chain decreased the reaction time and significantly increased lysis time 30 on citrated native thrombelastographies (p < 0.05). The PLG and α-globin chain had interaction kinetics similar to tPA:PLG, and the α-globin chain increased tPA-induced plasmin activity.

CONCLUSIONS

The α-globin chain caused HF in vitro by binding to PLG and augmenting plasmin activity and may represent a circulating “moonlighting” mediator released by the tissue damage and hemorrhagic shock inherent to severe injury.

LEVEL OF EVIDENCE

Prognostic, level III.
Long-term Follow-up of a Randomized Trial of Tacrolimus or Cyclosporine A Microemulsion in Children Post Liver Transplantation
Authors: Lloyd Carla , Arshad Adam , Jara Paloma , Burdelski Martin , Gridelli Bruno , Manzanares J. , Colledan Michele , Jacquemin Emmanuel , Reding Raymond , Baumann Ulrich , Kelly Deirdre
Published: September 2021

Background.

The aim of this study was to determine the long-term efficacy and safety of tacrolimus (Tac) and cyclosporine immunosuppression in pediatric liver transplantation (LTx).

Methods.

One hundred fifty-six patients who had taken part in a multicenter, randomized, open, parallel study of Tac and corticosteroids versus cyclosporine A microemulsion (CyA-ME), corticosteroids, and azathioprine. Patients were assessed at regular intervals up to 14 y after LTx. Analysis was conducted descriptively.

Results.

In a long-term follow-up, there was a similar incidence of acute rejection (Tac versus CyA-ME, 5 versus 8) and graft loss (5 versus 10). There were 11 deaths in the cohort, which were from infectious complications/malignancy in the Tac group (n = 2/5) and from chronic rejection/liver failure in the CyA-ME group (n = 3/6). A similar incidence of Epstein-Barr virus and posttransplant lymphoproliferative disease was observed (8 versus 8, 3 versus 3). However, there was a greater incidence of cosmetic adverse events in the CyA-ME cohort, with higher incidences of hypertrichosis (8 versus 27) and gum hyperplasia (20 versus 6). Growth improved equally in both groups. Overall, 81% of patients randomized to Tac remained on Tac therapy at study end, compared with 31% of patients randomized to CyA-ME. Common reasons for switching from CyA-ME included steroid-resistant/acute rejection (n = 12/8) and cosmetic changes (n = 8).

Conclusions.

This study is the first prospective, observational follow-up study of pediatric patients randomized to Tac and CyA-ME to evaluate long-term outcomes. Our analysis was limited by the degree of switchover between the cohorts; however, there were fewer deaths from chronic rejection/liver failure and reduced adverse events with Tac. Long-term use of Tac and Tac combination therapy appears to be safe and effective immunosuppression for pediatric LTx recipients.
Two siblings with autism spectrum disorder and two different genetic abnormalities: paternal 16p11.2 microdeletion and maternal 17q12 microduplication
Authors: Erbay Muhammed Furkan , Karayağmurlu Ali
Published: September 2021

Etiopathogenesis of autism spectrum disorder (ASD) is highly heterogeneous. Genetic factors play a major role in the etiology of ASD, and 16p11.2 microdeletion is one of the best-known genetic abnormalities thought to be strongly linked to ASD. Conversely, 17q12 microduplication is observed relatively rarely, yet it is reported that 17q12 recurrent duplication also results in a predisposition to ASD. Additionally, 16p11.2 microdeletion is characterized by developmental delay, intellectual disability, ASD and seizures, while 17q12 recurrent duplication is thought to be related to intellectual disability, seizures, eye or vision problems and, rarely, cardiac and renal anomalies. It also has been linked to ASD, schizophrenia, aggression and self-injury. This paper presents two different genetic abnormalities and their relations to ASD. Two siblings were studied; in one of the siblings, maternally originated 17q12 duplication was identified, and paternally originated 16p11.2 microdeletion was identified in the other sibling. To the best of the authors’ knowledge, the present paper is a rare case report which shows the coexistence of 17q12 duplication, clubfoot deformity and ASD as well as 16p11.2 microdeletion, spina bifida occulta and ASD.
The ghost of hosts past: impacts of host extinction on parasite specificity
Authors: Farrell Maxwell J. , Park Andrew W. , Cressler Clayton E. , Dallas Tad , Huang Shan , Mideo Nicole , Morales-Castilla Ignacio , Davies T. Jonathan , Stephens Patrick
Published: September 2021

A growing body of research is focused on the extinction of parasite species in response to host endangerment and declines. Beyond the loss of parasite species richness, host extinction can impact apparent parasite host specificity, as measured by host richness or the phylogenetic distances among hosts. Such impacts on the distribution of parasites across the host phylogeny can have knock-on effects that may reshape the adaptation of both hosts and parasites, ultimately shifting the evolutionary landscape underlying the potential for emergence and the evolution of virulence across hosts. Here, we examine how the reshaping of host phylogenies through extinction may impact the host specificity of parasites, and offer examples from historical extinctions, present-day endangerment, and future projections of biodiversity loss. We suggest that an improved understanding of the impact of host extinction on contemporary host–parasite interactions may shed light on core aspects of disease ecology, including comparative studies of host specificity, virulence evolution in multi-host parasite systems, and future trajectories for host and parasite biodiversity.

This article is part of the theme issue ‘Infectious disease macroecology: parasite diversity and dynamics across the globe’.
Predictors of zoonotic potential in helminths
Authors: Majewska Ania A. , Huang Tao , Han Barbara , Drake John M.
Published: September 2021

Helminths are parasites that cause disease at considerable cost to public health and present a risk for emergence as novel human infections. Although recent research has elucidated characteristics conferring a propensity to emergence in other parasite groups (e.g. viruses), the understanding of factors associated with zoonotic potential in helminths remains poor. We applied an investigator-directed learning algorithm to a global dataset of mammal helminth traits to identify factors contributing to spillover of helminths from wild animal hosts into humans. We characterized parasite traits that distinguish between zoonotic and non-zoonotic species with 91% accuracy. Results suggest that helminth traits relating to transmission (e.g. definitive and intermediate hosts) and geography (e.g. distribution) are more important to discriminating zoonotic from non-zoonotic species than morphological or epidemiological traits. Whether or not a helminth causes infection in companion animals (cats and dogs) is the most important predictor of propensity to cause human infection. Finally, we identified helminth species with high modelled propensity to cause zoonosis (over 70%) that have not previously been considered to be of risk. This work highlights the importance of prioritizing studies on the transmission of helminths that infect pets and points to the risks incurred by close associations with these animals.

This article is part of the theme issue ‘Infectious disease macroecology: parasite diversity and dynamics across the globe’.
Forecasting parasite sharing under climate change
Authors: Morales-Castilla Ignacio , Pappalardo Paula , Farrell Maxwell J. , Aguirre A. Alonso , Huang Shan , Gehman Alyssa-Lois M. , Dallas Tad , Gravel Dominique , Davies T. Jonathan
Published: September 2021

Species are shifting their distributions in response to climate change. This geographic reshuffling may result in novel co-occurrences among species, which could lead to unseen biotic interactions, including the exchange of parasites between previously isolated hosts. Identifying potential new host–parasite interactions would improve forecasting of disease emergence and inform proactive disease surveillance. However, accurate predictions of future cross-species disease transmission have been hampered by the lack of a generalized approach and data availability. Here, we propose a framework to predict novel host–parasite interactions based on a combination of niche modelling of future host distributions and parasite sharing models. Using the North American ungulates as a proof of concept, we show this approach has high cross-validation accuracy in over 85% of modelled parasites and find that more than 34% of the host–parasite associations forecasted by our models have already been recorded in the literature. We discuss potential sources of uncertainty and bias that may affect our results and similar forecasting approaches, and propose pathways to generate increasingly accurate predictions. Our results indicate that forecasting parasite sharing in response to shifts in host geographic distributions allow for the identification of regions and taxa most susceptible to emergent pathogens under climate change.

This article is part of the theme issue ‘Infectious disease macroecology: parasite diversity and dynamics across the globe’.
Characteristics of the 100 largest modern zoonotic disease outbreaks
Authors: Stephens Patrick R. , Gottdenker N. , Schatz A. M. , Schmidt J. P. , Drake John M.
Published: September 2021

Zoonotic disease outbreaks are an important threat to human health and numerous drivers have been recognized as contributing to their increasing frequency. Identifying and quantifying relationships between drivers of zoonotic disease outbreaks and outbreak severity is critical to developing targeted zoonotic disease surveillance and outbreak prevention strategies. However, quantitative studies of outbreak drivers on a global scale are lacking. Attributes of countries such as press freedom, surveillance capabilities and latitude also bias global outbreak data. To illustrate these issues, we review the characteristics of the 100 largest outbreaks in a global dataset (
n
= 4463 bacterial and viral zoonotic outbreaks), and compare them with 200 randomly chosen background controls. Large outbreaks tended to have more drivers than background outbreaks and were related to large-scale environmental and demographic factors such as changes in vector abundance, human population density, unusual weather conditions and water contamination. Pathogens of large outbreaks were more likely to be viral and vector-borne than background outbreaks. Overall, our case study shows that the characteristics of large zoonotic outbreaks with thousands to millions of cases differ consistently from those of more typical outbreaks. We also discuss the limitations of our work, hoping to pave the way for more comprehensive future studies.

This article is part of the theme issue ‘Infectious disease macroecology: parasite diversity and dynamics across the globe’.
Identification of serotonin as a gut regulator of liver hepcidin expression
Authors: Coman Tereza , Falabrègue Marion , Rossignol Julien , Bonneau Pierre , Djebar Morgane , Bigorgne Amélie , Mathieu Jacques RR , Foretz Marc , Kautz Léon , Peoc’h’ Katel , Launay Jean-Marie , Maroteaux Luc , Peyssonnaux Carole , Hermine Olivier , Côté Francine
Published: September 2021

Iron is essential to key biological processes of all living organisms. Proper iron levels must be maintained to meet biological needs and prevent toxicity. Given the central role played by the hormone hepcidin in systemic iron homeostasis, extensive research has sought to identify regulators of its expression. Diverse evidence shows the gut to be an essential sensor and regulator of iron homeostasis, independently of other known hepcidin regulators, including bone marrow signals. Here we identify gut-derived serotonin as a key physiological factor in hepcidin regulation. In response to hypoxia, serotonin synthesized and secreted by enterochromaffin cells can act beyond the gut to repress hepcidin expression in the liver, through a 5-HT2Breceptor-dependent pathway. Bone marrow transplant experiments clearly indicate the gut is responsible for hepcidin repression. This regulatory system appears to be conserved in humans: a significant negative correlation exists between hepcidin and serotonin levels in the serum of healthy individuals. Our findings imply hepcidin regulation by serotonin is a physiological process, and modulation of the gut serotonergic system may have broad therapeutic implications.
Intergenerational effects of a paternal Western diet during adolescence on offspring gut microbiota, stress reactivity and social behavior
Authors: Bodden Carina , Pang Terence Y. , Feng Yingshi , Mridha Faria , Kong Geraldine , Li Shanshan , Watt Matthew J. , Reichelt Amy C. , Hannan Anthony J.
Published: September 2021

The global consumption of highly processed, calorie-dense foods has contributed to an epidemic of overweight and obesity, along with negative consequences for metabolic dysfunction and disease susceptibility. As it becomes apparent that overweight and obesity have ripple effects through generations, understanding of the processes involved is required, in both maternal and paternal epigenetic inheritance. We focused on the patrilineal effects of a Western-style high-fat (21%) and high-sugar (34%) diet (WD) compared to control diet (CD) during adolescence and investigated F0 and F1 mice for physiological and behavioral changes. F0 males (fathers) showed increased body weight, impaired glycemic control, and decreased attractiveness to females. Paternal WD caused significant phenotypic changes in F1 offspring, including higher body weights of pups, increased Actinobacteria abundance in the gut microbiota (ascertained using 16S microbiome profiling), a food preference for WD pellets, increased male dominance and attractiveness to females, as well as decreased behavioral despair. These results collectively demonstrate the long-term intergenerational effects of a Western-style diet during paternal adolescence. The behavioral and physiological alterations in F1 offspring provide evidence of adaptive paternal programming via epigenetic inheritance. These findings have important implications for understanding paternally mediated intergenerational inheritance, and its relevance to offspring health and disease susceptibility.
An ultra-low frequency spike timing dependent plasticity-based approach for treating alcohol use disorder
Authors: Asp Anders J. , Boschen Suelen Lucio , Lujan J. Luis
Published: September 2021

Alcohol use disorder (AUD) is a chronic relapsing brain disorder characterized by an impaired ability to stop or control alcohol consumption despite adverse social, occupational, or health consequences. AUD affects nearly one-third of adults at some point during their lives, with an associated cost of approximately $249 billion annually in the U.S. alone. The effects of alcohol consumption are expected to increase significantly during the COVID-19 pandemic, with alcohol sales increased by approximately 54%, potentially exacerbating health concerns and risk-taking behaviors. Unfortunately, existing pharmacological and behavioral therapies for AUD have historically been associated with poor success rates, with approximately 40% of individuals relapsing within three years of treatment.

Pre-clinical studies have shown that chronic alcohol consumption leads to significant changes in synaptic function within the dorsal medial striatum (DMS), one of the brain regions associated with AUD and responsible for mediating goal-directed behavior. Specifically, chronic alcohol consumption has been associated with hyperactivity of dopamine receptor 1 (D1) medium spiny neurons (MSN) and hypoactivity of dopamine receptor 2 (D1) MSNs within the DMS. Optogenetic, chemogenetic, and transgenic approaches have demonstrated that reducing the D1/D2 MSN signaling imbalance decreases alcohol self-administration in rodent models of AUD. However, these approaches cannot be studied clinically at this time.

Here, we present an electrical stimulation alternative that uses ultra-low (<=1Hz) frequency (ULF) spike-timing dependent plasticity (STDP) to reduce DMS D1/D2 MSN signaling imbalances by stimulating D1-MSN afferents into the GPi and ACC glutamatergic projections to the DMS in a time-locked stimulation sequence. Our data suggest that GPi/ACC ULF-STDP selectively decreases DMS D1-MSN hyperactivity leading to reduced alcohol consumption without evoking undesired affective behaviors in a two-bottle choice mouse model of AUD.
Increased Activation in the Fusiform Face Area to Greebles is a Result of Expertise Training, Not by its Face-likeness
Authors: Liu Kuo , Chen Chiu-Yueh , Wang Le-Si , Kung Chun-Chia
Published: September 2021

In 2011, Brants, Wagemans, & Op de Beeck (JOCN 23:12, pp. 3949-3958) trained eight individuals to become Greeble experts, and found neuronal inversion effects [NIEs; i.e., higher Fusiform Face Area (FFA) activity for upright, rather than inverted Greebles]. These effects were also found for faces, both before and after training. By claiming to have replicated the seminal Greeble training study (i.e., Gauthier, Tarr, Anderson, Skudlarski, & Gore, 1999, Nat Neurosci, 2, 568-573), Brants et al. interpreted these results as participants viewing Greebles as faces throughout training, contrary to the original argument of subjects becoming Greeble experts only after training. However, such a claim presents two issues. First, the behavioral training results of Brants et al. did not replicate those of Gauthier et al (1999), raising concerns of whether the right training regime had been adopted. Second, both a literature review and meta-analysis of NIE in the FFA suggest its unreliability as an index of face(-like) processing. To empirically evaluate these issues, the present study compared two documented training paradigms (i.e., Gauthier & Tarr, 1997, Vision Res, 37, 1673-1682; and Gauthier, Williams, Tarr, & Tanaka, 1998, Vision Res, 38, 2401-2428) and explored their impact on the FFA. The results showed significant increases in the FFA for Greebles, and a clear neural “adaptation” (i.e., decreased activity for faces following Greebles, but not following non-face objects, in the FFA) both only in the Gauthier97 group, and only after training, reflecting clear modulation of expertise following “appropriate” training. In both groups, no clear NIE for faces nor Greebles were found. Collectively, these data invalidate the two assumptions behind the Brants et al. findings, and provide not only the updated support, but also the new evidence, for the perceptual expertise hypothesis of FFA.
A machine learning model that emulates experts’ decision making in vancomycin initial dose planning
Authors: Matsuzaki Tetsuo , Kato Yoshiaki , Mizoguchi Hiroyuki , Yamada Kiyofumi
Published: September 2021

Vancomycin is a glycopeptide antibiotic that has been used primarily in the treatment of methicillin-resistantStaphylococcus aureusinfections. To enhance its clinical effectiveness and prevent nephrotoxicity, therapeutic drug monitoring (TDM) of trough concentrations is recommended.

Initial vancomycin dosing regimens are determined based on patient characteristics such as age, body weight, and renal function, and dosing strategies to achieve therapeutic concentration windows at initial TDM have been extensively studied. Although numerous dosing nomograms for specific populations have been developed, no comprehensive strategy exists for individually tailoring initial dosing regimens; therefore, decision making regarding initial dosing largely depends on each clinician’s experience and expertise.

In this study, we applied a machine-learning (ML) approach to integrate clinician knowledge into a predictive model for initial vancomycin dosing. A dataset of vancomycin initial dose plans defined by pharmacists experienced in vancomycin TDM (i.e., experts) was used to build the ML model. The target trough concentration was attained at comparable rates with the model- and expert-recommended dosing regimens, suggesting that the ML model successfully incorporated the experts’ knowledge. The predictive model developed here will contribute to improved decision making for initial vancomycin dosing and early attainment of therapeutic windows.
Cerebellar stimulations prevent Levodopa-induced dyskinesia in mice and normalize brain activity
Authors: Coutant Bérénice , Frontera Jimena Laura , Perrin Elodie , Combes Adèle , Tarpin Thibault , Menardy Fabien , Mailhes-Hamon Caroline , Perez Sylvie , Degos Bertrand , Venance Laurent , Léna Clément , Popa Daniela
Published: September 2021

Chronic Levodopa therapy, the gold-standard treatment of Parkinson’s Disease (PD), leads to the emergence of involuntary movements, called levodopa-induced dyskinesia (LID). Cerebellar stimulations have been shown to decrease LID severity in PD patients. Here, in order to determine how cerebellar stimulations induce LID alleviation, we performed daily short trains of optogenetic stimulations of Purkinje cells (PC) in freely moving mice. We demonstrated that these stimulations are sufficient to suppress LID or even prevent their development. This symptomatic relief is accompanied by the normalization of aberrant neuronal discharge in the cerebellar nuclei, the motor cortex and the parafascicular thalamus. Inhibition of the cerebello-parafascicular pathway counteracted the beneficial effect of cerebellar stimulations. Moreover, cerebellar stimulations reversed plasticity in D1 striatal neurons and normalized the overexpression of FosB, a transcription factor causally linked to LID. These findings demonstrate LID alleviation and prevention by daily PC stimulations, which restore the function of a wide brain motor network, and may be valuable for LID treatment.
ProteoDisco: A flexible R approach to generate customized protein databases for extended search space of novel and variant proteins in proteogenomic studies
Authors: van de Geer Wesley S. , van Riet Job , van de Werken Harmen J. G.
Published: September 2021

We present an R-based open-source software termed ProteoDisco that allows for flexible incorporation of genomic variants, fusion-genes and (aberrant) transcriptomic variants from standardized formats into protein variant sequences. ProteoDisco allows for a flexible step-by-step workflow allowing for in-depth customization to suit a myriad of research approaches in the field of proteogenomics, on all organisms for which a reference genome and transcript annotations are available.

Availability and Implementation

ProteoDisco (R package version ≥ 0.99) is available from https://github.com/ErasmusMC-CCBC/ProteoDisco/.

Contact

h.vandewerken@erasmusmc.nl

Supplementary information

Supplementary table, figures and data files available.
Perception affects the brain’s metabolic response to sensory stimulation
Authors: DiNuzzo Mauro , Mangia Silvia , Moraschi Marta , Mascali Daniele , Hagberg Gisela E. , Giove Federico
Published: September 2021

Processing of incoming sensory stimulation triggers an increase of cerebral perfusion and blood oxygenation (neurovascular response) as well as an alteration of the metabolic neurochemical profile (neurometabolic response). Here we show that perceived and unperceived isoluminant chromatic flickering stimuli designed to have similar neurovascular responses as measured by blood oxygenation level dependent functional MRI (BOLD-fMRI) in primary visual cortex (V1) have markedly different neurometabolic responses as measured by functional MRS. In particular, a significant regional buildup of lactate, an index of aerobic glycolysis, and glutamate, an index of malate-aspartate shuttle, occurred in V1 only when the flickering is perceived, without any relation with behavioral or physiological variables. Wheras the BOLD-fMRI signal in V1, a proxy for input to V1, was insensitive to flickering perception by design, the BOLD-fMRI signal in secondary visual areas was larger during perceived than unperceived flickering indicating increased output from V1. These results indicate that the upregulation of energy metabolism induced by visual stimulation depends on the type of information processing taking place in V1, and that 1H-fMRS provides unique information about local input/output balance that is not measured by BOLD-fMRI.

Significance statement

Visual perception has a measurable metabolic effect in the primary visual cortex (V1). Here we show that the upregulation of energy metabolism induced by isoluminant chromatic flickering depends on subjective visual perception. Within V1, perceived and unperceived stimuli that are contrast-matched to elicit similar blood-oxygenation level-dependent fMRI response are associated with clearly distinct neurochemical profiles. Specifically, regional accumulations of lactate (an index of aerobic glycolysis) and glutamate (an index of malate-aspartate shuttle) only develop during perceived stimuli, together with a larger activation of secondary visual areas. Our results imply a dissociation between metabolic and functional response, and indicate that that the upregulation of energy metabolism induced by visual stimulation depends on the type of information processing taking place in V1.
Limitations of a proposed correction for slow drifts in decision criterion
Authors: Gupta Diksha , Brody Carlos D.
Published: September 2021

Trial history biases in decision-making tasks are thought to reflect systematic updates of decision variables, therefore their precise nature informs conclusions about underlying heuristic strategies and learning processes. However, random drifts in decision variables can corrupt this inference by mimicking the signatures of systematic updates. Hence, identifying the trial-by-trial evolution of decision variables requires methods that can robustly account for such drifts. Recent studies (Lak’20, Mendonça‘20) have made important advances in this direction, by proposing a convenient method to correct for the influence of slow drifts in decision criterion, a key decision variable. Here we apply this correction to a variety of updating scenarios, and evaluate its performance. We show that the correction fails for a wide range of commonly assumed systematic updating strategies, distorting one’s inference away from the veridical strategies towards a narrow subset. To address these limitations, we propose a model-based approach for disambiguating systematic updates from random drifts, and demonstrate its success on real and synthetic datasets. We show that this approach accurately recovers the latent trajectory of drifts in decision criterion as well as the generative systematic updates from simulated data. Our results offer recommendations for methods to account for the interactions between history biases and slow drifts, and highlight the advantages of incorporating assumptions about the generative process directly into models of decision-making.