bluuebunny/crossref_metadata_2025 huggingface dataset:
Borderline Personality Disorder
Authors: Bogetti Curtis C. , Fertuck Eric A.
Published: February 2022

This chapter provides an overview of borderline personality disorder (BPD), beginning with the historical antecedents of the diagnosis. Next is a review of the DSM-5’s polythetic, categorical conceptualization of BPD. Currently, several dimensional and hybrid conceptualizations are under investigation. Epidemiologically, BPD has a community point prevalence between >1.0 and 4.5 percent and a lifetime prevalence between 2.7 and 5.9 percent. Individuals with BPD have high rates of attempted and completed suicide and non-suicidal self-injury. Further, BPD frequently co-occurs with a number of other psychiatric disorders, including mood disorders, anxiety disorders, post-traumatic stress disorder, and substance use disorders.

Both genetic factors and environmental factors appear to play a role in the development of BPD. Its estimated heritability is 40 percent. Individuals with BPD may have neural abnormalities in brain regions subserving social-emotional processing and inhibitory control. Childhood adversity, neglect and trauma, and insecure and disorganized attachment styles are robust developmental risk factors for the development of adult BPD. While BPD is high risk and can be difficult to treat, most individuals with BPD in young adulthood experience significant remission of symptoms as they age. Moreover, several specialized psychosocial treatments have a promising efficacy in reducing suicidality and BPD symptoms. Finally, the chapter reviews common clinical challenges in the clinical management of BPD, followed by a framework for conducting assessment and recommending evidence-based treatment approaches.
Dependent Personalities
Authors: Bornstein Robert F. , Natoli Adam P.
Published: February 2022

Interpersonal dependency—the tendency to look to others for nurturance, guidance, protection, and support, even in situations where autonomous functioning is possible—has become associated with passivity and submissiveness in the minds of mental health professionals. However, evidence suggests that dependent persons behave quite actively, even aggressively, in certain contexts. This chapter reviews research and clinical writing on interpersonal dependency and dependent personality disorder (DPD) to facilitate therapeutic work with dependent patients. The epidemiology of DPD, sex differences, prevalence rates, issues regarding differential diagnosis and comorbidity, and research documenting biological and environmental antecedents of DPD are described. We will describe an integrative framework, the cognitive/interactionist (C/I) model, which specifies the core cognitive, motivational, behavioral, and affective components of normal and pathological dependency. We also provide an overarching structure for conceptualizing contextual variations in dependency-related responding. Although dependency leads to increased risk for a number of negative outcomes (e.g., suicide and parasuicide, perpetration of domestic violence in men), it is also linked with an array of adaptive behavior patterns (e.g., conscientiousness in complying with medical and psychotherapeutic treatment regimens). A case formulation and discussion of treatment challenges in therapeutic work with dependent patients are presented; major psychosocial and pharmacological treatment approaches are evaluated; and guidelines for maximizing treatment efficacy are offered.
Psychological medicine (hospital psychiatry)
Authors: O'Dwyer Anne-Marie , Campion Mariel
Published: February 2022

Psychological medicine (hospital or liaison psychiatry) refers to the interface between medicine and psychiatry—a complex interrelationship It is typically based in a general hospital setting. In its broadest remit, the liaison psychiatrist provides education, support, and guidance to medical/surgical colleagues who are unfamiliar with mental illness and treating patients with comorbid mental illnesses. As one of the authors of this Handbook is a liaison psychiatrist, it could be argued that a liaison perspective permeates much of this book. As most doctors will encounter psychiatry in a (non-psychiatric) hospital or medical setting, it could equally be argued that this perspective is most useful in the context of training medical staff. Certainly, many of the topics normally considered under this heading are presented in other chapters. This chapter, therefore, examines the broad role of liaison psychiatry in medical settings before focusing on some specific areas: neuropsychiatry, disorders presenting with physical symptoms, and those associated with medical/surgical treatments. This chapter provides key information about psychological medicine, including:
• Management of complex co-morbid mental and physical illness.
• Aspects of neuro-psychiatry.
• Disorders presenting with prominent physical symptoms—factitious disorder, Munchausen’s.
• Treatment and illness effects (on depression; steroid-induced mania; cancer-related fatigue.
Physical treatments
Authors: O'Dwyer Anne-Marie , Campion Mariel
Published: February 2022

This chapter focuses on physical treatments (medication and ECT). Medications are a vital intervention for many types of mental illness. They are used in combination with education for patients and their families. They may be used on their own or together with psychological treatments. Electro-convulsive therapy (ECT) is used in specialist situations only but may be a treatment of choice in these specific, high-risk situations. As with any medication, medication for mental illness, while effective, does carry side-effects, including effects on sleep, weight, and physical mobility. Emergencies such as lithium toxicity and neuroleptic malignant syndrome are also reviewed. The chapter opens by discussing the importance of engaging the patient with treatment and presenting an overview of psychotropics. It then discusses key concepts in the biological treatment of mood, anxiety, sleep, and psychosis. Key issues in maintaining physical health, including baseline tests and monitoring, are also discussed.
Acrosomal alkalinization occurs during human sperm capacitation
Authors: Carrasquel Martínez Gabriela , Aldana Andrés , Carneiro Jorge , Treviño Claudia Lydia , Darszon Alberto
Published: February 2022

Mammalian sperm capacitation is a prerequisite for successful fertilization. Capacitation involves biochemical and physiological modifications of sperm as they travel through the female reproductive tract. These modifications prepare the sperm to undergo the acrosome reaction (AR), an acrosome vesicle exocytosis that is necessary for gamete fusion. Capacitation requires an increase in both intracellular calcium ([Ca2+]i) and pH (pHi). Mouse sperm capacitation is accompanied by acrosomal alkalinization and artificial elevation of the acrosome pH (pHa) is sufficient to trigger the AR in mouse and human sperm, but it is unknown if pHa increases naturally during human sperm capacitation. We used single-cell imaging and image-based flow cytometry to evaluate pHa during capacitation and its regulation. We found that pHa progressively increases during capacitation. The V-ATPase, which immunolocalized to the acrosome and equatorial segment, is mainly responsible for the acidity of the acrosome. It is likely that the regulation of V-ATPase is at least in part responsible for the progressive increase in pHa during capacitation. Acrosome alkalinization was dependent on extracellular HCO3− and Ca2+. Inhibition of the HCO3−-dependent adenylyl cyclase and protein kinase A induced significant pHa changes. Overall, alkalinization of the acrosome may be a key step in the path toward the AR.
Nesfatin-1 treatment preserves antioxidant status and attenuates renal fibrosis in rats with unilateral ureteral obstruction
Authors: Tezcan Neslihan , Özdemir-Kumral Zarife Nigâr , Özkan Yenal Naziye , Çilingir-Kaya Özlem T , Virlan Aysin Tulunay , Özbeyli Dilek , Çetinel Şule , Yeğen Berrak Ç , Koç Mehmet
Published: February 2022

Background

Nesfatin-1 (NES-1), an anorexigenic peptide, was reported to have anti-inflammatory and anti-apoptotic actions in several inflammation models.

Methods

To elucidate potential renoprotective effects of NES-1, unilateral ureteral obstruction (UUO) was induced in male Sprague Dawley rats by ligating left ureters. The rats were injected intraperitoneally with either saline (SL) or NES-1 (10 µg/kg/day) for 7 or 14 days (n = 8 in each group). On the 7th or 14th day, obstructed kidneys were removed for the isolation of leucocytes for flow-cytometric analysis and the assessments of biochemical and histopathological changes.

Results

Opposite to glutathione levels, renal myeloperoxidase activity in the SL-treated UUO group was significantly increased compared with the sham-operated group, while NES-1 treatment abolished the elevation. The percentages of CD8+/CD4+ T-lymphocytes infiltrating the obstructed kidneys were increased in the SL-treated groups but treatment with NES-1 did not prevent lymphocyte infiltration. Elevated tumour necrosis factor-alpha (TNF-α) levels in SL-treated UUO group were decreased with NES-1. Although total degeneration scores were similarly increased in all UUO groups, tubular dilatation scores were significantly increased in UUO groups and lowered by NES-1 only in the 7-day treated group. Elevated interstitial fibrosis scores in the SL-treated groups were decreased in both 7- and 14-day NES-1 treated groups, while alpha-smooth muscle actin (α-SMA) and apoptosis scores were depressed in both NES-1 treated groups.

Conclusion

The present data demonstrate that UUO-induced renal fibrosis is ameliorated by NES-1, which appears to involve the inhibition of neutrophil infiltration and thereby amelioration of oxidative stress and inflammation. These data suggest that NES-1 may have a regulatory role in protecting the kidneys against obstruction-induced renal injury.
A preclinical model of patient-derived cerebrospinal fluid circulating tumor cells for experimental therapeutics in leptomeningeal disease from melanoma
Authors: Law Vincent , Chen Zhihua , Vena Francesca , Smalley Inna , Macaulay Robert , Evernden Brittany R , Tran Nam , Pina Yolanda , Puskas John , Caceres Gisela , Bayle Simon , Johnson Joseph , Liu James K C , Etame Arnold , Vogelbaum Michael , Rodriguez Paulo , Duckett Derek , Czerniecki Brian , Chen Ann , Smalley Keiran S M , Forsyth Peter A
Published: February 2022

Background

Leptomeningeal disease (LMD) occurs as a late complication of several human cancers and has no rationally designed treatment options. A major barrier to developing effective therapies for LMD is the lack of cell-based or preclinical models that recapitulate human disease. Here, we describe the development of in vitro and in vivo cultures of patient-derived cerebrospinal fluid circulating tumor cells (PD-CSF-CTCs) from patients with melanoma as a preclinical model to identify exploitable vulnerabilities in melanoma LMD.

Methods

CSF-CTCs were collected from melanoma patients with melanoma-derived LMD and cultured ex vivo using human meningeal cell-conditioned media. Using immunoassays and RNA-sequencing analyses of PD-CSF-CTCs, molecular signaling pathways were examined and new therapeutic targets were tested for efficacy in PD-CSF-CTCs preclinical models.

Results

PD-CSF-CTCs were successfully established both in vitro and in vivo. Global RNA analyses of PD-CSF-CTCs revealed several therapeutically tractable targets. These studies complimented our prior proteomic studies highlighting IGF1 signaling as a potential target in LMD. As a proof of concept, combining treatment of ceritinib and trametinib in vitro and in vivo demonstrated synergistic antitumor activity in PD-CSF-CTCs and BRAF inhibitor-resistant melanoma cells.

Conclusions

This study demonstrates that CSF-CTCs can be grown in vitro and in vivo from some melanoma patients with LMD and used as preclinical models. These models retained melanoma expression patterns and had signaling pathways that are therapeutically targetable. These novel models/reagents may be useful in developing rationally designed treatments for LMD.
T lymphocytes as dynamic regulators of glioma pathobiology
Authors: Cordell Elizabeth C , Alghamri Mahmoud S , Castro Maria G , Gutmann David H
Published: February 2022

The brain tumor microenvironment contains numerous distinct types of nonneoplastic cells, which each serve a diverse set of roles relevant to the formation, maintenance, and progression of these central nervous system cancers. While varying in frequencies, monocytes (macrophages, microglia, and myeloid-derived suppressor cells), dendritic cells, natural killer cells, and T lymphocytes represent the most common nonneoplastic cellular constituents in low- and high-grade gliomas (astrocytomas). Although T cells are conventionally thought to target and eliminate neoplastic cells, T cells also exist in other states, characterized by tolerance, ignorance, anergy, and exhaustion. In addition, T cells can function as drivers of brain cancer growth, especially in low-grade gliomas. Since T cells originate in the blood and bone marrow sinuses, their capacity to function as both positive and negative regulators of glioma growth has ignited renewed interest in their deployment as immunotherapeutic agents. In this review, we discuss the roles of T cells in low- and high-grade glioma formation and progression, as well as the potential uses of modified T lymphocytes for brain cancer therapeutics.
Pattern of treatment failures in patients with central nervous system non-germinomatous germ cell tumors (CNS-NGGCT): A pooled analysis of clinical trials
Authors: Fonseca Adriana , Faure-Conter Cecile , Murray Matthew J , Fangusaro Jason , Bailey Shivani , Goldman Stewart , Khatua Soumen , Frappaz Didier , Calaminus Gabriele , Dhall Girish , Nicholson James C , Bouffet Eric , Bartels Ute
Published: February 2022

Background

Central Nervous System Non-Germinomatous Germ Cell Tumors (CNS-NGGCT) are rare but curable tumors. Due to their rarity, patients with treatment failures remain a poorly characterized group with unfavorable outcomes. In this study, we sought to characterize patients with treatment failures in a large, prospectively treated cohort.

Methods

European and North American clinical trials for patients with CNS-NGGCT (SIOP-GCT-96, SFOP-TGM-TC 90/92, COG-ACNS0122, and COG-ACNS1123) were pooled for analysis. Additionally, patients included and treated in the UK and France national registries under strict protocol guidelines were included as an independent, non-overlapping cohort.

Results

A total of 118 patients experienced a treatment failure. Twenty-four patients had progressive disease during therapy, and additional 11 patients were diagnosed with growing teratoma syndrome (GTS). Patients with GTS are significantly younger and present with local failures and negative tumor markers. Eighty-three individuals experienced disease relapses after treatment ended. Patients’ metastatic relapses presented significantly earlier than local relapses and were associated with tumor marker elevation (OR: 4.39; P = .026). In our analysis, focal or whole-ventricular radiation therapy was not associated with an increased risk of metastatic relapses.

Conclusions

Herein, we present the largest pooled dataset of prospectively treated patients with relapsed CNS-NGGCT. Our study identified younger age and negative tumor markers to be characteristic of GTS. Additionally, we elucidated that metastatic relapses occur earlier than local relapses are associated with elevated tumor markers and are not associated with the field of radiation therapy. These findings are of utmost importance for the planning of future clinical trials and the implementation of surveillance strategies in these patients.
ADXS31142 Immunotherapy ± Pembrolizumab Treatment for Metastatic Castration-Resistant Prostate Cancer: Open-Label Phase I/II KEYNOTE-046 Study
Authors: Stein Mark N , Fong Lawrence , Tutrone Ronald , Mega Anthony , Lam Elaine T , Parsi Megan , Vangala Surya , Gutierrez Andres A , Haas Naomi B
Published: February 2022

Background

ADXS31-142 is an attenuated Listeria monocytogenes-based immunotherapy targeting prostate-specific antigen (PSA), being evaluated as monotherapy and combined with pembrolizumab for metastatic castration-resistant prostate cancer (mCRPC).

Patients and Methods

The 2-part phase I/II KEYNOTE-046 study enrolled men with mCRPC who have progressed after 2 or fewer prior systemic treatment regimens in the metastatic setting. In Part A, intravenous ADXS31-142 monotherapy was given every 3 weeks (q3w) to 3 dose-escalation cohorts. In Part B, ADXS31-142 (1 × 109 colony-forming units) plus pembrolizumab (200 mg) was administered intravenously q3w for 3 doses with a fourth pembrolizumab dose 3 weeks later (12-week cycles) for up to 24 months or until progression/toxicity. Endpoints included safety, overall response rate, progression-free survival (PFS), overall survival (OS), and immunogenicity.

Results

Fifty patients received ADXS31-142 alone (n = 13) or with pembrolizumab (n = 37). Among the 37 RECIST-evaluable patients (n = 8 Part A; n = 29 Part B), there were no objective responses. Median PFS was 2.2 months (95% CI: 0.8-7.4) with monotherapy and 5.4 months (95% CI: 2.3-7.9) with the combination; median OS was 7.8 months (95% CI: 4.4-18.5) and 33.7 months (95% CI: 15.4–not evaluable), respectively. Promising OS benefit was observed in combination-treated patients who had received prior docetaxel (16.0 months, 95% CI: 6.4-34.6; n = 20) and those with visceral metastasis (16.4 months, 95% CI 4.0-not evaluable; n = 11). All patients had ≥1 treatment-related adverse event, mostly grade 1/2 manageable events. No additive toxicity was observed with combination treatment.

Conclusions

Combining ADXS31-142 with pembrolizumab was safe and well tolerated. The observed OS in mCRPC warrants further testing of this combination.

Clinical Trial registration

NCT02325557.
Temporal factors and distance to human settlement affect nest survival of the endangered Yellow-headed Parrot in Belize, Central America
Authors: Tarazona-Tubens Fabio L , Britt Charles R , Abadi Fitsum , Muschamp Mario , Desmond Martha J
Published: February 2022

The endangered Yellow-headed Parrot (Amazona oratrix) has experienced a considerable reduction in abundance and distribution. Identifying natural and anthropogenic causes of nest failure is a critical step towards developing conservation actions that increase nest survival. In this study, we examined daily nest survival in relation to temporal, habitat, and anthropogenic factors, as well as nest site properties. We monitored nests (n = 124) across 6 study sites in Belize during 2017 and 2018 and independently modeled the effects of predation, abandonment and poaching on daily nest survival rates. Overall, the estimated cumulative nest survival probability was 0.18 (95% CI: 0.12–0.25). Predation was the main cause of nest failure, followed by abandonment, and poaching. Our results showed that nest predation and abandonment usually occurred early in the nesting cycle. Day within the nesting season negatively influenced daily survival for abandoned nests and had a quadratic effect on survival for poached nests. Poaching events occurred at a specific date range later in the season, with nests farther from the nearest human settlement having higher daily survival. Findings from this study highlight the additive mortality effect that nest poaching is having on Yellow-headed Parrot populations in Belize and show that managers can anticipate the timing and location of nests most vulnerable to poaching.
Proteomic characterization of isolated Arabidopsis clathrin-coated vesicles reveals evolutionarily conserved and plant-specific components
Authors: Dahhan Dana A , Reynolds Gregory D , Cárdenas Jessica J , Eeckhout Dominique , Johnson Alexander , Yperman Klaas , Kaufmann Walter A , Vang Nou , Yan Xu , Hwang Inhwan , Heese Antje , De Jaeger Geert , Friml Jiří , Van Damme Daniël , Pan Jianwei , Bednarek Sebastian Y
Published: February 2022

In eukaryotes, clathrin-coated vesicles (CCVs) facilitate the internalization of material from the cell surface as well as the movement of cargo in post-Golgi trafficking pathways. This diversity of functions is partially provided by multiple monomeric and multimeric clathrin adaptor complexes that provide compartment and cargo selectivity. The adaptor-protein assembly polypeptide-1 (AP-1) complex operates as part of the secretory pathway at the trans-Golgi network (TGN), while the AP-2 complex and the TPLATE complex jointly operate at the plasma membrane to execute clathrin-mediated endocytosis. Key to our further understanding of clathrin-mediated trafficking in plants will be the comprehensive identification and characterization of the network of evolutionarily conserved and plant-specific core and accessory machinery involved in the formation and targeting of CCVs. To facilitate these studies, we have analyzed the proteome of enriched TGN/early endosome-derived and endocytic CCVs isolated from dividing and expanding suspension-cultured Arabidopsis (Arabidopsis thaliana) cells. Tandem mass spectrometry analysis results were validated by differential chemical labeling experiments to identify proteins co-enriching with CCVs. Proteins enriched in CCVs included previously characterized CCV components and cargos such as the vacuolar sorting receptors in addition to conserved and plant-specific components whose function in clathrin-mediated trafficking has not been previously defined. Notably, in addition to AP-1 and AP-2, all subunits of the AP-4 complex, but not AP-3 or AP-5, were found to be in high abundance in the CCV proteome. The association of AP-4 with suspension-cultured Arabidopsis CCVs is further supported via additional biochemical data.
The Counteracting Nature of Contextual Influences: Peer Effects and Offsetting Mechanisms in Schools
Authors: Borgen Nicolai T , Borgen Solveig T , Birkelund Gunn Elisabeth
Published: February 2022

There is currently a mismatch between the theoretical expectations of peer effects held by many scholars and the quantitative empirical literature. This paper contributes to the understanding of peer effects by highlighting the oft-overlooked conceptual distinction between social influences and a well-defined causal effect; peers may influence one another via several potentially contradicting mechanisms that result in small overall causal peer effects on educational outcomes. We exploit the idiosyncratic variation in gender composition across cohorts within schools to study offsetting mechanisms. Using population-wide Norwegian register and survey data, we find two distinct ways in which the share of girls in lower secondary schools (grades 8–10) affects academic outcomes. First, more girl peers improve the learning environment at school. Simultaneously, however, more girl peers reduce the students’ motivation for schoolwork. Such results suggest that peer effects stem from a complex process where various mechanisms are at odds with one another, and where the influence of peers on academic outcomes is a composite of different mechanisms. Overall, we find that more girl peers lower students’ school grades and reduce students’ likelihood of attending an academic track in upper secondary school (which qualifies for higher education). Supplementary analyses suggest that the achievement level of girls is the main reason for the gender peer effects found in our study.
Downregulation of Odd-Skipped Related 2, a Novel Regulator of Epithelial-Mesenchymal Transition, Enables Efficient Somatic Cell Reprogramming
Authors: Anh Le Phuong Hoang , Nishimura Ken , Kuno Akihiro , Linh Nguyen Thuy , Kato Tetsuo , Ohtaka Manami , Nakanishi Mahito , Sugihara Eiji , Sato Taka-Aki , Hayashi Yohei , Fukuda Aya , Hisatake Koji
Published: February 2022

Somatic cell reprogramming proceeds through a series of events to generate induced pluripotent stem cells (iPSCs). The early stage of reprogramming of mouse embryonic fibroblasts is characterized by rapid cell proliferation and morphological changes, which are accompanied by downregulation of mesenchyme-associated genes. However, the functional relevance of their downregulation to reprogramming remains poorly defined. In this study, we have screened transcriptional regulators that are downregulated immediately upon reprogramming, presumably through direct targeting by reprogramming factors. To test if these transcriptional regulators impact reprogramming when expressed continuously, we generated an expression vector that harbors human cytomegalovirus upstream open reading frame 2 (uORF2), which reduces translation to minimize the detrimental effect of an expressed protein. Screening of transcriptional regulators with this expression vector revealed that downregulation of (odd-skipped related 2 [Osr2]) is crucial for efficient reprogramming. Using a cell-based model for epithelial-mesenchymal transition (EMT), we show that Osr2 is a novel EMT regulator that acts through induction of transforming growth factor-β (TGF-β) signaling. During reprogramming, Osr2 downregulation not only diminishes TGF-β signaling but also allows activation of Wnt signaling, thus promoting mesenchymal-epithelial transition (MET) toward acquisition of pluripotency. Our results illuminate the functional significance of Osr2 downregulation in erasing the mesenchymal phenotype at an early stage of somatic cell reprogramming.
For Subacute Pain After Surgically Managed Fractures, Strong Opioids Not Superior to Mild Opioids
Authors: Rosenberg Karen
Published: February 2022

According to this study:

In patients with surgically managed orthopedic fractures, treatment with strong opioid medication isn't superior to treatment with milder opioid medication for the management of postdischarge pain.

Ongoing use of strong opioids after hospital discharge shouldn't be supported.
Efficacy Comparison of 3 Kinds of Distal Tibial Hemiepiphyseal Implants in the Treatment of Postoperative Ankle Valgus of Congenital Pseudarthrosis of the Tibia
Authors: Hu Xiongke , Li Anping , Liu Kun , Mei Haibo
Published: February 2022

Background:

Congenital pseudarthrosis of the tibia (CPT) is a complex and serious disease in orthopaedics which often requires multiple operations for treatment. Postoperative ankle valgus deformity is easily seen after the operation of CPT. The aim of this study is to retrospectively evaluate the effectiveness of three different implants for treating postoperative ankle valgus after CPT.

Methods:

A total of 41 patients with postoperative ankle valgus after CPT from December 2010 to July 2019 were selected. Of these 41 patients, 23 patients were treated with “U”-shaped staple, 10 patients were treated with hollow screw and 8 patients were treated with cortical bone screw. The evaluation index was tibiotalar angle. The general data, preoperative, postoperative, and final follow-up imaging data were recorded, and the deformity correction rate and complications were compared.

Results:

All the patients were performed with postoperative follow-up visit for at least 12 months (31 mo on average). In the “U”-shaped staple group, the preoperative tibiotalar angle was 74.8±4.8 degrees, the tibiotalar angle was 85.8±4.5 degrees when the internal fixation was removed; in the hollow screw group, the average preoperative tibiotalar angle was 72.2±6.1 degrees, the average tibiotalar angle was 88.4±5.1 degrees when the internal fixation was removed; in the cortical bone screw group, the average preoperative tibiotalar angle was 75.1±4.2 degrees, the average tibiotalar angle was 88.4±5.1 degrees when the internal fixation was removed. The correction rate of the “U”-shaped staple group was 0.71 degrees/month, with that of in the hollow screw group and cortical bone screw group being 0.64 degrees/month and 0.61 degrees/month, respectively. There was no significant difference in the correction rate between the 3 groups. One case of internal fixation complication was reported in the hollow screw group; 2 cases of missing correction effect were reported, 1 in cortical bone screw group and 1 in hollow screw group; and 2 cases showing symptom of wound pain were reported in the “U”-shaped staple group.

Conclusion:

Ankle valgus is a common postoperative complication of congenital tibial pseudarthrosis. Temporary hemiepiphysiodesis with “U”-shaped staple or screws is an effective treatment for postoperative ankle valgus deformity of CPT in children.

Level of Evidence:

Level IV—retrospective study.
Targeting Apoptosis Pathways With BCL2 and MDM2 Inhibitors in Adult B-cell Acute Lymphoblastic Leukemia
Authors: Hohtari Helena , Kankainen Matti , Adnan-Awad Shady , Yadav Bhagwan , Potdar Swapnil , Ianevski Aleksandr , Dufva Olli , Heckman Caroline , Sexl Veronika , Kytölä Soili , Mustjoki Satu , Porkka Kimmo
Published: February 2022

In adult patients, the treatment outcome of acute lymphoblastic leukemia (ALL) remains suboptimal. Here, we used an ex vivo drug testing platform and comprehensive molecular profiling to discover new drug candidates for B-ALL. We analyzed sensitivity of 18 primary B-ALL adult patient samples to 64 drugs in a physiological concentration range. Whole-transcriptome sequencing and publicly available expression data were used to examine gene expression biomarkers for observed drug responses. Apoptotic modulators targeting BCL2 and MDM2 were highly effective. Philadelphia chromosome–negative (Ph–) samples were sensitive to both BCL2/BCL-W/BCL-XL-targeting agent navitoclax and BCL2-selective venetoclax, whereas Ph-positive (Ph+) samples were more sensitive to navitoclax. Expression of BCL2 was downregulated and BCL-W and BCL-XL upregulated in Ph+ ALL compared with Ph– samples, providing elucidation for the observed difference in drug responses. A majority of the samples were sensitive to MDM2 inhibitor idasanutlin. The regulatory protein MDM2 suppresses the function of tumor suppressor p53, leading to impaired apoptosis. In B-ALL, the expression of MDM2 was increased compared with other hematological malignancies. In B-ALL cell lines, a combination of BCL2 and MDM2 inhibitor was synergistic. In summary, antiapoptotic proteins including BCL2 and MDM2 comprise promising targets for future drug studies in B-ALL.
Establishment and Evaluation of a Prediction Model of BLR for Severity in Coronavirus Disease 2019
Authors: He Zebao , Rui Fajuan , Yang Hongli , Ge Zhengming , Huang Rui , Ying Lingjun , Zhao Haihong , Wu Chao , Li Jie
Published: February 2022

Background:

Coronavirus disease 2019 (COVID-19) is an emerging infectious disease and has spread worldwide. Clinical risk factors associated with the severity in COVID-19 patients have not yet been well delineated. The aim of this study was to explore the risk factors related with the progression of severe COVID-19 and establish a prediction model for severity in COVID-19 patients.

Methods:

We retrospectively recruited patients with confirmed COVID-19 admitted in Enze Hospital, Taizhou Enze Medical Center (Group) and Nanjing Drum Tower Hospital between January 24 and March 12, 2020. Take the Taizhou cohort as the training set and the Nanjing cohort as the validation set. Severe case was defined based on the World Health Organization Interim Guidance Report criteria for severe pneumonia. The patients were divided into severe and non-severe groups. Epidemiological, laboratory, clinical, and imaging data were recorded with data collection forms from the electronic medical record. The predictive model of severe COVID-19 was constructed, and the efficacy of the predictive model in predicting the risk of severe COVID-19 was analyzed by the receiver operating characteristic curve (ROC).

Results:

A total of 402 COVID-19 patients were included in the study, including 98 patients in the training set (Nanjing cohort) and 304 patients in the validation set (Nanjing cohort). There were 54 cases (13.43%) in severe group and 348 cases (86.57%) in non-severe group. Logistic regression analysis showed that body mass index (BMI) and lymphocyte count were independent risk factors for severe COVID-19 (all P 
< 0.05). Logistic regression equation based on risk factors was established as follows: Logit (BL)=–5.552–5.473 ×
L + 0.418 × BMI. The area under the ROC curve (AUC) of the training set and the validation set were 0.928 and 0.848, respectively (all P 
< 0.001). The model was simplified to get a new model (BMI and lymphocyte count ratio, BLR) for predicting severe COVID-19 patients, and the AUC in the training set and validation set were 0.926 and 0.828, respectively (all P < 0.001).

Conclusions:

Higher BMI and lower lymphocyte count are critical factors associated with severity of COVID-19 patients. The simplified BLR model has a good predictive value for the severe COVID-19 patients. Metabolic factors involved in the development of COVID-19 need to be further investigated.
Human IFN-κ Inhibited Respiratory RNA Virus Replication Dependent on Cell-to-Cell Interaction in the Early Phase
Authors: Fu Weihui , Sun Peng , Fan Jun , Ding Longfei , Yuan Songhua , Zhai Guanxing , Zhang Miaomiao , Qiu Chenli , Zhang Shuye , Zhang Xiaoyan , Xu Jianqing
Published: February 2022

Background:

Interferon kappa (IFN-κ) is a type I interferon (IFN-I) that inhibits virus replication by evoking interferon-stimulated genes (ISGs). However, as an evolutionarily ancient interferon, IFN-κ may function differently from the later emerged interferon-α and β.

Methods:

Conventional molecular biology methods were used to determine the localization of IFN-κ and its structure and function. In addition, we employed RT-PCR, western blot, and RNA-Seq technologies to characterize the ISGs expression profile and antiviral activities exerted by IFN-κ or IFN-α2.

Results:

Human IFN-κ exists in two forms upon ectopic expression, one located on the cell membrane and the other secreted outside the cells. The membrane-anchored IFN-κ showed the ability to induce ISGs and curtail RNA virus replication, whereas the secreted IFN-κ failed to do so. Structural analyses indicated that 1-27aa at the N-terminus was the signal peptide, and 28-37aa was predicted as the transmembrane region. However, our data demonstrated that both of them were not associated with membrane localization of IFN-κ; the former influenced the expression and secretion of IFN-κ, and the latter had an impact on the induction of ISGs. In addition, prokaryotic purified soluble mature human IFN-κ was also capable of inducing ISGs and inhibiting RNA virus replication. Importantly, human IFN-κ induced a faster ISG response but with a lower intensity and a shorter half-life than the response of IFN-α2. In contrast, IFN-α2 started to function later but was stronger and more durable than IFN-κ.

Conclusions:

Human IFN-κ-induced ISG response and inhibited respiratory RNA virus replication dependent on cell-to-cell interactions. In addition, compared with IFN-α2, IFN-κ exerted effects more rapidly in the early phase, with less intensity and a shorter half-life. Therefore, IFN-κ may constitute the first line of IFN-I against respiratory virus infections.
From Discovery to Cure, A Great Journey of the Hepatitis C Virus Study
Authors: Yi Zhigang , Yuan Zhenghong
Published: February 2022

Hepatitis C virus (HCV) causes chronic infection in over 75% of the HCV-infected individuals, resulting in liver cancer in substantial patients. Since its discovery in 1989, HCV experiences a journey from discovery to cure, largely due to the virology studies and success of direct antiviral agent (DAA) development. We reviewed the HCV research journey, from the discovery of this virus to the development of DAAs for cure. Learning the methodology used in HCV studies and the knowledge of developing DAAs against HCV may inspire the studies of other difficult-to-culture viruses, such as hepatitis E virus and norovirus, as well as the development of DAAs for other single-stranded positive-sense RNA viruses, including the pandemic-causing SARS-CoV-2 virus, which shares the common replication strategy of forming a membrane-bound viral replicase.
General Practice in England
Authors: Razai Mohammad S. , Majeed Azeem
Published: February 2022

General practice or family medicine has historically been lauded as the “jewel in the crown” of the English National Health Service (NHS) (M. Marshall, 2015). General practice, at the heart of primary care, has continued to contribute to the high ranking of the NHS in international comparisons (M. S. Razai & A. Majeed, 2021) and evidence from several decades of research has shown that general practice in the UK has improved the nation's health (Royal College of General Practitioners, 2013). Furthermore, it has provided equitable, cost-effective, and accessible care for all with the flexibility to adapt rapidly to a changing society and political climates, such as during the COVID-19 pandemic when there was rapid implementation of remote consultation models (Royal College of General Practitioners, 2013). However, this much-admired public sector service has recently come under unprecedented political and media spotlight instigated by the pressures of the current pandemic on the NHS (M. S. Razai & A. Majeed, 2021). This coupled with collapsing morale among general practitioners (GPs), a shrinking GP workforce, inexorable demands, increasing workload, and decreasing real-terms per capita funding have caused many to sound alarm on a general practice in “crisis” (C. Gerada, 2021). In this article, we describe the evolving nature of general practice and the current crisis, as well as potential solutions and opportunities going forward.
Preterm birth and human milk proteome: are we ready for individualized fortification?
Authors: Zhu Jing , Liu Mengyuan , Xing Yan
Published: February 2022

Purpose of review

Preterm birth is one of the most pressing clinical problems in obstetrics and neonatology worldwide. One of the most sophisticated components of human milk is the proteome and a better understanding of it can lead to precision guides for feeding preterm infants. In this review, we will examine recent research focused on the human milk proteome and individualized protein fortification of human milk.

Recent findings

In both preterm and term birth, the protein content in mother's own milk dropped rapidly in the early postnatal period. Preterm milk had a higher protein content and contained different protein and endogenous peptide compositions compared with term milk. The peptides in gastrointestinal fluids of preterm infants still need further investigation. Individualized fortification is more superior to standard fortification, but it only focuses on the total protein amount. There is no data concerning the composition and posttranslational modifications of proteins and endogenous peptides with fortification and their longterm effects.

Comprehensive identification and characterization of the human milk proteome have led to the targeted breast milk fortification theory of preterm infant feeding and has also been enriched by clinical trials. However, to achieve fortification of key proteins and/or endogenous peptides, as standard clinical practice, requires additional studies. Future research should explore the long-term effect of protein fortification and pay more attention to quality rather than quantity in relation to infant body composition and growth outcomes.
Gastrointestinal coronavirus disease 2019 manifestations in childhood
Authors: Sansotta Naire , Norsa Lorenzo , D’Antiga Lorenzo
Published: February 2022

Purpose of the review

The pandemic of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has emerged and caused a massive global health crisis. The aim of this review is first, to provide the latest evidence on what is known about the pathophysiology and the transmission of SARS-CoV-2 and then to focus on the manifestations of the gastrointestinal (GI) tract in children with COVID-19. Lastly, we summarise the impact of COVID-19 on patients with preexisting GI diseases.

Recent findings

Even though the virus is mostly transmitted from human to human via respiratory droplets, ACE2 is known to be expressed throughout the GI tract, and SARS-CoV-2 ribonucleic acid has been isolated from patients’ stools. GI symptoms including abdominal pain, diarrhoea and vomiting are frequently reported in paediatric patients. Interestingly, a small number of patients seem to exhibit solely GI symptoms. In addition, a multisystem inflammatory syndrome in children (MIS-C) related to SARS-COV-2 described in children, has a high rate of GI involvement. Several etiopathogenetic mechanisms have been postulated to explain the GI involvement of COVID-19.

Clinicians should not underestimate or disregard these early or mild GI symptoms, because the patients may be infected and transmit the virus, or develop a more severe condition such as MIS-C.
COVID-19: vaccines, efficacy and effects on variants
Authors: Rudan Igor , Adeloye Davies , Sheikh Aziz
Published: February 2022

Purpose of review

We reviewed three leading strategies of vaccine development against coronavirus disease 2019 (COVID- 19): mRNA vaccines, adenoviral vector vaccines and recombinant nanoparticles. We also considered the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants and their impact on the effectiveness of the most widely implemented vaccines.

Recent findings

General properties, efficacy, safety and global uptake of Pfizer/BioNTech's Comirnaty (BNT162b2), Moderna's Spikevax (mRNA-1273), Oxford/AstraZeneca's ChAdOx1 nCoV-19, J&J/Janssen's Ad26.COV2.S and Novavax's NVX-CoV2373 vaccines at the end of the year 2021 were presented. We summarized the information on the effectiveness against COVID-19 infection, severe disease and death. We then focused on important missense mutations in the five variants of concern (VoC): Alpha, Beta, Gamma, Delta and Omicron. We explored the evidence for the effectiveness of the vaccines against those five VoC.

It is difficult to predict the further development of the COVID-19 pandemic. The development of vaccines of an increasingly broad spectrum against coronaviruses, more easily deliverable and conferring more durable immune protection is likely. However, the very large number of infections may lead to new mutations with unpredictable impacts. Interventions that would control COVID-19 more effectively and enable a safer coexistence with the SARS-CoV-2 virus and its emerging variants are still needed in early 2022.
Characterization of Inhaled Nitric Oxide Use for Cardiac Indications in Pediatric Patients*
Authors: Yates Andrew R. , Berger John T. , Reeder Ron W. , Banks Russell , Mourani Peter M. , Berg Robert A. , Carcillo Joseph A. , Carpenter Todd , Hall Mark W. , Meert Kathleen L. , McQuillen Patrick S. , Pollack Murray M. , Sapru Anil , Notterman Daniel A. , Holubkov Richard , Dean J. Michael , Wessel David L. ,   on behalf of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Collaborative Pediatric Critical Care Research Network
Published: February 2022

OBJECTIVES:

Characterize the use of inhaled nitric oxide (iNO) for pediatric cardiac patients and assess the relationship between patient characteristics before iNO initiation and outcomes following cardiac surgery.

DESIGN:

Observational cohort study.

SETTING:

PICU and cardiac ICUs in seven Collaborative Pediatric Critical Care Research Network hospitals.

PATIENTS:

Consecutive patients, less than 18 years old, mechanically ventilated before or within 24 hours of iNO initiation. iNO was started for a cardiac indication and excluded newborns with congenital diaphragmatic hernia, meconium aspiration syndrome, and persistent pulmonary hypertension, or when iNO started at an outside institution.

INTERVENTIONS:

None.

MEASUREMENTS AND MAIN RESULTS:

Four-hundred seven patients with iNO initiation based on cardiac dysfunction. Cardiac dysfunction patients were administered iNO for a median of 4 days (2–7 d). There was significant morbidity with 51 of 407 (13%) requiring extracorporeal membrane oxygenation and 27 of 407 (7%) requiring renal replacement therapy after iNO initiation, and a 28-day mortality of 46 of 407 (11%). Of the 366 (90%) survivors, 64 of 366 patients (17%) had new morbidity as assessed by Functional Status Scale. Among the postoperative cardiac surgical group (n = 301), 37 of 301 (12%) had a superior cavopulmonary connection and nine of 301 (3%) had a Fontan procedure. Based on echocardiographic variables prior to iNO (n = 160) in the postoperative surgical group, right ventricle dysfunction was associated with 28-day and hospital mortalities (both, p < 0.001) and ventilator-free days (p = 0.003); tricuspid valve regurgitation was only associated with ventilator-free days (p < 0.001), whereas pulmonary hypertension was not associated with mortality or ventilator-free days.

CONCLUSIONS:

Pediatric patients in whom iNO was initiated for a cardiac indication had a high mortality rate and significant morbidity. Right ventricular dysfunction, but not the presence of pulmonary hypertension on echocardiogram, was associated with ventilator-free days and mortality.
A safe protocol to identify low risk patients with COVID-19 pneumonia for outpatient management
Authors: Teigell Muñoz Francisco Javier , García-Guijarro Elena , García-Domingo Paula , Pérez-Nieto Guadalupe , Rojas Fernando Roque , García-Peña María , Nieto Gallo María Antonia , Melero Bermejo Jose Antonio , de Guzman García-Monge Maria Teresa , Granizo Juan José
Published: February 2022

Background

The coronavirus disease 2019 (COVID-19) outbreak has made necessary to rationalize health-care resources, but there are no published data to this moment regarding ambulatory management of patients with COVID-19 pneumonia.

Objective

Evaluate the results of a protocol for ambulatory management of patients with COVID-19 pneumonia according to the rate of readmissions, admission into the Intensive Care Unit (ICU) and deaths. Identify unfavorable prognostic factors that increase the risk of readmission, ICU admission and/or death.

Methods

Prospective cohort study of patients with COVID-19 pneumonia discharged from the emergency ward of Infanta Cristina Hospital (Madrid, Spain), that met the criteria of the hospital protocol for outpatient management. We describe outcomes of those patients and compare those who needed readmission versus those we did not. We use logistic regression to explore factors associated with readmissions.

Findings

314 patients were included, of which 20 (6.4%) needed readmission, 3 (1%) developed severe respiratory failure, and none needed ICU admission nor died. 29.9% of patients had any one comorbidity. Hypertension, leukopenia, lymphocytopenia, increased lactate dehydrogenase (LDH), increased aminotransferases were associated to a higher risk of readmission. A clinical course of 10 days or longer, and an absolute eosinophil count over 200/µL were associated with a lower risk. After multivariate analysis, only hypertension (OR 4.99, CI 1.54-16.02), temperature over 38°C in the emergency ward (OR 9.03, CI: 1.89-45.77), leukopenia (OR 4.92, CI 1.42-17.11) and increased LDH (OR 6.62, CI 2.82-19.26) remained significantly associated to readmission.

Conclusion

Outpatient management of patients with low-risk COVID-19 pneumonia is safe, if adequately selected. The protocol presented here has allowed avoiding 30% of the admissions for COVID-19 pneumonia in our hospital, with a very low readmission rate and non-existing mortality.

Funding

The authors received no specific funding for this work.