bluuebunny/crossref_metadata_2025 huggingface dataset:
Abdominal Extension of Fournier Gangrene From Undiagnosed Crohn’s Disease: A Case Report
Authors: Carius Brandon M , Long Brit
Published: March 2021

Cellulitis and abscess are common skin infections in military populations. Although complications of necrotizing soft tissue infections (NSTIs) such as Fournier Gangrene (FG) are rare, they are associated with significant morbidity and mortality. Laboratory and radiological studies may aid in the evaluation of NSTI; however, focus should remain on physical examination and prompt surgical consultation, as these infections can spread rapidly with significant increases in mortality with delayed management. We present the case of a 37-year-old male soldier with reported history of two distant left inguinal hernia repairs, complaining of increasing buttock pain despite outpatient antibiotic therapy for perineal cellulitis from his primary clinician. Despite normal vital signs and low risk from established NSTI calculator scores, examination revealed crepitus and severe tenderness extending from the buttock through the perineum and scrotum characteristic of FG. Preoperative computed tomography found additional spread of subcutaneous air from these areas into the lower abdomen, likely facilitated by the previously repaired left inguinal hernia. Surgical management necessitated debridement, multiple washouts, and ileostomy. Follow-up evaluations revealed previously undiagnosed Crohn’s disease with fistula-in-ano as the inciting factor.
Ultra-compact X-ray binaries as dual-line gravitational-wave sources
Authors: Suvorov A G
Published: March 2021

By virtue of their sub-hour orbital periods, ultra-compact X-ray binaries are promising sources for the space-borne gravitational-wave interferometers LISA, Taiji, and TianQin. Some of these systems contain a neutron star primary, whose spin period can be measured directly via pulse timing, or indirectly through rotational modulations of burst phenomena. It is pointed out here that since actively accreting stars, with spin frequencies in the hundreds of Hz, may continuously emit appreciable gravitational waves due to the presence of accretion-built mountains, toroidal magnetic fields, and/or r-mode oscillations, such binaries are also candidate sources for ground-based interferometers. Two Galactic systems (4U 1728−34 and 4U 1820−30) are identified as being potentially detectable by both LISA and aLIGO simultaneously: a dual-line detection of this sort could provide percent-level constraints on the mass, radius, and internal magnetic field strength of the neutron star. With the Einstein Telescope, we find that at least four of the known ultra-compact binaries become dual-line visible.
RNA N6-methyladenosine modification, spermatogenesis, and human male infertility
Authors: Cai Zhonglin , Niu Yamei , Li Hongjun
Published: March 2021

RNA N6-methyladenosine (m6A) modification is one of the main forms of posttranscriptional modification, and its dysregulation is involved in a series of pathological processes. RNA m6A regulators, which mediate dynamic RNA m6A modification, are expressed in almost all types of testicular cells, including spermatogenetic cells and somatic cells. Cumulative studies have found that knockout of RNA m6A regulators in the testis leads to abnormal metabolism of the target mRNAs, which eventually causes spermatogenetic disorders and infertility. To date, a role for dysregulated RNA m6A modification in human male infertility remains elusive; however, dysregulated expression of RNA m6A regulators in abnormal human semen samples, including oligospermia, asthenozoospermia and azoospermia, has been found. Therefore, we speculate that abnormal RNA m6A methylation may be an important mechanism of male infertility. In this review, we summarize the recent findings regarding the spatiotemporal expression of RNA m6A regulators in the testes, mechanisms of RNA m6A modification in spermatogenesis and the relation between dysregulated RNA m6A regulators and human male infertility. In addition, we also discuss future directions in studying the molecular mechanism of male infertility and exploring their clinical applications from the viewpoint of RNA m6A modification.
Disparities in Integrase Inhibitor Usage in the Modern HIV Treatment Era: A Population-Based Study in a US City
Authors: Spinelli Matthew A , Hessol Nancy A , Schwarcz Sandra K , Scheer Susan , Gandhi Monica , Chin Hsu Ling
Published: March 2021

Integrase inhibitor–based (INSTI) antiretroviral therapy (ART) regimens are preferred for most people with HIV (PWH). We examined factors associated with INSTI use among PWH in San Francisco who started ART in 2009–2016. PWH who experienced homelessness were less likely, and older PWH were more likely, to use an INSTI.
GRAS-domain transcription factor PAT1 regulates jasmonic acid biosynthesis in grape cold stress response
Authors: Wang Zemin , Wong Darren Chern Jan , Wang Yi , Xu Guangzhao , Ren Chong , Liu Yanfei , Kuang Yangfu , Fan Peige , Li Shaohua , Xin Haiping , Liang Zhenchang
Published: March 2021

Cultivated grapevine (Vitis) is a highly valued horticultural crop, and cold stress affects its growth and productivity. Wild Amur grape (Vitis amurensis) PAT1 (Phytochrome A signal transduction 1, VaPAT1) is induced by low temperature, and ectopic expression of VaPAT1 enhances cold tolerance in Arabidopsis (Arabidopsis thaliana). However, little is known about the molecular mechanism of VaPAT1 during the cold stress response in grapevine. Here, we confirmed the overexpression of VaPAT1 in transformed grape calli enhanced cold tolerance. Yeast two-hybrid and bimolecular fluorescence complementation assays highlighted an interaction between VaPAT1 with INDETERMINATE-DOMAIN 3 (VaIDD3). A role of VaIDD3 in cold tolerance was also indicated. Transcriptome analysis revealed VaPAT1 and VaIDD3 overexpression and cold treatment coordinately modulate the expression of stress-related genes including lipoxygenase 3 (LOX3), a gene encoding a key jasmonate biosynthesis enzyme. Co-expression network analysis indicated LOX3 might be a downstream target of VaPAT1. Both electrophoretic mobility shift and dual luciferase reporter assays showed the VaPAT1-IDD3 complex binds to the IDD-box (AGACAAA) in the VaLOX3 promoter to activate its expression. Overexpression of both VaPAT1 and VaIDD3 increased the transcription of VaLOX3 and JA levels in transgenic grape calli. Conversely, VaPAT1-SRDX (dominant repression) and CRISPR/Cas9-mediated mutagenesis of PAT1-ED causing the loss of the C-terminus in grape calli dramatically prohibited the accumulation of VaLOX3 and JA levels during cold treatment. Together, these findings point to a pivotal role of VaPAT1 in the cold stress response in grape by regulating JA biosynthesis.
The Sound of Many Funds Rebalancing
Authors: Chinco Alex , Fos Vyacheslav
Published: March 2021

This paper proposes that computational complexity generates noise. The same asset is often held for completely different reasons by many funds following a wide variety of threshold-based trading rules. Under these conditions, we show it can be computationally infeasible to predict how these various trading rules will interact with one another, turning the net demand from these funds into unpredictable noise. This noise-generating mechanism can operate in a wide range of markets and also predicts how noise volatility will vary across assets. We confirm this prediction empirically using data on exchange-traded funds. (JEL G00, G02, G14).

Received May 28 2019; editorial decision December 16 2020 by Editor Thierry Foucault. Authors have furnished an Internet Appendix, which is available on the Oxford University Press Web site next to the link to the final published paper online.
Are neutrophil extracellular traps the link for the cross-talk between periodontitis and rheumatoid arthritis physiopathology?
Authors: Oliveira Sicília Rezende , de Arruda José Alcides Almeida , Schneider Ayda Henriques , Carvalho Valessa Florindo , Machado Caio Cavalcante , Corrêa Jôice Dias , Moura Marcela Faria , Duffles Letícia Fernanda , de Souza Flávio Falcão Lima , Ferreira Gilda Aparecida , Costa Fernando Oliveira , Abreu Lucas Guimarães , Taba Júnior Mário , Fukada Sandra Yasuyo , de Oliveira Renê Donizeti Ribeiro , Louzada-Júnior Paulo , Cunha Fernando de Queiroz , Silva Tarcília Aparecida
Published: March 2021

Objectives

Neutrophil extracellular traps (NETs) play a role in the pathogenesis of periodontitis and rheumatoid arthritis (RA). However, it remains poorly understood whether NETs participate in the cross-talk between periodontitis and RA. Herein, we investigated the production of NETs in individuals with periodontitis and RA and its association with clinical parameters. The impact of periodontal therapy on RA and NET release was also assessed.

Methods

The concentration of NETs and cytokines was determined in the saliva and plasma of individuals with early RA (n = 24), established RA (n = 64) and individuals without RA (n = 76). The influence of periodontitis on the production of NETs and cytokines was also evaluated.

Results

Individuals with early RA had a higher concentration of NETs in saliva and plasma than individuals with established RA or without RA. Periodontitis resulted in an increase in the concentration of NETs of groups of individuals without RA and with early RA. The proportion of individuals with high concentrations of IL-6, IL-10 and GM-CSF was higher among individuals with periodontitis than among individuals without periodontitis. The concentrations of TNF-α, IL-6, IL-17/IL-25 and IL-28A were particularly high in individuals with early RA. Worse periodontal clinical parameters, RA onset and RA activity were significantly associated with circulating NETs. Periodontal therapy was associated with a reduction in the concentration of NETs and inflammatory cytokines and amelioration in periodontitis and RA.

Conclusion

This study reveals that NETs are a possible link between periodontitis and RA, with periodontal therapy resulting in a dramatic switch in circulating NET levels.
Misreporting of Results of Research in Psychiatry
Authors: Bowcut Jana , Levi Linda , Livnah Ortal , Ross Joseph S , Knable Michael , Davidson Michael , Davis John M , Weiser Mark
Published: March 2021

Few studies address publication and outcome reporting biases of randomized controlled trials (RCTs) in psychiatry. The objective of this study was to determine publication and outcome reporting bias in RCTs funded by the Stanley Medical Research Institute (SMRI), a U.S. based, non-profit organization funding RCTs in schizophrenia and bipolar disorder. We identified all RCTs (n = 280) funded by SMRI between 2000 and 2011, and using non-public, final study reports and published manuscripts, we classified the results as positive or negative in terms of the drug compared to placebo. Design, outcome measures and statistical methods specified in the original protocol were compared to the published manuscript. Of 280 RCTs funded by SMRI between 2000 and 2011, at the time of this writing, three RCTs were ongoing and 39 were not performed. Among the 238 completed RCTs, 86 (36.1%) reported positive and 152 (63.9%) reported negative results: 86% (74/86) of those with positive findings were published in contrast to 53% (80/152) of those with negative findings (P < .001). In 70% of the manuscripts published, there were major discrepancies between the published manuscript and the original RCT protocol (change in the primary outcome measure or statistics, change in a number of patient groups, 25% or more reduction in sample size). We conclude that publication bias and outcome reporting bias is common in papers reporting RCTs in schizophrenia and bipolar disorder. These data have major implications regarding the validity of the reports of clinical trials published in the literature.
The effects of partially replacing animal protein sources with full fat black soldier fly larvae meal (Hermetia illucens) in nursery diets on growth performance, gut morphology, and immune response of pigs
Authors: Crosbie Michelina , Zhu Cuilan , Karrow Niel A , Huber Lee-Anne
Published: March 2021

One hundred and forty-four newly weaned pigs (6.74 ± 0.23 kg initial BW; 21 d of age) were used to determine the effect of partially replacing animal protein sources with black solider fly larvae meal (BSFLM) in nursery diets on growth performance, gut morphology, and immune response. After weaning, pigs were placed in 24 pens (six pigs per pen) and pens were randomly assigned to one of four dietary treatments (study d 0; n = 6), which were fed over three phases (phases I, II, and III were fed for 7, 14, and 21 d, respectively). Two nursery diets were formulated with 25% (LowFF) and 50% (HighFF) of the animal protein sources replaced by full fat BSFLM. Conventional nursery diets including animal protein sources without (CON−) and with antibiotics (220 mg Aureomycin per kg of complete feed; CON+) served as controls. On d 8, two pigs per pen were sacrificed to collect organ weights and for intestinal histomorphological measurements. On d 9 and d 23, two pigs per pen were vaccinated with the novel antigen ovalbumin (OVA). Blood samples were collected on d 9, d 23, and d 38 to assess concentrations of plasma haptoglobin and OVA-specific immunoglobulins G (IgG) and IgG1. On d 38, the same two pigs per pen underwent a dermal hypersensitivity test and skin-fold thickness was measured at 0, 6, 24, and 48 h postintradermal injection with OVA. Pigs fed the CON- had greater ADFI and lower G:F in phase II vs. those fed CON+ and HighFF diets (P < 0.05 and P < 0.05); intermediate ADFI was observed for pigs fed the LowFF diet. Overall in the nursery period, ADG (496 ± 13 g), ADFI (743 ± 23 g), G:F, and final BW (27.61 ± 0.66 kg) were not different among dietary treatments. There were no differences in organ weights, jejunal or ileal villus heights, or crypt depths among dietary treatments. There were no differences in OVA-specific IgG, IgG1, or plasma haptoglobin among dietary treatments at any of the blood sampling times. Although not different, pigs fed the LowFF, HighFF, and CON+ diets had respectively 2.0×, 1.7×, and 1.4× greater dermal hypersensitivity response to OVA versus those fed CON−. Both inclusion levels of BSFLM in nursery diets supported growth performance, gut morphology, and indices of immune function not different from the CON+, which suggest that full fat BSFLM can replace at least 50% of animal protein sources in nursery diets of pigs without any deleterious effects on pig growth.
How Memory Switches Brain Responses of Patients with Post-traumatic Stress Disorder
Authors: Inoue Jun , Matsuo Kayako , Iwabuchi Toshiki , Takehara Yasuo , Yamasue Hidenori
Published: March 2021

To characterize the brain responses to traumatic memories in post-traumatic stress disorder (PTSD), we conducted task-employed functional magnetic resonance imaging and, in the process, devised a simple but innovative approach—correlation computation between task conditions. A script-driven imagery task was used to compare the responses with a script of the patients’ own traumatic memories and with that of tooth brushing as a daily activity and to evaluate how eye movement desensitization and reprocessing (EMDR), an established therapy for PTSD, resolved the alterations in patients. Nine patients with PTSD (seven females, aged 27–50 years) and nine age- and gender-matched healthy controls participated in this study. Six patients underwent the second scan under the same paradigm after EMDR. We discovered intense negative correlations between daily and traumatic memory conditions in broad areas, including the hippocampus; patients who had an intense suppression of activation during daily recognition showed an intense activation while remembering a traumatic memory, whereas patients who had a hyperarousal in daily recognition showed an intense suppression while remembering a traumatic memory as a form of “shut-down.” Moreover, the magnitude of the discrepancy was reduced in patients who remitted after EMDR, which might predict an improved prognosis of PTSD.
Supplementation of milk polar lipids to obese dams improves neurodevelopment and cognitive function in male offspring
Authors: Yuan Qi‐chen , Gong Han , Du Min , Mao Xue‐ying
Published: March 2021

Milk contains about 4% fat globules with its surface covered by polar lipids. Despite the abundant consumption of dairy products, the biological effects of dietary milk polar lipids on metabolic health have only been sparsely examined. Maternal obesity results in neurodevelopmental disorders and cognitive impairment in offspring. Considering the importance of maternal nutrition, the effects of polar lipids‐enriched milk fat globule membrane (MFGM‐PL) supplementation to dams during pregnancy and lactation on neurodevelopment and its long‐term programming effects on offspring cognition were examined. Female Sprague‐Dawley rats consumed 8‐week control diet (CON) or high‐fat diet (HFD) to induce obesity before mating. Then, female rats were fed CON or HFD with or without the supplementation of 400 mg/kg body weight MFGM‐PL during pregnancy and lactation. The offspring were fed 11‐week HFD after weaning. MFGM‐PL supplementation to obese dams suppressed body weight gain and hyperinsulinemia in both dams and offspring. Offspring born to obese dams displayed delayed neurological reflexes development, impaired neurogenesis before weaning, and cognitive impairment in adulthood, which were recovered by maternal MFGM‐PL supplementation. Insulin resistance and aberrant brain‐derived neurotrophic factor signaling were induced in the hippocampus of neonatal and adult offspring due to maternal and progeny HFD, but recovered by maternal MFGM‐PL administration. This study demonstrates that maternal MFGM‐PL supplementation can promote neurodevelopment and exert long‐term effects against HFD‐induced cognitive impairment in offspring via alleviating hippocampal insulin resistance. Hence, MFGM‐PL is a promising ingredient for exerting beneficial programming effects on the brain health of offspring.
Bifunctional protein PCBD2 operates as a co‐factor for hepatocyte nuclear factor 1β and modulates gene transcription
Authors: Tholen Lotte E. , Bos Caro , Jansen Pascal W. T. C. , Venselaar Hanka , Vermeulen Michiel , Hoenderop Joost G. J. , de Baaij Jeroen H. F.
Published: March 2021

Hepatocyte nuclear factor 1β (HNF1β) is an essential transcription factor in development of the kidney, liver, and pancreas. HNF1β‐mediated transcription of target genes is dependent on the cell type and the development stage. Nevertheless, the regulation of HNF1β function by enhancers and co‐factors that allow this cell‐specific transcription is largely unknown. To map the HNF1β interactome we performed mass spectrometry in a mouse kidney inner medullary collecting duct cell line. Pterin‐4a‐carbinolamine dehydratase 2 (PCBD2) was identified as a novel interaction partner of HNF1β. PCBD2 and its close homolog PCBD1 shuttle between the cytoplasm and nucleus to exert their enzymatic and transcriptional activities. Although both PCBD proteins share high sequence identity (48% and 88% in HNF1 recognition helix), their tissue expression patterns are unique. PCBD1 is most abundant in kidney and liver while PCBD2 is also abundant in lung, spleen, and adipose tissue. Using immunolocalization studies and biochemical analysis we show that in presence of HNF1β the nuclear localization of PCBD1 and PCBD2 increases significantly. Promoter luciferase assays demonstrate that co‐factors PCBD1 and PCBD2 differentially regulate the ability of HNF1β to activate the promoters of transcriptional targets important in renal electrolyte homeostasis. Deleting the N‐terminal sequence of PCBD2, not found in PCBD1, diminished the differential effects of the co‐factors on HNF1β activity. All together these results indicate that PCBD1 and PCBD2 can exert different effects on HNF1β‐mediated transcription. Future studies should confirm whether these unique co‐factor activities also apply to HNF1β‐target genes involved in additional processes besides ion transport in the kidney.
Dermal fibroblast phagocytosis of apoptotic cells: A novel pathway for wound resolution
Authors: Romana‐Souza Bruna , Chen Lin , Leonardo Trevor R. , Chen Zhenlong , DiPietro Luisa A.
Published: March 2021

The effective clearance of apoptotic cells is an essential step in the resolution of healing wounds. In particular, blood vessel regression during wound resolution produces a significant number of apoptotic endothelial cells (ApoEC) that must be cleared. In considering the fate of ApoEC and the presence of fibroblasts during wound resolution, we hypothesized that fibroblasts might serve as phagocytes involved in endothelial cell removal. The current study investigated whether dermal fibroblasts engulf ApoEC, whether this uptake alters the phenotype of dermal fibroblasts, and the biological molecules involved. In both in vitro and in vivo studies, following ApoEC engulfment, fibroblasts acquired a pro‐healing phenotype (increased cell migration, contractility, α‐smooth muscle actin expression, and collagen deposition). In addition, fibroblast uptake of ApoEC was shown to be mediated in part by the milk fat globule‐EGF factor 8 protein/integrin αvβ5 pathway. Our study demonstrates a novel function of fibroblasts in the clearance of ApoEC and suggests that this capability has significant implications for tissue repair and fibrosis.
Molecular mechanisms of voiding dysfunction in a novel mouse model of acute urinary retention
Authors: Xie Xiang , Chen Huan , Zhang Lanlan , Chan Daniel , Hill Warren G. , Zeidel Mark L. , Yu Weiqun
Published: March 2021

Acute urinary retention (AUR) is a common urological emergency and affects a significant patient population. The inability to eliminate urine may lead to permanent damage to the bladder’s structure and functioning. However, we know little about the underlying molecular sequelae to the urine retention. To closely mirror the potential high pressures that patients with AUR could experience, we catheterized anesthetized female mice via the urethra and filled the bladder by pumping saline (25 µL/min) into the bladder lumen to 50 cm or 80 cm water pressure. A water column with designated height (50 or 80 cm) was then adjusted to maintain constant pressure in the bladder lumen for 30 minutes. Functional and morphological evaluations were performed from 0 to 24 hours after AUR treatment. Mice exhibited incontinence and overactivity with diminished voiding pressure. Significant injury was confirmed which revealed bladders with disrupted urothelial barrier, edematous lamina propria, and distorted muscle bundles. Bladder smooth muscle (BSM) from pressure‐treated mice have significantly diminished contraction force, suggesting that bladder voiding dysfunction can be attributed to impaired BSM contractility. Indeed, dysregulation of acetylcholine and purinergic signaling pathways were demonstrated, indicating that reduced efficacy of these pathways contributes to impaired BSM contractility. Finally, altered expression of β1‐integrin and extracellular matrix mediated mechanotransduction pathways were detected, suggesting a profound remodeling process. These data demonstrated an easy to perform, quantifiable, and reproducible AUR mouse model, which mimics well the characteristics of human AUR patients, and our data generate new insights into the molecular mechanisms that occur following AUR.
A mouse model of endometriosis that displays vaginal, colon, cutaneous, and bladder sensory comorbidities
Authors: Castro Joel , Maddern Jessica , Grundy Luke , Manavis Jim , Harrington Andrea M. , Schober Gudrun , Brierley Stuart M.
Published: March 2021

Endometriosis is a painful inflammatory disorder affecting ~10% of women of reproductive age. Although chronic pelvic pain (CPP) remains the main symptom of endometriosis patients, adequate treatments for CPP are lacking. Animal models that recapitulate the features and symptoms experienced by women with endometriosis are essential for investigating the etiology of endometriosis, as well as developing new treatments. In this study, we used an autologous mouse model of endometriosis to examine a combination of disease features and symptoms including: a 10 week time course of endometriotic lesion development; the chronic inflammatory environment and development of neuroangiogenesis within lesions; sensory hypersensitivity and altered pain responses to vaginal, colon, bladder, and skin stimulation in conscious animals; and spontaneous animal behavior. We found significant increases in lesion size from week 6 posttransplant. Lesions displayed endometrial glands, stroma, and underwent neuroangiogenesis. Additionally, peritoneal fluid of mice with endometriosis contained known inflammatory mediators and angiogenic factors. Compared to Sham, mice with endometriosis displayed: enhanced sensitivity to pain evoked by (i) vaginal and (ii) colorectal distension, (iii) altered bladder function and increased sensitivity to cutaneous (iv) thermal and (v) mechanical stimuli. The development of endometriosis had no effect on spontaneous behavior. This study describes a comprehensive characterization of a mouse model of endometriosis, recapitulating the clinical features and symptoms experienced by women with endometriosis. Moreover, it delivers the groundwork to investigate the etiology of endometriosis and provides a platform for the development of therapeutical interventions to manage endometriosis‐associated CPP.
Impact of rheumatoid arthritis and biologic and targeted synthetic disease modifying antirheumatic agents on cancer risk and recurrence
Authors: Singh Namrata , Li Christopher I.
Published: March 2021

Purpose of review

Several new therapeutic drugs are now available for the management of rheumatoid arthritis (RA). Given that RA has been associated with an increased risk of certain cancers like lymphoma and lung cancer, concern remains about the safety of (newer) immunosuppressants used in RA management as it relates to the risk of cancer.

Recent findings

Most meta-analyses of randomized clinical trials of tumor necrosis factor inhibitors (TNFi) have not observed an association between TNFi and risk of incident cancer. Studies of non-TNFi biologic disease modifying antirheumatic drugs (bDMARDs) and targeted synthetic DMARDs and cancer are also reassuring but limited and of short-term follow-up. Regarding the use of DMARDs in patients with RA and a prior malignancy, retrospective studies have shown that TNFi use is not associated with recurrence.

There is a need for ongoing studies on the safety of non-TNFi bDMARDs and targeted synthetic disease modifying anti-rheumatic drugs and recurrent cancer. Further research is also needed to guide the patients, rheumatologists, and oncologists regarding the safest DMARDs to choose for patients with RA and a recent diagnosis of cancer.
The use of mycophenolate mofetil area under the curve
Authors: Chakrabarti Katherine , Frame David , Al Abbas Mousa , McCune W. Joseph
Published: March 2021

Purpose of review

Although mycophenolate mofetil (MMF) has been used successfully to treat a myriad of autoimmune diseases, its complex pharmacokinetics make it difficult to determine the true drug exposure for an individual patient. This review summarizes the body of literature focused on the gold standard measurement of the area under the curve (AUC) of mycophenolic acid (MPA), the active metabolite of MMF.

Recent findings

Fixed dosing of MMF leads to highly variable drug exposure. Retrospective series have reported improved clinical outcomes when a minimum AUC value from 0 to 12 h (AUC0–12h) ≥30 mg h/l is achieved. MPA levels are affected by various drug interactions, hypoalbuminemia, and renal insufficiency and the measurement of free rather than total MPA levels is prudent in some situations. A limited number of studies employing prospective dose adjustment of MMF based on AUC0–12h measurements have yielded mixed results.

Given the wide range of MPA AUC encountered in autoimmune diseases, dose adjustments of MMF based on AUC rather than fixed dosing of MMF should be considered in both clinical practice and clinical trials. Limited sampling strategies have been proposed to improve clinical feasibility of measurements, but a standard is yet to be defined.
20 years of functional treatment for clubfoot: advantages and limitations compared with the Ponseti method
Authors: Elbaum Robert , Noel Brigitte , Degueldre Vincent , Hallez Marie , Filloque Erelle , Guerin Virginie , Duvivier Amandine
Published: March 2021

Currently, the Ponseti method has become the most popular technique for the management of congenital clubfoot. Besides this treatment, the functional method or the ‘French method’ (FFM) represents another treatment option. Throughout our study, we will describe this method, based on the ‘Saint Vincent de Paul’ protocol with some modifications that we bring progressively. Carried out over the last 20 years at our institution. In total 145 children (210 clubfeet) were treated using FFM. Our technique is based on the ‘Saint Vincent de Paul’ protocol from Paris. This method consists of daily manipulations of the feet by specialised physiotherapists associated with thermoformable orthotics devices. An evaluation of the patient at 5 year of age is performed. Gait analysis was introduced in 2011 as a complementary assessment tool. Less than 15% of the feet underwent a surgical procedure at walking age. Compliance to treatment was significantly higher than with the Ponseti method. At the last follow-up, 80% of the children had good to excellent results without major residual deformity. Totally 7% of the children required a later intervention either for recurrence or for major residual deformity. FFM is an alternative approach in the management of clubfoot that has proven to be successful due to the precision and modularity of its splinting system. Good compliance and low recurrence rate are other elements to consider. However, it requires a well-trained physical therapist. The main disadvantages of this method are the high cost compared to the Ponseti method and the difficulty of applying this method in developing countries.
Preliminary results: continuous double luminal catheter drainage for the management of septic hip arthritis in children
Authors: Essa Ahmad , Asa’af Michael , Shtarker Haim
Published: March 2021

Septic arthritis in children is considered an orthopedic surgical emergency, which requires prompt intervention to prevent later sequela. In the last decades, several minimal invasive techniques were suggested as an alternative to the standard treatment of septic arthritis in the pediatric hip via open arthrotomy. We aimed to investigate the efficacy and safety of a new minimal invasive technique—double luminal catheter drainage (DLDC)—in treating septic hip arthritis in children. Retrospective case series analysis was performed on all patients 1–18 years of age diagnosed with septic hip arthritis and treated by the new suggested minimal invasive technique between the years 2009–2019 at medium-sized medical center. Five patients were treated by DLDC with a follow-up period of 12 months posttreatment. The diagnosis was based on joint aspirated fluid analysis criteria. During the follow-up period, no later sequel, including avascular necrosis, or infection recurrence were observed. The new minimal invasive treatment technique suggested in this study seems to be efficient and safe in treating septic hip arthritis in children without later sequela or the need for open arthrotomy, especially if performed early on. However, due to the small study sample, no generalization of the findings can be made as future studies with larger study samples are needed to validate the DLDC technique.
Vitamin D level, body mass index and fracture risk in children: vitamin D deficiency and fracture risk
Authors: Varkal Muhammet Ali , Gulenc Baris , Yildiz Ismail , Kandemir Ibrahim , Bilgili Fuat , Toprak Sadik , Kilic Ayse , Unuvar Emin
Published: March 2021

The objective of this study was to determine the impacts of preventable causes of fracture, such as vitamin D deficiency, disturbed calcium homeostasis and obesity on fracture occurrence in minor traumas. In this way, the effects of relevant parameters on fracture may be further elucidated. A prospective case-control study in children aged 2–18 years children with and without fractures was performed. Participants with a pediatric trauma score higher than 10 presenting to minor trauma were included to exclude the significant impact of severe trauma on fracture. The effects of obesity, parameters associated with vitamin D and Ca homeostasis on fracture occurrence were evaluated. Univariate and multivariate analyses were used to test for associations between fracture status and the assessed variables. The relationships between the variables and the odds of fracture occurrence were examined using logistic regression models. The sample consisted of 76 patients and 50 controls. There were no significant differences between the patients and controls in terms of age, sex, trauma type and pubertal period. The patients had a significantly higher mean BMI percentile (61.2 ± 30.7, 36.7 ± 30.7; P < 0.001). Likewise, patients were more likely than controls to have a lower mean 25(OH)D level and mean phosphorus level (respectively, 13.4 ± 7.0, 17.3 ± 7.8; P = 0.004, and 4.6 ± 0.7, 5.1 ± 0.8; P < 0.001). Moreover, fractures were substantially more frequent in children with vitamin D deficiency (<20 ng/mL, χ2: 7.781, df: 1, P = 0.005). In the multivariate logistic model, BMI percentile and vitamin D levels remained significantly associated with increased odds of fracture [1.02 (1.01–1.04), P < 0.001 and 0.93 (0.89–0.98), P = 0.01]. The present study supports an association of high BMI and vitamin D deficiency with an increased odds of fracture occurrence in children. The findings may help physicians to reduce the risk factors of fracture by preventive efforts. Thus, unexpected health costs and morbidity may be minimized.
Management of Bone Defects of the Foot and Ankle
Authors: Kulwin Robert , Weatherford Brian
Published: March 2021

Effective management of bone loss in foot and ankle surgery requires the application of a wide variety of techniques and implants. Autograft, allograft, cement spacers, bone transport, and recently custom titanium cages are all methods that can effectively manage bone defects. This article serves as an overview and technical guide for the indications and applications of these techniques with demonstrative case examples.

Level of Evidence: Diagnostic Level V. See Instructions for Authors for a complete description of levels of evidence.
Proximal Rotational Metatarsal Osteotomy for Treatment of Hallux Valgus: A Technique Guide
Authors: Wallace Stephen Blake , Hunt Kenneth J.
Published: March 2021

There is increasing interest in rotational correction of the first metatarsal during hallux valgus correction. This article provides a technique guide for the proximal rotational metatarsal osteotomy technique, which corrects both the intermetatarsal angle and the rotational deformity with a single oblique osteotomy.

Level of Evidence: Diagnostic Level V. See Instructions for Authors for a complete description of levels of evidence.
Arthrodesis of the Pubic Symphysis With Compression Plating and Femoral Strut Allograft for Pubic Instability and Osteitis Pubis: A Novel Surgical Technique
Authors: Catanzano Anthony A. , Kollmorgen Robert , Olson Steven A.
Published: March 2021

Introduction:

Osteitis pubis and pubic instability represent an uncommon, yet a potentially debilitating problem for patients. While many cases are amendable to conservative measures, the few recalcitrant cases present a difficult challenge for surgical management with the risk of implant failure, nonunion, and potential complications.

Materials and Methods:

A retrospective review of 3 patients undergoing symphyseal arthrodesis with a strut allograft for osteitis pubis and/or pubic instability after failed conservative management was conducted at a single institution. Preoperative evaluation, surgical technique, and postoperative regimen are thoroughly described. Surgical complications, reoperation rate, pain, and Patient-Reported Outcomes Measurement Information System (PROMIS) scores, as well as radiographic outcomes were reported.

Results:

Three patients undergoing our symphyseal arthrodesis technique after failed conservative management were identified. All patients had an improvement from preoperative pain levels and the 2 patients with >12-month follow-up were able to return to full activity, including 1 patient returning to full active duty in the United States Army.

Discussion:

The unique technique presented here utilizes both implant fixation, as well as allograft supplementation to improve fusion rates. Although a limited sample with limited follow-up, the early results of this novel technique are encouraging and may represent a more reliable surgical option for patients with chronic, recalcitrant pubic instability.
Reconstruction of Complex Acromion Nonunions and Fractures With a Locking Mesh Plate
Authors: Ogunleye Temi D. , Dugarte Anthony J. , Gilbertson Jeffrey A. , Cole Peter A.
Published: March 2021

Objectives:

To assess surgical and functional outcomes in a cohort of patients having surgically reconstructed acromion nonunions or severely comminuted acute fracture patterns treated with a variable angle, locking mesh plate with a matrix of screw options.

Design:

Retrospective case series.

Setting:

Level I trauma center.

Patients:

Between 2012 and 2017, 10 patients, 4 patients with acromion nonunions and 6 patients with severely comminuted acromion fractures presented to a single institution and underwent surgical treatment.

Intervention:

Surgical repair of complex acromion fractures and nonunions utilizing a 2.4/2.7 locking mesh plate (Depuy-Synthes) with bone grafting (nonunions).

Main Outcome Measurements:

Primary outcome measures include range of motion; strength; Disabilities of the Arm, Shoulder, and Hand; and Short Form 36 Health Survey.

Results:

Seven of 10 patients (70%) achieved 1 year follow-up, mean 23.3 months (range, 12 to 46 mo). Nine of 10 patients achieved union following the index reconstruction procedure and 1 patient achieved union after revision of failed mesh plate fixation. At final follow-up, the mean Disabilities of the Arm, Shoulder, and Hand score was 20.0 (11.2 in fracture group and 31.6 in nonunion group) and mean mental and physical component Short Form 36 scores were 51.4 and 42.9, respectively.

Conclusions:

A variable angle, locking mesh plate may be a useful implant choice for complex nonunions and severely comminuted fracture patterns of the acromion process. In this series, union rate and perioperative complications were acceptable in extreme fracture variants.
A Unified Platelet-rich Plasma Preparation Protocol Using a Customizable Concentration System for Knee Osteoarthritis
Authors: Baria Michael R. , Magnussen Robert A. , Lau Melissa , Miller Meghan Maume , Vasileff William Kelton , Borchers James R.
Published: March 2021

Introduction:

Platelet-rich plasma (PRP) is an autologous solution of platelets, concentrated over baseline, that delivers a high dose of anti-inflammatory and anabolic proteins. High-quality data support its use for pathology like knee osteoarthritis (OA), but vast heterogeneity among PRP processing methods and product content make synthesizing clinical data very challenging. Most processing techniques rely upon centrifugation and often involve manual processing steps, such as resuspension or extraction of platelets, which can introduce further heterogeneity in the final product. The Angel cPRP device is a fully automated device that uses both centrifugation and principles of flow cytometry in its PRP processing. However, the system has a wide range of preprocessing settings that alter PRP composition and there are no recommendations or standards on which settings should be used for OA. The aims of this manuscript are to (1) describe a unified PRP processing technique using this system and (2) report preliminary outcomes using that unified protocol when treating knee OA.

Methods:

For the processing of PRP, all patients had whole blood drawn under aseptic conditions (104 cc whole blood for unilateral OA, 156 cc whole blood for bilateral OA) that was then processed at the unified setting of 0% hematocrit, first spin performed at 4000 rpm for 11 minutes and the second spin at 3000 rpm for 2 minutes. The device automatically separated the resulting PRP that was then injected. For the second aim of this work, 90 knees (63 patients) met the criteria for inclusion. International Knee Documentation Committee (IKDC) subjective scores completed at baseline and 3 months were collected and analyzed.

Results:

Overall, IKDC score improved from 42.3±14.1 preinjection to 59.7±17.5 at 3 months postinjection (P<0.001). Of the 90 knees injected with PRP, 57% met the criteria for a positive response at 3 months with an average final IKDC score of 66.5±15.0 (Δ 24.7±10.9). Increased patient age (P=0.008) and body mass index (P=0.008) were associated with lower 3-month subjective IKDC scores.

Discussion:

A single PRP injection created with the unified preparation protocol described here resulted in significant improvement in preliminary patient-reported outcomes. There was a positive response in 57% of patients. Higher age and body mass index were associated with worse outcomes. Given the wide range of preprocessing settings available on this device, the protocol described here can serve as an initial guide for clinical and research implementation.
Treatment of in-transit melanoma metastases using intralesional PV-10
Authors: Thompson John F. , P.M. Saw Robyn , Dalton Johanna M. , Stretch Jonathan R. , Spillane Andrew J. , Osborne Natalie S. , Williams Gabrielle J. , Lo Serigne N.
Published: March 2021

Melanoma in-transit metastases (ITMs) can sometimes be difficult to manage by surgical excision due to their number, size or location. Treatment by intralesional injection of PV-10, a 10% solution of rose bengal, has been reported to be a simple, safe and effective alternative, but more outcome data are required to confirm its value in the management of ITMs. Two hundred and twenty-six melanoma ITMs in 48 patients were treated with intralesional PV-10 supplied under a special-access scheme. By 8 weeks a complete response in all injected ITMs was achieved in 22 patients (46%) and a partial response in 19 patients (40%). Of 19 patients who had uninjected metastases, 3 (16%) had a response in these. The most common adverse event was transient localised pain in injected tumours. New ITMs developed in 25 patients within 8 weeks, and later in another 8 patients. Repeat injection cycles were given to 21 patients: 13 of these received repeat injection into partially responding or nonresponding tumours, 5 had new ITMs, as well as partially-responding lesions injected, and 3 received injection into new ITMs only. Twenty-two patients received subsequent systemic therapy. At 1 year 37 of the 48 patients were alive, 28 with melanoma, and at 2 years 27 were alive, and 19 with melanoma. Injection of PV-10 was simple and safe and resulted in tumour involution in most patients and sometimes in noninjected tumours. However, many patients developed new lesions; these were treated by further PV-10 injections or with alternative therapies.
Response to immune checkpoint inhibitor rechallenge after high-grade immune related adverse events in patients with advanced melanoma
Authors: Shah Payal , Punekar Salman R. , Pavlick Anna C.
Published: March 2021

Twenty to sixty percent of patients receiving immune checkpoint inhibitors (ICIs) experience high-grade immune-related adverse events (irAEs) which may prevent the continuation of treatment. Limited clinical evidence is available to guide treatment for these patients. Patients with stage IV or unresectable stage III melanoma at NYU Langone Health were reviewed from 1 January 2014 to 1 July 2019. Patients with first-line ICI systemic therapy, a high-grade irAE and a rechallenge with ICI therapy were included. Postrechallenge irAE recurrence, response rate, overall survival (OS) and progression-free survival (PFS) were evaluated. Postrechallenge irAEs recurred in 71.9% (n = 23/32) of patients at a median of 5.1 weeks from rechallenge, with 46.9% (15/32) recurring as high-grade events. Clinical response was achieved in 46.9% (15/32) of patients, including 40.6% (13/32) with a complete response and 6.3% (2/32) with partial response. Median OS from first ICI initiation was 85.4 weeks (45.7–140.7; 25th—75th percentile) and median PFS was 42.9 weeks (29.2–114.2; 25th–75th percentile). Patients with a shorter time to initial irAE and shorter time to postrechallenge irAE were at greater risk for disease progression [hazard ratio 7.80; 95% confidence interval (CI), 1.91–32.83; P = 0.004; hazard ratio 7.45, 95% CI, 1.57–35.35; P = 0.012). Those with greater duration to rechallenge (>10 weeks) were at lower risk for disease progression (hazard ratio 0.15, 0.03–0.68; P = 0.015). ICI rechallenge can be considered in patients with advanced melanoma, as the risk-benefit profile appears favorable. Treatment toxicity should be appropriately managed, as longer durations to rechallenge may lower the risk of disease progression.
Developmental Status of Young Children in Foster Care
Authors: McLeigh Jill D. , Tunnell Karlyn , Lazcano Cecilia
Published: March 2021

Objective:

Children in foster care (CFC) may be at higher risk for developmental problems. This study sought to determine (1) the percentage of CFC with developmental problems seen at an integrated primary care clinic and (2) whether the presence of various risk factors was associated with increased odds of developmental problems in general and across developmental domains.

Method:

This cross-sectional study used the Ages and Stages Questionnaire, Third Edition, demographic, and health-related data retrieved from electronic health records. The study included 796 children aged 1 to 66 months seen at an integrated primary care clinic exclusively serving CFC. Frequencies and percentages of children with developmental problems were calculated, and relationships between developmental status and potential risk factors were accessed using χ2 and bivariate logistic regression analyses.

Results:

Overall, 68.5% had scores indicative of developmental concern (DC), and 39.8% had scores indicating developmental delay (DD). After adjusting for other risk factors, analysis suggested that being male (odds ratio [OR] 2.169, 95% confidence interval [CI] 1.595–2.950) and exhibiting trauma symptoms (OR 1.51, 95% CI 0.993–2.295) were associated with higher odds of exhibiting DC, whereas being in a kinship placement (OR 0.55, 95% CI 0.359–0.842) was associated with lower odds. Odds were higher for exhibiting DD for children who were male (OR 1.716, 95% CI 1.278–2.303), born prematurely (OR 2.165, 95% CI 1.438–3.259), experienced physical abuse (OR 1.541, 95% CI 1.040–2.283), and presented trauma symptoms (OR 1.441, 95% CI 0.975–2.130).

Conclusion:

The findings suggest that early screening is vital for CFC to identify developmental impairment so that appropriate education and interventions can be offered.