bluuebunny/crossref_metadata_2025 huggingface dataset:
Hypertensive Disorders of Pregnancy: Common Clinical Conundrums
Authors: Ohamadike Onyinye , Lim Stephanie L. , Siegel Anne , Zemtsov Gregory , Kuller Jeffrey A. , Dotters-Katz Sarah
Published: March 2022

Importance

Hypertensive complications of pregnancy comprise 16% of maternal deaths in developed countries and 7.4% of deaths in the United States. Rates of preeclampsia increased 25% from 1987 to 2004, and rates of severe preeclampsia have increased 6.7-fold between 1980 and 2003.

Objective

The aim of this study was to review current and available evidence for common clinical questions regarding the management of hypertensive disorders of pregnancy.

Evidence Acquisition

Original research articles, review articles, and guidelines on hypertension in pregnancy were reviewed.

Results

Severe gestational hypertension should be managed as preeclampsia with severe features. Serum uric acid levels can be useful in predicting development of superimposed preeclampsia for women with chronic hypertension. When presenting with preeclampsia with severe features before 34 weeks, expectant management should be considered only when both maternal and fetal conditions are stable. In the setting of hypertensive disorders of pregnancy, oral antihypertensive medications should be initiated when systolic blood pressure is greater than 160 mm Hg or when diastolic blood pressure is greater than 110 mm Hg, with the most ideal agents being labetalol or nifedipine. Furthermore, although risk of preeclampsia recurrence in future pregnancy is low, women with a history of preeclampsia should be managed with 81 mg aspirin daily for preeclampsia prevention.

Conclusion and Relevance

Despite the frequency with which hypertensive disorders of pregnancy are encountered clinically, situations arise frequently with limited evidence to guide providers in their management. An urgent need exists to better understand this disease to optimize outcomes for impacted patients.

Target Audience

Obstetricians and gynecologists, family physicians

Learning Objectives

After completing this activity, the learner should be better able to describe the diagnosis and delineation between various preeclampsia spectrum disorders; distinguish imitators of preeclampsia from preeclampsia; and explain best practices for management of various clinical conundrums related to hypertensive disorders of pregnancy.
Gluteal and Posterior Thigh Pain From a Suture Compared With an Anchor-Based Device in Patients Undergoing Sacrospinous Ligament Fixation: A Randomized Controlled Trial
Authors: Plair Andre , Smith Whitney , Hines Katherine , Schachar Jeffrey , Parker-Autry Candace , Matthews Catherine
Published: March 2022

(Abstracted from Obstet Gynecol 2022;139:97–106)

Repair of apical vaginal prolapse is commonly performed by suspension of the vaginal apex or cervix to the sacrospinous ligament. Some widely used suture-capturing devices for sacrospinous suspension are associated with postoperative pain in the gluteal and posterior thigh.
Children With a Soft Scalp Hematoma Presenting to the Emergency Department More Than 24 Hours After a Head Injury
Authors: Ferro Valentina , Boccuzzi Elena , Colafati Giovanna Stefania , De Benedictis Alessandro , Supino Maria Chiara , Faa Maria Francesca , Musolino Anna Maria , Reale Antonino , Raucci Umberto
Published: March 2022

Objectives

The soft scalp hematoma is one of the clinical markers used as a predictor for the presence of intracranial injury in children with a head trauma. We evaluated the significance of time presentation in the management of these patients.

Methods

We conducted a retrospective study of children and adolescents aged 0 to <18 years by comparing the clinical, radiological, and epidemiological features in those presenting within 24 hours with those presenting greater than 24 hours after a head injury.

Results

We identified 188 and 98 patients with early presentation and late presentation, respectively. The percentage of children aged 0 to <6 months was lower in those with late presentation (6.12%) than those with early presentation (20.21%) with a significant difference (P < .001). Likewise, the percentage of children aged ≥24 months was lower in children with late presentation (7.14%) than those with early presentation (34.04%) with a significant difference (P < .001). The severe mechanism rate was more elevated in early presentation (38.83%) with a significant difference (−14.34%; 95% confidence interval [CI], −25.34% to −3.34%; P = .015). The symptom rate resulted higher in early presentation (14.36%) with a significant difference (−11.30%; 95% CI, −17.36% to 5.22%; P = .003). The parietal scalp hematoma occurred mostly in children with late presentation (85.71%) with a significant difference (19.76%; 95% CI, 10.07% to 29.45%; P < .001). The occipital scalp hematoma rate was higher in early presentation with a significant difference (−17.50%; 95% CI, −22.99% to −12.12%; P < .001). There was no significant difference in the prevalence of different types of intracranial injury, and the only 5 patients needing a neurosurgical intervention were exclusively children with an early presentation.

Conclusion

Although children with soft scalp hematoma presenting to the emergency department greater than 24 hours after a head injury may have pathological findings on computed tomography, all of them had a good short- and long-term outcomes, and no neurological deterioration aroused the medical attention on follow-up. For this subset of patients that does not experience red flags (neurological symptoms, focal signs on examination, or severe injury mechanism), a wait-and-see approach might be more appropriate rather than neuroimaging.
Clinical Characteristics of Acute Hematogenous Osteomyelitis With and Without Subperiosteal Abscesses in the Acute Care Setting
Authors: Hartman Neal R. , Gerard James M. , Puryear Aki , Sethi Anchal , Flood Robert G.
Published: March 2022

Background

Acute hematogenous osteomyelitis (AHO) is a common pediatric disease that can progress to involve nearby structures leading to complications including subperiosteal abscesses (SPAs). Those with SPAs, in particular, often require surgical intervention for complete treatment. Staphylococcus aureus remains one of the most common causes of AHO. With the emergence of community-associated methicillin-resistant Ataphylococcus aureus and its propensity to form abscesses, there has been an observed increased frequency of AHO with SPAs in children. Although magnetic resonance imaging (MRI) remains the gold standard of imaging for AHO, it is not readily available on a 24/7 basis and often necessitates procedural sedation in children. Delay in MRI and surgical intervention in patients with SPAs may lead to increased complications. The goal of this study is to identify, using clinical features easily obtained in the acute care setting, patients at high risk for AHO with SPAs who may benefit from emergent MRI and/or surgical intervention.

Design/Methods

A retrospective chart review of patients aged birth to younger than 18 years diagnosed with AHO, who presented to a tertiary pediatric hospital from June 10, 2012, to November 1, 2017, were evaluated. Demographic, clinical, laboratory, and imaging data were collected. Patients were divided into 2 groups: AHO alone and AHO with SPAs.

Results

A final cohort of 110 subjects were included and analyzed. Of these, 73 (66%) were identified as having AHO alone and 37 (33.6%) as having AHO with SPAs. Patients had a higher risk of AHO with SPAs if they had a history of fever, decreased range of motion, edema, or elevated laboratory studies including white blood cell, absolute neutrophil count, erythrocyte sedimentation rate, and C-reactive protein. C-reactive protein was shown to have the highest correlation of AHO with SPAs, with an optimal cut point of 10.3 mg/dL, yielding a sensitivity of 67.7% and specificity of 77.6%. Patients with AHO with SPAs were at higher risk of having a positive blood culture for methicillin-resistant Staphylococcus aureus.

Conclusions

Clinicians in acute care settings should have a high index of suspicion of AHO with SPAs in children with history of fever, decreased range of motion, or elevated laboratory values (white blood cell, absolute neutrophil count, erythrocyte sedimentation rate, and C-reactive protein). In particular, those with a significantly elevated CRP are at a higher risk for having AHO with SPAs in comparison with an uncomplicated AHO. However, with the significant overlap in historical and clinical variables in the initial presentations of children with AHO with and without SPAs, the clinical urgency in obtaining a magnetic resonance imaging must continue to be individualized based on overall clinical suspicion and availability of resources.
Clinical Effect of Intrauterine 3-Dimensional Ultrasound on the Function of the Intrauterine Cavity of Puerpera With Intrauterine Adhesions and Safety of Pregnancy
Authors: Li Qin
Published: April 2022

This study aimed to analyze the diagnostic value of intrauterine 3-dimensional ultrasound and the functional characteristics of the intrauterine cavity for puerpera with intrauterine adhesions, and to explore the safety of pregnancy after treatment. A total of 102 puerperas with intrauterine adhesions were randomly selected, and intrauterine 3-dimensional ultrasound and 2-dimensional ultrasound were performed, respectively. Patients were followed up for 3 years to observe the pregnancy outcome and safety. The overall accuracy of diagnosing intrauterine adhesions through intrauterine 3-dimensional ultrasound was significantly higher than that through 2-dimensional ultrasound, and the accuracy of detecting mild intrauterine adhesions was significantly higher than that through 2-dimensional ultrasound, with statistically significant difference (P < 0.05). There was no significant difference in the accuracy between intrauterine 3-dimensional and 2-dimensional ultrasound in detecting moderate and severe intrauterine adhesions (P > 0.05). The difference in missed diagnosis and misdiagnosis rates between the 2 methods was statistically significant (P < 0.05). All patients received hysteroscopic surgery, and 78 cases (76.47%) were naturally fertilized during postoperative follow-up, including 24 cases of mature delivery, 45 cases of cesarean delivery, and 9 cases of spontaneous abortion. The intrauterine 3-dimensional ultrasound examination of the intrauterine cavity will provide intuitive and comprehensive diagnostic information for a parturient with intrauterine adhesion. Its detection accuracy is higher, and the clinical application is noninvasive and safe, which has certain guiding significance for treatment.
Early expression of IL-10, IL-12, ARG1, and NOS2 genes in peripheral blood mononuclear cells synergistically correlate with patient outcome after burn injury
Authors: Mahung Cressida , Stepp Wesley H. , Long Clayton , Malfitano Madison , Saklayici Irmak , Wallet Shannon M. , Zhou Laura Y. , Zhou Haibo , Cairns Bruce A. , Maile Robert
Published: April 2022

BACKGROUND

No methods exist to rapidly and accurately quantify the immune insult created by burn injuries. The development of a rapid, noninvasive clinical biomarker assay that evaluates a burn patient's underlying immune dysfunction and predicts clinical outcomes could transform burn care. We aimed to determine a set of peripheral biomarkers that correlates with clinical outcomes of burn patients.

METHODS

This prospective observational study enrolled two patient cohorts within a single burn center into an institutionally approved institutional review board study. Blood draws were performed <48 hours after injury. Initial unbiased immune gene expression analysis compared 23 burn patients and 6 healthy controls using multiplex immune gene expression analysis of RNA from peripheral blood mononuclear cells. We then performed confirmatory outcomes analysis in 109 burn patients and 19 healthy controls using a targeted rapid quantitative polymerase chain reaction. Findings were validated and modeled associations with clinical outcomes using a regression model.

RESULTS

A total of 149 genes with a significant difference in expression from burn patients compared with controls were identified. Pathway analysis identified pathways related to interleukin (IL)-10 and inducible nitric oxide synthase signaling to have significant z scores. quantitative polymerase chain reaction analysis of IL-10, IL-12, arginase 1 (ARG1), and inducible nitric oxide synthase demonstrated that burn injury was associated with increased expression of ARG1 and IL-10, and decreased expression of nitric oxide synthase 2 (NOS2) and IL-12. Burn severity, acute lung injury, development of infection, failure of skin autograft, and mortality significantly correlated with expression of one or more of these genes. Ratios of IL-10/IL-12, ARG1/NOS2, and (ARG1–IL-10)/(NOS2–IL-12) transcript levels further improved the correlation with outcomes. Using a multivariate regression model, adjusting for patient confounders demonstrated that (ARG1–IL-10)/(NOS2–IL-12) significantly correlated with burn severity and development of acute lung injury.

CONCLUSION

We present a means to predict patient outcomes early after burn injury using peripheral blood, allowing early identification of underlying immune dysfunction.

LEVEL OF EVIDENCE

Prognostic/Epidemiological; Level II.
Epidemiology and outcomes of multiple organ dysfunction syndrome following pediatric trauma
Authors: Killien Elizabeth Y. , Zahlan Jana M. , Lad Hetal , Watson R. Scott , Vavilala Monica S. , Huijsmans Roel L.N. , Rivara Frederick P.
Published: March 2022

BACKGROUND

Existing studies have found a low prevalence of multiple organ dysfunction syndrome (MODS) in pediatric trauma patients, typically applying adult criteria to single-center pediatric cohorts. We used pediatric criteria to determine the prevalence, risk factors, and outcomes of MODS among critically injured children in a national pediatric intensive care unit (PICU) database.

METHODS

We conducted a retrospective cohort study of PICU patients 1 month to 17 years with traumatic injury in the Virtual Pediatric Systems, LLC database from 2009 to 2017. We used International Pediatric Sepsis Consensus Conference criteria to identify MODS on Day 1 of PICU admission and estimated the risk of mortality and poor functional outcome (Pediatric Overall/Cerebral Performance Category ≥3 with ≥1 point worsening from baseline) for MODS and for each type of organ dysfunction using generalized linear Poisson regression adjusted for age, comorbidities, injury type and mechanism, and postoperative status.

RESULTS

Multiple organ dysfunction syndrome was present on PICU Day 1 in 23.1% of 37,177 trauma patients (n = 8,592), with highest risk among patients with injuries associated with drowning, asphyxiation, and abuse. Pediatric intensive care unit mortality was 20.1% among patients with MODS versus 0.5% among patients without MODS (adjusted relative risk, 32.3; 95% confidence interval, 24.1–43.4). Mortality ranged from 1.5% for one dysfunctional organ system to 69.1% for four or more organ systems and was highest among patients with hematologic dysfunction (43.3%) or renal dysfunction (29.6%). Death or poor functional outcome occurred in 46.7% of MODS patients versus 8.3% of patients without MODS (adjusted relative risk, 4.3; 95% confidence interval 3.4–5.3).

CONCLUSION

Multiple organ dysfunction syndrome occurs more frequently following pediatric trauma than previously reported and is associated with high risk of morbidity and mortality. Based on existing literature using identical methodology, both the prevalence and mortality associated with MODS are higher among trauma patients than the general PICU population. Consideration of early organ dysfunction in addition to injury severity may aid prognostication following pediatric trauma.

LEVEL OF EVIDENCE

Prognostic and Epidemiological; Level III.
Perspectives on competencies for care in austere settings
Authors: Kauvar David S. , Yelon Jay A. , Wilson Alison , Gaines Barbara A. , Martin Matthew J. , Cannon Jeremy W.
Published: March 2022

Austerity in surgical care may manifest by limited equipment/supplies, deficient infrastructure (power, water), rationing/triage requirements, or the unavailability of specialty surgical or medical expertise. Some settings in which surgeons may experience austerity include the following: military deployed operations (domestic and foreign), humanitarian surgical missions, care in rural or remote settings, mass-casualty events, natural disasters, and/or care in low- and some middle-income countries. Expanded competencies beyond those required in routine surgical practice can optimize the quality of surgical care in such settings. The purpose of this expert panel review is to introduce those competencies.
A cystic fibrosis lung disease modifier locus harbors tandem repeats associated with gene expression
Authors: Roshandel Delnaz , Mastromatteo Scott , Wang Cheng , Gong Jiafen , Thiruvahindrapuram Bhooma , Sung Wilson W.L. , Wang Zhuozhi , Hamdan Omar , Whitney Joe , Panjwani Naim , Lin Fan , Keenan Katherine , Chen Angela , Esmaeili Mohsen , Halevy Anat , Avolio Julie , Ratjen Felix , Celedón Juan C. , Forno Erick , Chen Wei , Kim Soyeon , Sun Lei , Rommens Johanna M. , Strug Lisa J.
Published: April 2022

Variable number of tandem repeats (VNTRs) are major source of genetic variation in human. However due to their repetitive nature and large size, it is challenging to genotype them by short-read sequencing. Therefore, there is limited understanding of how they contribute to complex traits such as cystic fibrosis (CF) lung function. Genome-wide association study (GWAS) of CF lung disease identified two independent signals near SLC9A3 displaying a high density of VNTRs and CpG islands. Here, we used long-read (PacBio) phased sequence (N=58) to identify the boundaries and lengths of 49 common (frequency >2%) VNTRs in the region. Subsequently, associations of the VNTRs with gene expression were investigated in CF nasal epithelia using RNA sequencing (N=46). Two VNTRs tagged by the two GWAS signals and overlapping CpG islands were independently associated with SLC9A3 expression in CF nasal epithelia. The two VNTRs together explained 24% of SLC9A3 gene expression variation. One of them was also associated with TPPP expression. We then showed that the VNTR lengths can be estimated with good accuracy in short-read sequence in a subset of individuals with data on both long (PacBio) and short-read (10X Genomics) technologies (N=52). VNTR lengths were then estimated in the Genotype-Tissue Expression project (GTEx) and their association with gene expression was investigated. Both VNTRs were associated with SLC9A3 expression in multiple non-CF GTEx tissues including lung. The results confirm that VNTRs can explain substantial variation in gene expression and be responsible for GWAS signals, and highlight the critical role of long-read sequencing.
External Validation of the Predicting Asthma Risk in Children (PARC) tool in a clinical cohort
Authors: Berger Daria Olena , Pedersen Eva S L , Mallet Maria Christina , de Jong Carmen C M , Usemann Jakob , Regamey Nicolas , Spycher Ben D , Ardura-Garcia Cristina , Kuehni Claudia E
Published: March 2022

Rationale

The Predicting Asthma Risk in Children (PARC) tool uses questionnaire-based respiratory symptoms collected from preschool children to predict their risk of asthma 5 years later. The tool was originally developed and externally validated in population-based settings and has not yet been validated in a clinical setting.

Objective

To externally validate the PARC tool in children seen in paediatric pulmonology clinics.

Methods

The Swiss Paediatric Airway Cohort (SPAC) is a prospective study of children seen in respiratory outpatient clinics across Switzerland. This analysis included children seen at ages 1-6 years for cough or wheeze at baseline and who completed the follow-up questionnaire 2 years later. The outcome was defined as current wheeze plus use of asthma medication. In sensitivity analyses, we explored effects of varied inclusion criteria and outcomes. We assessed performance by describing sensitivity, specificity, negative and positive predictive value (NPV, PPV), area under the curve (AUC), scaled Brier’s score and Nagelkerke’s R2 scores and compared performance in SPAC to that achieved in the original population, the Leicester Respiratory Cohort (LRC).

Results

Among the 346 children included, 125 (36%) reported the outcome after 2 years. At a PARC score cut-off of 4, sensitivity was higher (95% vs 79%) but specificity lower (14% vs 57%) in SPAC compared to LRC. NPV was comparable (0.84 vs. 0.87) as was PPV (0.37 vs.0.42). Discrimination was lower in SPAC (AUC of 0.71 vs 0.78), as were Nagelkerke’s R2 (0.18 vs 0.28) and scaled Brier’s scores (0.13 vs 0.22). When the outcome was changed to moderately severe asthma (>4 attacks plus use of asthma medication), there were improvements in AUC (0.74), sensitivity (0.97), specificity (0.22) and NPV (0.99), but some deterioration in PPV (0.13), R2 (0.15) and scaled Brier score (0.09).

Conclusion

While the PARC tool performs well in a population-based setting and has some clinical utility, in particular for ruling out the development of asthma, this study highlights the need for new prognostic prediction tools to be developed specifically for the clinical setting.

Funding

SNSF:320030_182628, SLA2019-03_641670
Ivacaftor, not ivacaftor/lumacaftor, is associated with lower pulmonary inflammation in preschool cystic fibrosis
Authors: Shanthikumar Shivanthan , Ranganathan Sarath , Neeland Melanie R.
Published: March 2022

Airway inflammation is a key driver of cystic fibrosis (CF) lung disease. The advent of cystic fibrosis transmembrane conductance regulator (CFTR) modulators has the potential to transform the care of CF, however the direct effect of these therapies on lung inflammation is unknown. Here, we profile airway inflammation in bronchoalveolar lavage (BAL) of preschool aged children with CF on CFTR modulator therapy (ivacaftor or ivacaftor/lumacaftor), untreated children with CF, and age-matched healthy controls. We show that children treated with ivacaftor have lower pulmonary concentrations of inflammatory mediators CCL3, CXCL9, CCL2, IL-8, IL-1β, and IL-6 relative to untreated children with CF. Conversely, there was no significant effect of lumacaftor/ivacaftor treatment on airway inflammation. This is the first work to illustrate a difference in early life airway inflammation with CFTR treatment, highlights the effectiveness of ivacaftor in early life, and suggests that BAL inflammatory profile may represent a biomarker of therapeutic response to treatment.
Reduction in risk of death among patients admitted with COVID-19 between first and second epidemic waves in New York City
Authors: Bowen Anthony , Zucker Jason , Shen Yanhan , Huang Simian , Yan Qiheng , Annavajhala Medini K. , Uhlemann Anne-Catrin , Kuhn Louise , Sobieszczyk Magdalena , Castor Delivette
Published: March 2022

Many regions have experienced successive epidemic waves of COVID-19 since the emergence of SARS-CoV-2 with heterogeneous differences in mortality. Elucidating factors differentially associated with mortality between epidemic waves may inform clinical and public health strategies. We examined clinical and demographic data among patients admitted with COVID-19 during the first (March-June 2020) and second (December 2020-March 2021) epidemic waves at an academic medical center in New York City. Hospitalized patients (N=4631) had lower mortality during the second wave (14%) than the first (23%). Patients in the second wave had a lower 30-day mortality (Hazard Ratio (HR) 0.52, 95% CI 0.44, 0.61) than those in the first wave. The mortality decrease persisted after adjusting for confounders except for the volume of COVID-19 admissions (HR 0.88, 95% CI 0.70, 1.11), a measure of health system strain. Several demographic and clinical patient factors were associated with an increased risk of mortality independent of wave.

Article summary

Using clinical and demographic data from COVID-19 hospitalizations at a tertiary New York City medical center, we show that a reduction in mortality during the second epidemic wave was associated with decreased strain on healthcare resources.
The impact of reactive case detection on malaria transmission in Zanzibar in the presence of human mobility
Authors: Das Aatreyee M. , Hetzel Manuel W. , Yukich Joshua O. , Stuck Logan , Fakih Bakar S. , Al-mafazy Abdul-wahid H. , Ali Abdullah , Chitnis Nakul
Published: March 2022

Malaria persists at low levels on Zanzibar despite the use of vector control and case management. We use a metapopulation model to investigate the role of human mobility in malaria persistence on Zanzibar, and the impact of reactive case detection. The model was parameterized using survey data on malaria prevalence, reactive case detection, and travel history. We find that in the absence of imported cases from mainland Tanzania, malaria would likely cease to persist on Zanzibar. We also investigate potential intervention scenarios that may lead to elimination, especially through changes to reactive case detection. While we find that some additional cases are removed by reactive case detection, a large proportion of cases are missed due to many infections having a low parasite density that go undetected by rapid diagnostic tests, a low rate of those infected with malaria seeking treatment, and a low rate of follow up at the household level of malaria cases detected at health facilities. While improvements in reactive case detection would lead to a reduction in malaria prevalence, none of the intervention scenarios tested here were sufficient to reach elimination. Imported cases need to be treated to have a substantial impact on prevalence.
Telomere length and its associations with mental disorders, age and genetic risk for mental disorders
Authors: Mutz Julian , Lewis Cathryn M
Published: March 2022

Background

Mental disorders are associated with substantially increased morbidity and reduced life expectancy. Accelerated biological ageing might contribute to excess mortality of individuals with mental disorders. The aim of this study was to characterise telomere length, a biological hallmark of ageing, in individuals with mental disorders, and to examine associations between telomere length, age and genetic risk for mental disorders.

Methods

The UK Biobank is a multicentre, community-based observational study that recruited >500,000 middle-aged and older adults across England, Scotland and Wales. Average leukocyte telomere length (T/S ratio) was measured using quantitative polymerase chain reaction. Polygenic risk scores (PRS) were calculated for individuals of European ancestry. We estimated differences in T/S ratio and age-related changes in T/S ratio between individuals with anxiety disorder, depression or bipolar disorder and people without mental disorders. We also estimated associations between T/S ratio and PRS for these three disorders.

Results

The analyses included up to 308,725 participants. Individuals with depression had shorter telomeres than people without mental disorders (adjustedβ= -0.011, 95% CI -0.019 to -0.004,pBonf.= 0.027). There was only limited evidence of case-control differences in telomere length for anxiety disorders or bipolar disorders. Age-related changes in telomere length did not differ between individuals with and without mental disorders. PRS for depression were associated with shorter telomeres (β= -0.006, 95% CI -0.010 to -0.003,pBonf.= 0.001). There was no evidence that PRS for anxiety disorder or bipolar disorder were associated with telomere length.

Conclusion

Although telomere length is a biological hallmark of ageing, we observed limited evidence that leukocyte telomere length is a clinically useful marker to quantify accelerated biological ageing in middle-aged and older adults with a lifetime history of anxiety disorder, depression or bipolar disorder.
Endemicity is not a victory: the unmitigated downside risks of widespread SARS-CoV-2 transmission
Authors: Stoddard Madison , Novokhodko Alexander , Sarkar Sharanya , Van Egeren Debra , White Laura F. , Hochberg Natasha S. , Rogers Michael , Zetter Bruce , Joseph-McCarthy Diane , Chakravarty Arijit
Published: March 2022

We have entered a new phase of the ongoing COVID-19 pandemic, as the strategy of relying solely on the current SARS-CoV-2 vaccines to bring the pandemic to an end has become infeasible. In response, public-health authorities in many countries have advocated for a strategy of using the vaccines to limit morbidity and mortality while permitting unchecked SARS-CoV-2 spread (“learning to live with the disease”). The feasibility of this strategy is critically dependent on the infection fatality rate (IFR) of COVID-19. An expectation exists, both in the lay public and in the scientific community, that future waves of the virus will exhibit decreased IFR, either due to viral attenuation or the progressive buildup of immunity. In this work, we examine the basis for that expectation, assessing the impact of virulence on transmission. Our findings suggest that large increases in virulence for SARS-CoV-2 would result in minimal loss of transmission, implying that the IFR may be free to increase or decrease under neutral evolutionary drift. We further examine the effect of changes in the IFR on the steady-state death toll under conditions of endemic COVID-19. Our modeling suggests that endemic SARS-CoV-2 implies vast transmission resulting in yearly US COVID-19 death tolls numbering in the hundreds of thousands under many plausible scenarios, with even modest increases in the IFR leading to an unsustainable mortality burden. Our findings thus highlight the critical importance of enacting a concerted strategy (involving for example global access to vaccines, therapeutics, prophylactics and nonpharmaceutical interventions) to suppress SARS-CoV-2 transmission, thereby reducing the risk of catastrophic outcomes. Our findings also highlight the importance of continued investment in novel biomedical interventions to prevent viral transmission.
A Distinct Chromatin State Drives Therapeutic Resistance in Invasive Lobular Breast Cancer
Authors: Nardone Agostina , Qiu Xintao , Feiglin Ariel , Fu Xiaoyong , Spisak Sandor , Feit Avery , Feit Gabriela Cohen , Xie Yingtian , Font-Tello Alba , Guarducci Cristina , Hermida-Prado Francisco , Syamala Sudeepa , Lim Klothilda , Pun Matthew , Cornwell MacIntosh , Liu Weihan , Ors Aysegul , Mohammed Hisham , Brock Jane , Freedman Matthew L. , Schiff Rachel , Winer Eric P. , Long Henry , Filho Otto Metzger , Jeselsohn Rinath
Published: March 2022

Most invasive lobular breast cancers (ILC) are of the luminal A subtype and strongly hormone receptor positive. Yet, they are relatively resistant to tamoxifen and are associated with inferior long-term outcomes compared to invasive ductal cancers (IDC). In this study, we sought to gain mechanistic insights into these clinical findings that are not explained by the genetic landscape of ILC and to identify strategies to improve patient outcomes. Through a comprehensive analysis of the epigenome of ILC in pre-clinical models and clinical samples we found that compared to IDC, ILC has a distinct chromatin state that is linked to gained recruitment of FOXA1, a lineage-defining pioneer transcription factor. This results in an ILC-unique FOXA1-estrogen receptor (ER) axis that promotes the transcription of genes associated with tumor progression and poor outcomes. The ILC-unique FOXA1-ER axis leads to retained ER chromatin binding after tamoxifen treatment thereby facilitating tamoxifen resistance while remaining strongly dependent on ER signaling. Mechanistically, gained FOXA1 binding was associated with the auto-induction of FOXA1 in ILC through an ILC-unique FOXA1 binding site. Targeted silencing of this regulatory site resulted in the disruption of the feed-forward loop and growth inhibition in ILC.

In summary, we show that ILC is characterized by a unique cell state and FOXA1-ER axis that dictate tumor progression and offer a novel mechanism of tamoxifen resistance. These results underscore the importance of conducting clinical trials dedicated to patients with ILC to optimize endocrine treatments in this breast cancer subtype.
Convergent and non-additive impact of schizophrenia risk genes in human neurons
Authors: Deans PJ Michael , Townsley Kayla G. , Li Aiqun , Seah Carina , Johnson Jessica , Gonzalez Judit Garcia , Cao Evan , Schrode Nadine , Yu Alex , Cartwright Sam , Voloudakis Georgios , Zhang Wen , Wang Minghui , Fullard John F. , Girdhar Kiran , Stahl Eli , Akbarian Schahram , Zhang Bin , Roussos Panos , O’Reilly Paul , Huckins Laura M. , Brennand Kristen J.
Published: March 2022

Genetic studies of schizophrenia reveal a complex polygenic risk architecture comprised of hundreds of risk variants; most are common in the population at-large, non-coding, and act by genetically regulating the expression of one or more gene targets (“eGenes”). It remains unclear how genetic variants predicted to confer individually small effects combine to yield substantial clinical impacts in aggregate. Here, we demonstrate that eGenes have shared downstream transcriptomic effects (“convergence”) that may underlie unexpected interactions (“non-additive effects”) observed when eGenes are manipulated in combination. We apply a pooled CRISPR approach to perturb schizophrenia eGenes in human induced pluripotent stem cell-derived glutamatergic neurons. The strength and specificity of convergence increased between functionally similar eGenes. Predicting that convergence might impact additive relationships between risk loci when inherited together, we use an arrayed approach to explore bidirectional combinatorial perturbations of a partially overlapping set of fifteen schizophrenia eGenes. When specifically considering groups of synaptic or epigenetic eGenes, combinatorial eGene perturbations yield changes that are smaller than predicted by summing individual eGene effects (“sub-additive effects”). Moreover, convergent and non-additive downstream transcriptomic effects overlap, suggesting that functional redundancy of eGenes may be a major mechanism underlying non-additivity. Combinatorial perturbations result in outcomes that are not yet well-predicted by single eGene perturbations alone, indicating that the effects of polygenic risk cannot necessarily be extrapolated from experiments testing one risk gene at a time.
The plastomes of Hyalomonas oviformis and Hyalogonium fusiforme evolved dissimilar architecture after the loss of photosynthesis
Authors: DeShaw Alexandra E. , Figueroa-Martinez Francisco , Pröschold Thomas , Lorenz Maike , Nedelcu Aurora M. , Smith David R. , Reyes-Prieto Adrián
Published: March 2022

The loss of photosynthesis in land plants and algae is typically associated with parasitism but can also occur in free-living species, including chlamydomonadalean green algae. The plastid genomes (ptDNAs) of colorless chlamydomonadalean species are surprisingly diverse in architecture, including highly expanded forms (Polytoma uvella, Leontynka pallida) as well as outright genome loss (Polytomella species). Here, we explore the ptDNAs of Hyalomonas (Hm.) oviformis (SAG 62-27; formerly known as Polytoma oviforme) and Hyalogonium (Hg.) fusiforme (SAG 62-1c), each representing independent losses of photosynthesis within the Chlamydomonadales. The Hm. oviformis ptDNA is moderately sized (132 kb), smaller than that of its photosynthetic relative Hyalomonas chlamydogama SAG 11-48b (198.3 kb), with a reduced gene complement but still encoding the ATPase subunits. The Hg. fusiforme plastome, however, is the largest yet observed in colorless plants or algae (~463 kb) and has a coding repertoire that is almost identical to that of its photosynthetic relatives in the genus Chlorogonium. Furthermore, the ptDNA of Hg. fusiforme shows no clear evidence of pseudogenization, which is consistent with our analyses showing that Hg. fusiforme is the non-photosynthetic lineage of most recent origin among the known colorless Chlamydomonadales. Together, these new ptDNAs clearly show that, in contrast to parasitic algae, plastid genome compaction is not an obligatory route following the loss of photosynthesis in free-living algae, and that certain chlamydomonadalean algae have a remarkable propensity for genomic expansion, which can persist regardless of the trophic strategy.

One sentence summary

The plastid genomes of two free-living chlamydomonadalean algae, Hyalomonas oviformis and Hyalogonium fusiforme, reveal different evolutionary stages following the loss of photosynthesis.
Epidemiological and virological factors determining dengue transmission in Sri Lanka during the COVID-19 pandemic
Authors: Ariyaratne Dinuka , Gomes Laksiri , Jayadas Tibutius T.P. , Kuruppu Heshan , Kodituwakku Lahiru , Jeewandara Chandima , Hetti Nimalka Pannila , Dheerasinghe Anoja , Samaraweera Sudath , Ogg Graham S. , Malavige Gathsaurie Neelika
Published: March 2022

Background

With the onset of the COVID-19 pandemic in early 2020 there was a drastic reduction in the number of dengue cases in Sri Lanka, with an increase towards the end of 2021. We sought to study the contribution of virological factors, human mobility, school closure and mosquito factors in affecting these changes in dengue transmission in Sri Lanka during this time.

Methods and findings

To understand the reasons for the differences in the dengue case numbers in 2020 to 2021 compared to previous years, we determined the association between the case numbers in Colombo (which has continuously reported the highest number of cases) with school closures, stringency index, changes in dengue virus (DENV) serotypes and vector densities.

There was a 79.4% drop in dengue cases from 2019 to 2020 in Colombo. A significant negative correlation was seen with the number of cases and school closures (Spearman’s r=-0.4732, p=<0.0001) and a negative correlation, which was not significant, between the stringency index and case numbers (Spearman’s r= -0.3755 p=0.0587). There was no change in the circulating DENV serotypes with DENV2 remaining the most prevalent serotype by early 2022 (65%), similar to the frequencies observed by end of 2019. The Aedes aegypti premise and container indices showed positive but insignificant correlations with dengue case numbers (Spearman r= 0.8827, p=0.93).

Conclusions

Lockdown measures, especially school closures seemed to have had a significant impact on the number of dengue cases, while the vector indices had a limited effect.
Predicting the time course of replacements of SARS-CoV-2 variants using relative reproduction numbers
Authors: Piantham Chayada , Ito Kimihito
Published: April 2022

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has continuously evolved since its introduction to the human population in 2019. Natural selection selects variants with higher effective reproduction numbers, increasing the overall transmissibility of the circulating viruses. In order to establish effective control measures for a new variant, it is crucial to know its transmissibility and replacement time course in early phases of the variant replacement. In this paper, we conduct retrospective prediction tests of the variant replacement from Alpha to Delta in England. Our method firstly estimated the relative reproduction number, the ratio of the reproduction number of a variant to that of another, from partial observations up to a given time point. Secondly, the replacement time course after the time point was predicted based on the estimates of relative reproduction number. Thirdly, the estimated relative reproduction number and the predicted time course were evaluated by being compared to those estimated using the entire observations. We found that it is possible to estimate the relative reproduction number of Delta with respect to Alpha when the frequency of Delta was more than or equal to 0.25. Using these relative reproduction numbers, predictions targeting on 1stJune 2021, the date when the frequency of Delta reached 0.90, had maximum absolute prediction errors of 0.015 for frequencies of Delta and 0.067 for the average relative reproduction number of circulating viruses with respect to Alpha. These results suggest that our method allows us to predict the time course of variant replacement in future from partial datasets observed in early phases of variant replacement.
Homozygous CADPS2 mutations cause neurodegenerative disease with Lewy bodies in parrots
Authors: Lorenzo-Betancor Oswaldo , Galosi Livio , Bonfili Laura , Eleuteri Anna Maria , Cecarini Valentina , Verin Ranieri , Dini Fabrizio , Attili Anna-Rita , Berardi Sara , Biagini Lucia , Robino Patrizia , Stella Maria Cristina , Yearout Dora , Dorschner Michael O. , Tsuang Debby W. , Rossi Giacomo , Zabetian Cyrus P.
Published: March 2022

Background

Several genetic models that recapitulate neurodegenerative features of Parkinson’s disease (PD) exist, which have been largely based on genes discovered in monogenic PD families. However, spontaneous genetic mutations have not been linked to the pathological hallmarks of PD in non-human vertebrates.

Objective

To describe the genetic and pathological findings of three yellow crowned parrot (Amazona ochrocepahala) siblings with a severe and rapidly progressive neurological phenotype.

Methods

The phenotype of the three parrots included severe ataxia, head tilt, and stargazing, while their parents were phenotypically normal. Tests to identify avian viral infections and brain imaging studies were all negative. Due to their inability to survive independently, they were all euthanized at age 3 months and their brains underwent neuropathological examination and proteasome activity assays. Whole genome sequencing (WGS) was performed on the three affected parrots and their parents.

Results

The brains of affected parrots exhibited neuronal loss, spongiosis, and Lewy bodies in the neocortex, amygdala, hypothalamus, periaqueductal gray matter, dorsal vagal nucleus, in some cerebellar Purkinje cells, and in the basal ganglia. Proteasome activity was significantly reduced in the affected parrots compared to a control (p<0.05). WGS identified a single homozygous missense mutation (p.V559L) in a highly conserved amino acid residue within the pleckstrin homology (PH) domain of the Calcium Dependent Secretion Activator 2 (CADPS2) gene. Previous studies suggest that CADPS2 is expressed at high levels in the substantia nigra where it regulates BDNF release. Thus, disruption of CADPS2 function could impact survival of dopaminergic neurons. Furthermore, CADPS2 expression is in part regulated by two well established PD genes, LRRK2 and SNCA.

Conclusions

Our data suggest that a homozygous mutation in the CADPS2 gene causes a severe neurodegenerative phenotype with Lewy bodies in parrots. Although CADPS2 variants have not been reported to cause PD in humans, further investigation of the gene in model organisms might provide important insights into the pathophysiology of Lewy body disorders.
Evolution of CRISPR-associated Endonucleases as Inferred from Resurrected Proteins
Authors: Alonso-Lerma Borja , Jabalera Ylenia , Morin Matias , Fernandez Almudena , Samperio Sara , Quesada Ane , Reifs Antonio , Fernández-Peñalver Sergio , Benitez Yolanda , Soletto Lucia , Gavira Jose A , Diaz Adrian , Vranken Wim , Kleinstiver Benjamin P. , Sanchez-Mejias Avencia , Güell Marc , Mojica Francisco JM , Moreno-Pelayo Miguel A , Montoliu Lluis , Perez-Jimenez Raul
Published: March 2022

Clustered regularly interspaced short palindromic repeats (CRISPR)-associated Cas9 protein is an effector that plays a major role in a prokaryotic adaptive immune system, by which invading DNA can be targeted and cut for inactivation. The Cas9 endonuclease is directed to target sites by a guide RNA (gRNA) where Cas9 can recognize specific sequences (PAMs) in foreign DNA, which then serve as an anchoring point for cleavage of the adjacent RNA-matching DNA region. Although the CRISPR-Cas9 system has been widely studied and repurposed for diverse applications (notably, genome editing), its origin and evolution remain to be elucidated. Here, we investigate the evolution of Cas9 from resurrected ancient nucleases (anCas) in extinct firmicutes species as old as 2600 myr to the current day. Surprisingly, we demonstrate that these ancient forms were much more flexible in their PAM and gRNA scaffold requirements compared to modern day Cas9 enzymes. In addition, anCas portrays a gradual paleoenzymatic adaptation from nickase to double-strand break activity, suggesting a mechanism by which ancient CRISPR systems could propagate when harboring Cas enzymes with minimal PAMs. The oldest anCas also exhibit high levels of activity with ssDNA and ssRNA targets, resembling Cas nucleases in related system types. Finally, we illustrate editing activity of the anCas enzymes in human cells. The prediction and characterization of anCas proteins uncovers an unexpected evolutionary trajectory leading to ancient enzymes with extraordinary properties.
Improved performance of biohybrid muscle-based bio-bots doped with piezoelectric boron nitride nanotubes
Authors: Mestre Rafael , Fuentes Judith , Lefaix Laura , Wang Jiaojiao , Guix Maria , Murillo Gonzalo , Bashir Rashid , Sánchez Samuel
Published: April 2022

Biohybrid robots, or bio-bots, integrate living and synthetic materials following a synergistic strategy to acquire some of the unique properties of biological organisms, like adaptability or bio-sensing, which are difficult to obtain exclusively using artificial materials. Skeletal muscle is one of the preferred candidates to power bio-bots, enabling a wide variety of movements from walking to swimming. Conductive nanocomposites, like gold nanoparticles or graphene, can provide benefits to muscle cells by improving the scaffolds’ mechanical and conductive properties. Here, we integrate boron nitride nanotubes (BNNTs), with piezoelectric properties, in muscle-based bio-bots and demonstrate an improvement in their force output and motion speed. We provide a full characterization of the BNNTs, and we confirm their piezoelectric behavior with piezometer and dynamometer measurements.Wehypothesize that the improved performance is a result of an electric field generated by the nanocomposites due to stresses produced by the cells during differentiation, which in turns improves their maturation. We back this hypothesis with finite element simulations supporting that this stress can generate a non-zero electric field within the matrix. With this work, we show that the integration of nanocomposite into muscle-based bio-bots can improve their performance, paving the way towards stronger and faster bio-hybrid robots.