bluuebunny/crossref_metadata_2025 huggingface dataset:
Acute onset bilateral hearing loss in dorsomedial pontine hemorrhage
Authors: Hoshino Masashi , Akiyama Hisanao , Kashima Satoru , Soga Kaima , Shimizu Takahiro , Hasegawa Yasuhiro
Published: August 2019

Rationale:

Nontraumatic pontine hemorrhage represents approximately 10% of all cases of nontraumatic intracranial hemorrhage. The predominant cause and symptom of pontine hemorrhage are hypertension and disturbance of consciousness, respectively.

Patient concerns:

A 64-year-old man was transported to hospital by ambulance for sudden articulation disorder and right leg paralysis. He was neurologically alert with mild dysarthria, right leg paralysis, and increased deep tendon reflex in all limbs.

Diagnosis:

Plain head computed tomography showed an approximately 1.5 mL hemorrhage in the dorsomedial pons.

Intervention:

He was admitted to the Stroke Care Unit and received antihypertensive therapy.

Outcomes:

Around the time of admission, bilateral hearing loss suddenly developed with poorly defined wave V shown bilaterally on auditory brainstem response testing. As the hematoma subsequently resolved, the bilateral hearing loss recovered sufficiently to enable everyday conversation.

Lessons:

We report herein a rare case of acute onset bilateral hearing loss caused by nontraumatic pontine hemorrhage. Pontine hemorrhage is often associated with disturbance of consciousness; however, care is required as latent communication disorder due to impaired hearing is possible regardless of the state of consciousness.
Neuromyelitis optica spectrum disorders with vertigo as the initial symptom
Authors: Guo Qin , Han Dexiong , Liu Jing , He Kelin , Ma Ruijie
Published: August 2019

Rationale:

Brain abnormalities have frequently been reported in neuromyelitis optica spectrum disorders patients, but vertigo as an initial manifestation has rarely been described.

Patient concerns:

A 64-year-old woman who initially presented with vertigo, then accompanied with other brainstem manifestations and spinal cord involvement.

Diagnoses:

MRI revealed medulla oblongata, cervical and thoracic spinal cord lesions. NMO-IgG antibody was seropositive. Taken her previous medical history and clinical manifestations into consideration, the patient was eventually diagnosed as neuromyelitis optica spectrum disorders.

Interventions:

Before diagnosis, symptomatic treatment and acupuncture were adopted, whereas after diagnosis, steroid, intravenous immunoglobulin, and immunosuppressant were supplemented.

Outcomes:

Her dizziness, nausea and vomiting were gradually relieved by symptomatic treatment and acupuncture before the confirmed diagnosis and immunotherapy. After added treatment with steroid, immunosuppressant, especially intravenous immunoglobulin, diplopia and nystagmus disappeared, and superficial sensation was improving. She was fully recovered six months after admission.

Lessons:

Vertigo as a rare prodrome of neuromyelitis optica spectrum disorders deserves attention. The symptoms and signs were improved by a combined treatment of steroid, immunosuppressant, acupuncture, and particularly intravenous immunoglobulin.
Perioperative acute myocardial infarction in patients after non-cardiac surgery in China
Authors: Zhou Xiaoxin , Chen Lingke , Su Zhongxue , Li Yue , Tu Mengyun , Xiao Jie , Pan Zhiying , Su Diansan
Published: August 2019

To examine the characteristics and short-term outcome of perioperative myocardial infarction (PMI), a single-center retrospective study was carried out. The electronic medical records of 278,939 patients aged 45 years or older who underwent non-cardiac surgery at Renji Hospital from January 2003 to December 2015 were screened based on diagnostic codes (ICD121, ICD121.0, ICD121.1, ICD121.2, ICD121.3, ICD121.4, or ICD121.9). The incidence and characteristics of PMI and mortality risk factors were analyzed after non-cardiac surgery. PMI was reported in 45 patients, with an incidence rate of 1.61 per 10,000 and a mortality rate of 75.6% (34/45). The PMI incidence rate increased significantly with age. The PMI incidence rate was the highest for vascular surgery (5.82 per 10,000 cases). PMI occurs mainly within 48 h of surgery, with most cases showing an onset in the general wards. Logistic analysis showed that the use of nitrates is the independent protective factor for the outcomes of patients with PMI. The incidence of PMI in non-cardiac surgery is approximately 2 of 10,000 in patients aged 45 years or older, and increased significantly with age. The use of nitrates might be helpful for their survival.
Angioimmunoblastic T-cell lymphoma mimicking drug fever and infectious etiology after a thyroidectomy
Authors: Han Ping , Yang Lan , Yan Wei , Tian Dean
Published: August 2019

Introduction:

Angioimmunoblastic T-cell lymphoma (AITL) is a rare subtype of mature peripheral T-cell lymphoma and accounts for approximately 1% to 2% of non-Hodgkin lymphomas. Although the B symptoms with generalized lymphadenopathy are the most frequent manifestations of AITL, its diagnosis remains a challenge as clinical manifestations and pathological features are frequently misleading.

Patient concerns:

We report herein the case of a 70-year-old man with intermittent fever, pulmonary infection, and skin rash developed for 1 month before admission. Previously, he had undergone thyroidectomy for thyroid papillary carcinoma. Fever occurred on the day of discharge and occurred again during the next month. Symptoms worsened despite treatment with antibiotics and papular rash appeared. The local hospital diagnosed it as drug fever and stopped all antibiotics. Fever and rash were controlled temporarily; however, both relapsed 2 days before admission. On the night of admission, the patient developed fever again. Blood culture showed Staphylococcus epidermidis and Staphylococcus haemolyticus infection.

Interventions:

Taking into account the recent history of surgery, the patient was diagnosed with septicemia and was treated with anti-infective treatment. On 13th day after admission, the patient developed fever again accompanied by generalized lymphadenopathy. However, multiple blood cultures were negative and bone marrow aspiration cytology, biopsy, immunohistochemistry, and gene rearrangement results were normal.

Diagnosis:

The patient was finally subjected to cervical lymph node biopsy and was diagnosed with AITL.

Outcomes:

The patient was transferred to the Department of Hematology for further treatment.

Conclusion:

This case highlights the complex diagnostic challenges of AITL. AITL accompanied by thyroid carcinoma may not be a mere coincidence and administration of antibiotics may be a rare cause of AITL.
A comparison of clinical outcomes between simultaneous integrated boost (SIB) versus sequential boost (SEQ) intensity modulated radiation therapy (IMRT) for head and neck cancer
Authors: Jiang Li , Zhang Yong , Yang Zhendong , Liang Feifei , Wu Jiangtao , Wang Rensheng
Published: August 2019

Background:

The optimal intensity modulated radiation therapy (IMRT) technique for head and neck cancer (HNC) has not been determined yet. The present study aimed to compare the clinical outcomes of the simultaneous integrated boost (SIB)-IMRT versus the sequential boost (SEQ)-IMRT in HNC.

Methods:

A meta-analysis of 7 studies involving a total of 1049 patients was carried out to compare the treatment outcomes together with severe acute adverse effects of the SIB-IMRT versus the SEQ-IMRT in HNC patients.

Results:

Comparison of the SIB-IMRT and SEQ-IMRT showed no significant difference in the measurement of overall survival (OS) (hazard ratio [HR] 0.94; 95% confidence inerval [CI], 0.70–1.27; P = .71), progression free survival (PFS) (HR 1.03; 95% CI, 0.82–1.30; P = .79), locoregional recurrence free survival (LRFS) (HR 0.98; 95% CI, 0.65–1.47; P = .91), and distance metastasis free survival (DMFS) (HR 0.87; 95% CI, 0.50–1.53; P = .63). Moreover, there were no significant differences in adverse effect occurrence between the SIB-IMRT and SEQ-IMRT groups.

Conclusion:

SIB-IMRT and SEQ-IMRT can provide comparable outcomes in the treatment of patients afflicted by HNC. Both IMRT techniques were found to carry a similar risk of severe acute adverse effect. SIB-IMRT may have advantages due to its convenience and short-course of treatment; however, the optimum fractionation and prescribed dose remained unclear. Furthermore, both IMRT techniques can be advocated as the technique of choice for HNC. Treatment plan should be individualized for patients.
Probiotics supplement for the prevention of eczema in children
Authors: Yang Wenhao , Tu Renyuan , Hu Yanan , He Tao , Zhang Weijian , Gu Li , Liu Hanmin
Published: August 2019

Background:

Atopic dermatitis (AD), also called eczema, is one of the most familiar chronic diseases in childhood. A possible pathological mechanism is immune dysfunction resulting in IgE sensitization to allergens. The recent studies demonstrated that the immune system can be affected by probiotics or prebiotics. However, the effectiveness and safety of probiotics or prebiotics on prevention of eczema are still unclear. To investigate this question, we conduct a systematic review and meta-analysis.

Methods:

The protocol followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols. Four main databases (PubMed, Embase, the Cochrane Library, and the web of science) will be searched dating until 15 July 2019 for randomized controlled trials investigating the effects and safety of probiotics or prebiotics on prevention of eczema in children with no language restrictions. In addition, a manual search of the references of relevant published studies will also be considered.

Studies selection, data extraction, and risk of bias assessment will be conducted by two independent reviewers. The primary outcome is the incidence of eczema. The second outcome is adverse events. The duration of intervention, the timing of intervention and intervention organism will be taken into consideration.

Results:

The results will provide useful information about the effect and safety of probiotics or prebiotics on reducing the incidence of eczema in children.

Conclusion:

The findings of this study will be published in a peer-reviewed journal.

PROSPERO registration number: CRD42019136528.
Surveillance of Opioid Prescribing as a Public Health Intervention: Washington State Bree Collaborative Opioid Metrics
Authors: Fulton-Kehoe Deborah , Von Korff Michael , Mai Jaymie , Weir Virginia , Lofy Kathryn H. , Sabel Jennifer , Tauben David , Franklin Gary
Published: August 2019

Context:

To address risks associated with prescription opioid medications, guidelines recommend lower dose, shorter duration of use, and avoidance of concurrent sedatives. Monitoring opioid-prescribing practices is critical for assessing guideline impact, comparing populations, and targeting interventions to reduce risks.

Objective:

To describe development of Washington (WA) State opioid-prescribing metrics, provide purpose and definitions, and apply metrics to prescription data for WA health care organizations.

Design:

We describe the development and testing of opioid-prescribing metrics by the WA State Bree Collaborative opioid work group.

Setting:

Washington State.

Participants:

Kaiser Permanente of Washington (KPW) Integrated Group Practice, KPW-contracted care providers, and WA Medicaid.

Main Outcome Measures:

Set of 6 strategic metrics tested across 3 different health systems adopted by WA State in 2017 for uniform tracking of opioid-prescribing guidelines and state policies. These metrics include (1) overall prevalence of any opioid use, (2) chronic use, (3) high-dose chronic use, (4) concurrent chronic sedative use, (5) days' supply of new prescriptions, and (6) transition from acute to chronic use.

Results:

In the first quarter of 2010, 10% to 12% of KPW and 14% of Medicaid patients received at least 1 opioid prescription. Among opioid users, 22% to 24% of KPW and 36% of Medicaid patients received chronic opioids. Among patients receiving chronic opioids, 16% to 22% of KPW and 32% of Medicaid patients received high doses (≥90 morphine-equivalent dose per day) and 20% to 23% of KPW and 33% of Medicaid patients received concurrent chronic sedatives. Five percent of Medicaid and 2% to 3% of KPW patients receiving new opioid prescriptions transitioned to chronic opioid use.

Conclusions:

The metrics are relatively easy to calculate from electronic health care data and yield meaningful comparisons between populations or health plans. These metrics can be used to display trends over time and to evaluate the impact of opioid-prescribing policy interventions.
Comparative Study of Meshed and Nonmeshed Acellular Dermal Matrix in Immediate Breast Reconstruction
Authors: Maisel Lotan Adi , Ben Yehuda Dafna , Allweis Tanir M. , Scheflan Michael
Published: August 2019

Background:

Acellular dermal matrices are commonly used to support implant-based breast reconstruction. Meshing may enhance integration, reduce drain time and seroma, and decrease surgical costs.

Methods:

This was a retrospective, single-center analysis of 83 adult women (115 breasts) undergoing one-stage (84.3 percent) or two-stage (15.7 percent) immediate breast reconstruction with bovine-derived acellular dermal matrix (SurgiMend) meshed at a 2:1 ratio. Outcomes were compared with previously published data from a control group of 111 patients (147 breasts) undergoing the same procedure with nonmeshed (fenestrated) acellular dermal matrix.

Results:

The mean age of patients receiving meshed acellular dermal matrix was 48.3 years and the mean body mass index was 23.6 kg/m2. There were no significant differences in baseline characteristics versus controls, other than chemotherapy history (received by fewer patients in the meshed acellular dermal matrix group). Mean follow-up was 23.6 months. Overall rates of minor and major complications in the meshed acellular dermal matrix group were 16.5 percent and 13.0 percent, respectively—similar to controls (25.2 percent and 12.9 percent). However, with meshed acellular dermal matrix, there were significantly fewer major seromas (0 percent versus 8.2 percent; OR, ∞; 95 percent CI, 1.927 to ∞), fewer total hematomas (0 percent versus 4.8 percent; OR, ∞; 95 percent CI, 1.022 to ∞), and fewer total infections (10.4 percent versus 23.8 percent; OR, 2.682; 95 percent CI, 1.259 to 5.802) compared with controls. Time to drain removal was reduced. Rates of capsular contracture (5.2 percent versus 2.7 percent) and explantation (5.2 percent versus 2.7 percent) were similar in the meshed acellular dermal matrix and control groups.

Conclusion:

Acellular dermal matrix meshing reduces rates of postoperative seroma, hematoma, and infection and decreases drain removal time compared with nonmeshed acellular dermal matrix.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, III.
Can a Partially Injured Donor Nerve Restore Elbow Flexion in an Acute Brachial Plexus Injury in Rats?
Authors: Chang Tommy Nai-Jen , Shafarenko Mark , Dadouch Rachel , Tang Evelyn Ting-Hsuan , Zhang Jennifer , Gordon Tessa , Borschel Gregory H.
Published: August 2019

Background:

Loss of elbow flexion commonly occurs following acute brachial plexus injury. The double fascicular transfer is often used in acute C5-C6 and C5-C7 root injuries, but is rarely applied in cases involving concomitant C8 or T1 root injury. The authors designed a rat model using varying severities of lower trunk injury to determine whether partial injury to the lower trunk affects nerve transfers for elbow flexion.

Methods:

There were four different rat groups in which 0, 25, 75, or 100 percent of the donor lower trunk remained intact. One-fourth of the cross-sectional area of the ulnar nerve was then transferred to the musculocutaneous nerve immediately. The authors assessed outcomes using a grooming test, muscle mass, retrograde labeling of sensory/motor neurons that regenerated axons, and immunohistochemical stain of regenerated axons.

Results:

Five months after nerve transfer, rats that underwent partial injury of the lower trunk fared significantly worse than the rats in whom the donor lower trunk remained 100 percent intact, but significantly better than the rats with 0 percent intact lower trunk. Rats with 25 or 75 percent of the lower trunk intact recovered equivalent function, at both the donor and recipient sites.

Conclusions:

Although relatively weak compared with the 100 percent intact donor lower trunk group, the partially injured donor nerve was still functional; even though the nerve sustained a partial injury, the residual axons reinnervated the target muscles. The power of the muscles following either 25 percent or 75 percent injuries was equal after the recovery. Resorting to this approach may be useful in cases in which no alternatives are available.
Immediate Reconstruction of Oncologic Spinal Wounds Is Cost-Effective Compared with Conventional Primary Wound Closure
Authors: Mericli Alexander F. , Rhines Laurence , Bird Justin , Liu Jun , Selber Jesse C.
Published: August 2019

Background:

Several studies have demonstrated a reduced wound complication rate when immediate soft-tissue reconstruction is performed after complex spine instrumentations in high-risk patients; however, the cost-effectiveness of this technique is not known. The authors hypothesized that immediate soft-tissue reconstruction of oncologic spine wounds would be a cost-effective strategy compared with the standard of care (i.e., oncologic spine surgery with conventional primary wound closure).

Methods:

The authors used a decision tree model to evaluate the cost-utility, from the perspective of a hospital/insurer, of immediate reconstruction relative to the standard of care after oncologic spine surgery. A systematic review of the literature on oncologic spine surgery and immediate and delayed spinal wound reconstruction was performed to estimate health state probabilities. Overall expected cost and quality-adjusted life-years were assessed using a Monte Carlo simulation and sensitivity analyses.

Results:

Immediate soft-tissue reconstruction after oncologic spine surgery had an expected cost of $81,458.90 and an expected average of 24.19 quality-adjusted life-years, whereas primary wound closure (no reconstruction) had an expected cost of $83,434.34 and an expected average of 24.17 quality-adjusted life-years, making immediate reconstruction the dominant, most cost-effective strategy. Monte Carlo sensitivity analysis demonstrated that immediate reconstruction was the preferred and most cost-effective option in the majority of simulations. Even when the willingness-to-pay threshold varied from $0 to $100,000 per quality-adjusted life-year, immediate reconstruction remained the dominant strategy across all iterations.

Conclusion:

This cost-utility analysis suggests that immediate soft-tissue reconstruction after oncologic spine surgery is more cost-effective than primary closure alone.
The Supercharged Pedicled Jejunal Flap for Total Esophageal Reconstruction: A Retrospective Review of 100 Cases
Authors: Mays Ashley C. , Yu Peirong , Hofstetter Wayne , Liu Jun , Xue Amy , Klebuc Michael , Chevray Pierre , Selber Jesse
Published: August 2019

Background:

When gastric pull-up is unsuccessful or unsuitable for total esophageal reconstruction, a supercharged pedicled jejunum can be used to reestablish gastrointestinal continuity. The authors reviewed their technique and outcomes of the supercharged pedicled jejunum for total esophageal reconstruction.

Methods:

A retrospective review of a prospectively maintained database was performed of 100 patients who underwent supercharged pedicled jejunum for total esophageal reconstruction between 2000 and 2017 at the Texas Medical Center. Patient characteristics, technical details, and outcomes were analyzed.

Results:

Mean patient age was 59.5 ± 11.4 years. Forty-two patients (42 percent) had surgical complications (18 percent at the recipient site, 13 percent at the donor site, and 11 percent at both). Medical complications occurred in 28 patients (28 percent). A major surgical complication occurred in 20 patients (20 percent). The average length of stay was 15 days (range, 6 to 152 days). At last follow-up, 20 patients (20 percent) had metastatic disease and six (6 percent) had local recurrence. Fifty-four patients (54 percent) died during the follow-up period. Of 79 patients with follow-up longer than 6 months, 68 (86 percent) tolerated a solid or soft oral diet, with a 16 percent tube feed-dependence rate. Overall survival at 1, 3, and 5 years was 78.8, 53.7, and 33.1 percent, respectively. The median survival time was 38.7 months.

Conclusions:

The authors present their experience with 100 supercharged pedicled jejunums for total esophageal reconstruction. Functional outcomes are comparable to, or better than, other salvage modalities. With careful multidisciplinary planning and meticulous, well-orchestrated surgical technique, swallowing function can be restored to provide quality of life in patients with few remaining surgical options.
Statistical Process Control Charts for Monitoring Staphylococcus aureus Bloodstream Infections in Australian Health Care Facilities
Authors: Imam Nabeel , Spelman Tim , Johnson Sandra A. , Worth Leon J.
Published: August 2019

Background:

Staphylococcus aureus bloodstream infection (SAB) in health care settings contributes significantly to mortality, and improved processes are associated with reduced burden of infection. In Australia, health care–associated SAB (HA-SAB) rates are reported as a health care performance indicator, but standardized methods for analyzing longitudinal data are not applied. Our objective was to evaluate the utility of statistical process control chart methodology for reporting HA-SAB and flagging higher than expected rates.

Methods:

A real-world test data set was defined as HA-SAB surveillance data collected by 155 Australian health care facilities between June 1, 2015, and June 30, 2017. This included 788 HA-SAB events, corresponding to an overall rate of 0.7 HA-SAB events per 10 000 occupied bed-days. The u-chart was selected as an appropriate tool, given the need for reporting natural units (HA-SAB rates) to a range of stakeholders. Facility-level data were plotted as u-charts, applying warning and control limits (2- and 3-SD thresholds, respectively).

Results:

Sixty-eight of the 155 participating facilities (43.9%) observed at least 1 HA-SAB event during the studied period. Using the traditional method of Poisson modeling, 56 of these 68 facilities demonstrated overdispersion with variance-to-mean ratio spanning 1.03 to 42.82. Modeling by negative binomial (NB) distribution was therefore applied to enhance functionality.

Conclusion:

The u-chart is an accessible method for monitoring HA-SAB, interpretable by a range of stakeholders. We demonstrate the benefit of NB modeling to account for overdispersion, providing an effective tool to avoid inappropriate flags while maintaining early detection of out-of-control systems throughout a wide range of health care settings.
Tutorial on Data Balancing: Application to Benchmarking Clinicians
Authors: Alemi Roshan , Elrafey Amr , Neuhauser Duncan , Alemi Farrokh
Published: August 2019

In this tutorial, we show how data balancing, in general, and stratified covariate balancing, in particular, can be used to benchmark clinicians. This tutorial aims to explain the concepts behind data balancing to readers who do not have a strong statistical background. Data balancing enables the analyst to compare the performance of clinicians with their peer groups on the same set of patients. The comparison is done in 3 steps. First, the patients are described in terms of their conditions/comorbidities. Each combination of comorbidities is treated as a separate type of patient. Second, the analyst measures the frequency of observing different types of patients. Third, expected outcomes are calculated for both the clinician and the peer group. The expected outcome for the clinician is calculated as the sum of product of 2 terms: probability of and the average outcome for different types of patients. The expected outcome for the peer group is calculated in the same way, with one difference: the distribution of peer group's patients is switched with the distribution of the clinician's patients. This allows us to simulate the performance of peer group on the clinician's patients. This switch in frequencies accomplishes the same goal as using propensity weights, or covariate balancing weights, but it avoids the cumbersome need to estimate the weights. In switching the distributions, a problem arises when the peer group does not see the same type of patients as the clinician. When the peer group's outcome for some patient types is missing, a synthetic case is organized. These synthetic cases are constructed from the peer group's experience with 2 complementary parts of the missing case. The reliance on synthetic cases allows one to have a match for every type of clinician's patients. Together, the synthetic case and the switch of distribution allow one to simulate the performance of the clinician and the peer group on same set of cases. The tutorial walks the reader through examples. The procedures described here can be applied to data in electronic health records. We present Standard Query Language for doing so.
The innovation of the final moult and the origin of insect metamorphosis
Authors: Belles Xavier
Published: August 2019

The three modes of insect postembryonic development are ametaboly, hemimetaboly and holometaboly, the latter being considered the only significant metamorphosis mode. However, the emergence of hemimetaboly, with the genuine innovation of the final moult, represents the origin of insect metamorphosis and a necessary step in the evolution of holometaboly. Hemimetaboly derives from ametaboly and might have appeared as a consequence of wing emergence in Pterygota, in the early Devonian. In extant insects, the final moult is mainly achieved through the degeneration of the prothoracic gland (PG), after the formation of the winged and reproductively competent adult stage. Metamorphosis, including the formation of the mature wings and the degeneration of the PG, is regulated by the MEKRE93 pathway, through which juvenile hormone precludes the adult morphogenesis by repressing the expression of transcription factor E93, which triggers this change. The MEKRE93 pathway appears conserved in extant metamorphosing insects, which suggest that this pathway was operative in the Pterygota last common ancestor. We propose that the final moult, and the consequent hemimetabolan metamorphosis, is a monophyletic innovation and that the role of E93 as a promoter of wing formation and the degeneration of the PG was mechanistically crucial for their emergence.

This article is part of the theme issue ‘The evolution of complete metamorphosis’.
Where did the pupa come from? The timing of juvenile hormone signalling supports homology between stages of hemimetabolous and holometabolous insects
Authors: Jindra Marek
Published: August 2019

Insect metamorphosis boasts spectacular cases of postembryonic development when juveniles undergo massive morphogenesis before attaining the adult form and function; in moths or flies the larvae do not even remotely resemble their adult parents. A selective advantage of complete metamorphosis (holometaboly) is that within one species the two forms with different lifestyles can exploit diverse habitats. It was the environmental adaptation and specialization of larvae, primarily the delay and internalization of wing development, that eventually required an intermediate stage that we call a pupa. It is a long-held and parsimonious hypothesis that the holometabolous pupa evolved through modification of a final juvenile stage of an ancestor developing through incomplete metamorphosis (hemimetaboly). Alternative hypotheses see the pupa as an equivalent of all hemimetabolous moulting cycles (instars) collapsed into one, and consider any preceding holometabolous larval instars free-living embryos stalled in development. Discoveries on juvenile hormone signalling that controls metamorphosis grant new support to the former hypothesis deriving the pupa from a final pre-adult stage. The timing of expression of genes that repress and promote adult development downstream of hormonal signals supports homology between postembryonic stages of hemimetabolous and holometabolous insects.

This article is part of the theme issue ‘The evolution of complete metamorphosis’.
Links between metamorphosis and symbiosis in holometabolous insects
Authors: Hammer Tobin J. , Moran Nancy A.
Published: August 2019

Many animals depend on microbial symbionts to provide nutrition, defence or other services. Holometabolous insects, as well as other animals that undergo metamorphosis, face unique constraints on symbiont maintenance. Microbes present in larvae encounter a radical transformation of their habitat and may also need to withstand chemical and immunological challenges. Metamorphosis also provides an opportunity, in that symbiotic associations can be decoupled over development. For example, some holometabolous insects maintain the same symbiont as larvae and adults, but house it in different tissues; in other species, larvae and adults may harbour entirely different types or numbers of microbes, in accordance with shifts in host diet or habitat. Such flexibility may provide an advantage over hemimetabolous insects, in which selection on adult-stage microbial associations may be constrained by its negative effects on immature stages, and vice versa. Additionally, metamorphosis itself can be directly influenced by symbionts. Across disparate insect taxa, microbes protect hosts from pathogen infection, supply nutrients essential for rebuilding the adult body and provide cues regulating pupation. However, microbial associations remain completely unstudied for many families and even orders of Holometabola, and future research will undoubtedly reveal more links between metamorphosis and microbiota, two widespread features of animal life.

This article is part of the theme issue ‘The evolution of complete metamorphosis’.
Regulatory mechanisms underlying the specification of the pupal-homologous stage in a hemimetabolous insect
Authors: Ishimaru Yoshiyasu , Tomonari Sayuri , Watanabe Takahito , Noji Sumihare , Mito Taro
Published: August 2019

Juvenile hormones and the genetic interaction between the transcription factorsKrüppel homologue 1(Kr-h1) andBroad(Br) regulate the transformation of insects from immature to adult forms in both types of metamorphosis (holometaboly with a pupal stage versus hemimetaboly with no pupal stage); however, knowledge about the exact instar in which this occurs is limited. Using the hemimetabolous cricketGryllus bimaculatus(Gb), we demonstrate that a genetic interaction occurs amongGb′Kr-h1,Gb′Brand the adult-specifier transcription factorGb′E93from the sixth to final (eighth) nymphal instar.Gb′Kr-h1andGb′BrmRNAs were strongly expressed in the abdominal tissues of sixth instar nymphs, with precocious adult moults being induced byGb′Kr-h1orGb′Brknockdown in the sixth instar. The depletion ofGb′Kr-h1orGb′BrupregulatesGb′E93in the sixth instar. By contrast,Gb′E93knockdown at the sixth instar prevents nymphs transitioning to adults, instead producing supernumerary nymphs.Gb′E93also repressesGb′Kr-h1andGb′Brexpression in the penultimate nymphal instar, demonstrating its important role in adult differentiation. Our results suggest that the regulatory mechanisms underlying the pupal transition in holometabolous insects are evolutionarily conserved in hemimetabolousG.bimaculatus, with the penultimate and final nymphal periods being equivalent to the pupal stage.

This article is part of the theme issue ‘The evolution of complete metamorphosis’.
Characterizing traumatic brain injury and its association with homelessness in a community-based sample of precariously housed adults and youth
Authors: Stubbs Jacob L. , Thornton Allen E. , Gicas Kristina M. , O’Connor Tiffany A. , Livingston Emily M. , Lu Henri Y. , Mehta Amiti K. , Lang Donna J. , Vertinsky Alexandra T. , Field Thalia S. , Heran Manraj K. , Leonova Olga , Buchanan Tari , Barr Alasdair M. , MacEwan G. William , Honer William G. , Panenka William J.
Published: August 2019

We characterized the prevalence, mechanisms, and sex difference of lifetime traumatic brain injury (TBI) in a precariously housed sample. We also examined the impact of TBI severity and timing on becoming and staying homeless. 285 precariously housed participants (adults n = 226, youths n = 59) completed the Brain Injury Screening Questionnaire (BISQ) in addition to other health assessments. A history of TBI was reported in 82.1% of the sample, with 64.6% reporting > 1 TBI, and 21.4% reporting a moderate or severe TBI (msTBI). 10.1% of adults had traumatically-induced lesions on MRI scans. Assault was the most common mechanism of injury overall, and females reported significantly more TBIs due to physical abuse than males (adjusted OR = 1.26, 95% CI = 1.14 – 1.39, p = 9.18e-6). The first msTBI was significantly closer to the first experience of homelessness (b = 2.79, p = 0.003) and precarious housing (b = 2.69, p = 7.47e-4) than was the first mild TBI. Traumatic brain injuries more proximal to the initial loss of stable housing were associated with a longer lifetime duration of homelessness (RR = 1.04, 95% CI = 1.02 – 1.06, p = 6.8e-6) and precarious housing (RR = 1.03, 95% CI = 1.01 – 1.04, p = 5.5e-10). These findings demonstrate the high prevalence of TBI in vulnerable persons and the severity- and timing-related risk that TBI may confer for the onset and prolongation of homelessness.
Cell-derived plasma membrane vesicles are permeable to hydrophilic macromolecules
Authors: Skinkle AD , Levental I
Published: August 2019

Giant Plasma Membrane Vesicles (GPMVs) are a widely used model system for biochemical and biophysical analysis of the isolated mammalian plasma membrane (PM). A core advantage of these vesicles is that they maintain the native lipid and protein diversity of the plasma membrane while affording the experimental flexibility of synthetic giant vesicles. In addition to fundamental investigations of PM structure and composition, GPMVs have been used to evaluate the binding of proteins and small molecules to cell-derived membranes, and the permeation of drug-like molecules through them. An important assumption of such experiments is that GPMVs are sealed; i.e. that permeation occurs by diffusion through the hydrophobic core rather than through hydrophilic pores. Here we demonstrate that this assumption is often incorrect. We find that most GPMVs isolated using standard preparations are passively permeable to various hydrophilic solutes as large as 40 kDa, in contrast to synthetic giant unilamellar vesicles (GUVs). We attribute this leakiness to relatively large and heterogeneous pores formed by rupture of vesicles from cells. These pores are stable and persist throughout experimentally relevant time scales. Finally, we identify preparation conditions that minimize poration and allow evaluation of sealed GPMVs. These unexpected observations of GPMV poration are of critical importance for interpreting experiments utilizing GPMVs as plasma membrane models, particularly for drug permeation and membrane asymmetry.

STATEMENT OF SIGNIFICANCE

A critical assumption in using Giant Plasma Membrane Vesicles to study membrane penetration and interactions is that these vesicles maintain the permeability barrier of the native membrane from which they form. Using large fluorescently-labeled hydrophilic probes, we demonstrate that this assumption is often incorrect and conclude that macromolecular solutes permeate GPMVs through stable pores formed during shear-induced rupture of vesicles from cells. Using these insights into the mechanisms of poration, we demonstrate an approach to isolate sealed GPMVs.
Desmin is a modifier of dystrophic muscle features in Mdx mice
Authors: Ferry Arnaud , Messéant Julien , Parlakian Ara , Lemaitre Mégane , Roy Pauline , Delacroix Clément , Lilienbaum Alain , Hovhannisyan Yeranuhi , Furling Denis , Klein Arnaud , Li Zhenlin , Agbulut Onnik
Published: August 2019

Duchenne muscular dystrophy (DMD) is a severe neuromuscular disease, caused by dystrophin deficiency. Desmin is like dystrophin associated to costameric structures bridging sarcomeres to extracellular matrix that are involved in force transmission and skeletal muscle integrity. In the present study, we wanted to gain further insight into the roles of desmin which expression is increased in the muscle from the mouse Mdx DMD model. We show that a deletion of the desmin gene (Des) in Mdx mice (DKO, Mdx:desmin-/-) induces a marked worsening of the weakness (reduced maximal force production) as compared to Mdx mice. Fragility (higher susceptibility to contraction-induced injury) was also aggravated and fatigue resistance was reduced in DKO mice. Moreover, in contrast to Mdx mice, the DKO mice did not undergo a muscle hypertrophy because of smaller and less numerous fibers, with reduced percentage of centronucleated fibres. Interestingly, Desmin cDNA transfer with adeno-associated virus in 1-month-old DKO mice and newborn Mdx mice improved muscle weakness. Overall, desmin plays important and beneficial roles on muscle performance, fragility and remodelling in dystrophic Mdx mice.
Highly efficient site-directed gene insertion in primary human natural killer cells using homologous recombination and CRISPaint delivered by AAV
Authors: Kararoudi Meisam Naeimi , Likhite Shibi , Elmas Ezgi , Schwartz Maura , Meyer Kathrin , Lee Dean A.
Published: August 2019

Human peripheral blood natural killer (NK) cells have strong antitumor activity and have been used successfully in several clinical trials. Modifying NK cells with a chimeric antigen receptor (CAR) can improve their targeting and increase specificity. However, genetic modification of NK cells has been challenging due to the high expression of innate sensing mechanisms for viral nucleic acids. Recently, we described an efficient vector-free method using Cas9/ribonucleoprotein complexes for gene deletion in NK cells. Here, we combined this approach with single-stranded (ss) or self-complementary (sc) Adeno-associated virus (AAV)-mediated gene delivery for gene insertion into a user-defined locus using homology repair (HR) and non-homologous directed CRISPR-assisted insertion tagging (CRISPaint) approaches. Using these approaches, we identified scAAV6 as the superior serotype for successful generation of stable mCherry-expressing primary NK cells (up to 89%). To maximize transgene packaging in HR-directed gene insertion, we identified minimum optimal homology arm lengths of 300bp for the flanking region of the Cas9-targeting site. Lastly, we demonstrate that mCherry positive NK cells can be expanded to large numbers using feeder cells expressing membrane-bound IL-21. This efficient method for site-directed insertion of genetic material into NK cells has broad potential for basic discovery and therapeutic applications for primary NK cells.
Phenome-wide and Genome-wide Analyses of Quality of Life in Schizophrenia
Authors: Pazoki Raha , Lin Bochao Danae , van Eijk Kristel R. , Schijven Dick , Guloksuz Sinan ,   GROUP investigators, Luykx Jurjen J.
Published: August 2019

Background

Schizophrenia negatively impacts quality of life (QoL). A handful of variables from small studies have been reported to influence QoL of schizophrenia patients, but a study comprehensively dissecting the genetic and non-genetic contributing factors to QoL in these patients is currently lacking. We adopted a hypothesis-generating approach to assess the phenotypic and genotypic determinants of QoL in schizophrenia.

Method

The study population consisted of 1,119 patients with a psychotic disorder, 1,979 relatives and 586 healthy controls. Using linear regression, we tested >100 independent demographic, cognitive and clinical phenotypes for their association with QoL in patients. We then performed genome-wide association analyses of QoL and examined the association between polygenic risk scores (PRSs) for schizophrenia, major depressive disorder (MDD), and subjective wellbeing (SW) with QoL.

Results

We found nine phenotypes to be significantly and independently associated with QoL in patients, the most significant ones being negative (Beta=-1.17; SE=0.05, P=1×10-83; r2=53%), depressive (Beta=-1.07; SE=0.05; P=2×10-79; r2=51%) and emotional distress (Beta=-0.09; SE=0.01; P=4×10-59, r2=38%) symptoms. Schizophrenia and subjective wellbeing PRSs using various P-value thresholds were significantly and consistently associated with QoL (lowest association p-value = 6.8×10-6). Several sensitivity analyses confirmed the results.

Conclusions

Various clinical phenotypes of schizophrenia as well as schizophrenia and subjective wellbeing polygenic risk scores are associated with QoL in schizophrenia patients and their relatives. These may be targeted by clinicians to more easily identify vulnerable schizophrenia patients for further social and clinical interventions to improve their QoL.
Clarifying species dependence under joint species distribution modeling
Authors: Gelfand Alan E. , Shirota Shinichiro
Published: August 2019

Joint species distribution modeling is attracting increasing attention these days, acknowledging the fact that individual level modeling fails to take into account expected dependence/interaction between species. These models attempt to capture species dependence through an associated correlation matrix arising from a set of latent multivariate normal variables. However, these associations offer little insight into dependence behavior between species at sites.

We focus on presence/absence data using joint species modeling which incorporates spatial dependence between sites. For pairs of species, we emphasize the induced odds ratios (along with the joint probabilities of occurrence); they provide much clearer understanding of joint presence/absence behavior. In fact, we propose a spatial odds ratio surface over the region of interest to capture how dependence varies over the region.

We illustrate with a dataset from the Cape Floristic Region of South Africa consisting of more than 600 species at more than 600 sites. We present the spatial distribution of odds ratios for pairs of species that are positively correlated and pairs that are negatively correlated under the joint species distribution model.

The multivariate normal covariance matrix associated with a collection of species is only a device for creating dependence among species but it lacks interpretation. By considering odds ratios, the quantitative ecologist will be able to better appreciate the practical dependence between species that is implicit in these joint species distribution modeling specifications.
Pediatric Cancer Variant Pathogenicity Information Exchange (PeCanPIE): a cloud-based platform for curating and classifying germline variants
Authors: Edmonson Michael N. , Patel Aman N. , Hedges Dale J. , Wang Zhaoming , Rampersaud Evadnie , Kesserwan Chimene A. , Zhou Xin , Liu Yanling , Newman Scott , Rusch Michael C. , McLeod Clay L. , Wilkinson Mark R. , Rice Stephen V. , Soussi Thierry , Taylor J. Paul , Benatar Michael , Becksfort Jared B. , Nichols Kim E. , Robison Leslie L. , Downing James R. , Zhang Jinghui
Published: August 2019

Variant interpretation in the era of massively parallel sequencing is challenging. Although many resources and guidelines are available to assist with this task, few integrated end-to-end tools exist. Here, we present the Pediatric Cancer Variant Pathogenicity Information Exchange (PeCanPIE), a web- and cloud-based platform for annotation, identification, and classification of variations in known or putative disease genes. Starting from a set of variants in variant call format (VCF), variants are annotated, ranked by putative pathogenicity, and presented for formal classification using a decision-support interface based on published guidelines from the American College of Medical Genetics and Genomics (ACMG). The system can accept files containing millions of variants and handle single-nucleotide variants (SNVs), simple insertions/deletions (indels), multiple-nucleotide variants (MNVs), and complex substitutions. PeCanPIE has been applied to classify variant pathogenicity in cancer predisposition genes in two large-scale investigations involving >4000 pediatric cancer patients and serves as a repository for the expert-reviewed results. PeCanPIE was originally developed for pediatric cancer but can be easily extended for use for nonpediatric cancers and noncancer genetic diseases. Although PeCanPIE's web-based interface was designed to be accessible to non-bioinformaticians, its back-end pipelines may also be run independently on the cloud, facilitating direct integration and broader adoption. PeCanPIE is publicly available and free for research use.
High-efficiency fast X-ray imaging detector development at SSRF
Authors: Xie Honglan , Luo Hongxin , Du Guohao , Zhao Chengqiang , Xu Wendong , Zhou Guangzhao , Chen Rongchang , Xiao Tiqiao
Published: August 2019

Indirect X-ray imaging detectors consisting of scintillator screens, long-working-distance microscope lenses and scientific high-speed complementary metal-oxide semiconductor (CMOS) cameras are usually used to realize fast X-ray imaging with white-beam synchrotron radiation. However, the detector efficiency is limited by the coupling efficiency of the long-working-distance microscope lenses, which is only about 5%. A long-working-distance microscope lenses system with a large numerical aperture (NA) is designed to increase the coupling efficiency. It offers an NA of 0.5 at 8× magnification. The Mitutoyo long-working-distance microscope lenses system offers an NA of 0.21 at 7.5× magnification. Compared with the Mitutoyo system, the developed long-working-distance microscope lenses system offers about twice the NA and four times the coupling efficiency. In the indirect X-ray imaging detector, a 50 µm-thick LuAG:Ce scintillator matching with the NA, and a high-speed visible-light CMOS FastCAM SAZ Photron camera are used. Test results show that the detector realized fast X-ray imaging with a frame rate of 100000 frames s−1 and fast X-ray microtomography with a temporal sampling rate up to 25 Hz (25 tomograms s−1).