bluuebunny/crossref_metadata_2025 huggingface dataset:
Quantification of Antibiotics in Patient Samples: State of the Art in Standardization and Proficiency Testing
Authors: Schneider Heike , Hess Cornelius , Kessler Anja , Steimer Werner
Published: December 2021

Background:

For many antibiotics, the convenient one-fits-all dosing regimen had to be abandoned. Owing to highly variable pharmacokinetics, therapeutic drug monitoring has become an indispensable prerequisite. It is based on a suitable measuring method, sample materials, and standardization. Appropriate quality control including external quality assessment (EQA) is essential. For many antibiotics, EQAs have been established for many decades, whereas others have only lately been introduced. This article gives an insight into the state of the art regarding the therapeutic drug monitoring of antibiotics regarding standardization, EQAs, and reference measurement procedures (RMPs).

Methods:

An overview of the currently available international EQA schemes for antibiotics and a literature overview of available RMPs are given. EQAs including gentamicin and vancomycin have been offered by German providers for more than 25 years. The period 2000–2020 was selected for a detailed analysis. The experiences with a new EQA including linezolid, meropenem, and piperacillin are described.

Results:

EQAs for gentamicin and vancomycin are provided in many countries. Those for linezolid, meropenem, and piperacillin do not seem to be very common. Most of the antibiotics monitored for decades are measured by commercially available assays. EQAs for linezolid, meropenem, and piperacillin introduced in 2018 were rapidly accepted in Germany. Methods reported in this study were HPLC based either with UV or mass spectrometric detection. The number of participants succeeding was comparable between UV and mass spectrometry. Candidate RMPs for gentamicin, vancomycin, and linezolid based on isotope dilution mass spectrometry were published.

Conclusions:

EQAs are offered regularly for many antibiotics worldwide. The results of EQAs in Germany generally compare well, but there is potential for improvement. Both immunoassays and HPLC-based methods work properly in EQAs evaluated in Germany. From a quality control perspective, fast and inexpensive methods may be selected without endangering the patient's health based on clinical needs.
Role of sentinel lymph node biopsy for gynecologic cancers
Authors: Chow Stephanie , Karam Amer
Published: December 2021

Purpose of review

To provide an overview of the current knowledge and recent advances of sentinel lymph node (SLN) assessment in uterine, cervical, vulvar, and ovarian cancers.

Recent findings

In endometrial cancer, SLN evaluation has become increasingly utilized as part of the treatment of early-stage disease, with data showing improved detection of pelvic lymph node metastasis. In cervical cancer, SLN biopsy has also gained increasing traction with studies demonstrating the feasibility and accuracy of SLN detection. Evaluation with frozen section, however, remains limited in the detection of metastases. The prognostic significance of positive SLN in vulvar cancer is currently being investigated, with preliminary data showing lower recurrence rates in patients receiving adjuvant radiation.

SLN evaluation remains standard of care to detect lymph node metastasis in early-staged endometrial cancer. In cervical cancer, SLN biopsy has been shown to be reliable, while decreasing morbidity without impacting disease-free survival in select patients. The technique and high sensitivity of SLN biopsy in vulvar cancer has been demonstrated in large prospective trials. There are no randomized controlled trials in ovarian cancer that evaluate the role of SLN biopsy on treatment and outcome; current SLN evaluation remains investigational.
EFFECT OF RETINAL THICKNESS VARIABILITY ON VISUAL OUTCOMES AND FLUID PERSISTENCE IN NEOVASCULAR AGE-RELATED MACULAR DEGENERATION
Authors: Dugel Pravin U. , Jhaveri Chirag D. , Chakravarthy Usha , Wykoff Charles C. , Singh Rishi P. , Hamilton Robin , Weissgerber Georges , Mulyukov Zufar , Holz Frank G.
Published: December 2021

Purpose:

To determine the association between central subfield thickness (CST) variability and visual outcomes in eyes with neovascular age-related macular degeneration treated with anti–vascular endothelial growth factor therapies.

Methods:

In this post hoc, treatment-agnostic analysis, patients (N = 1,752) were grouped into quartiles of increasing CST variation. The association between CST variability and best-corrected visual acuity was measured from baseline, or from the end of the loading phase, until the end of the study using a multilevel modeling for repeated-measures model. The association between CST variability and the presence of retinal fluid was also assessed.

Results:

Increased CST variability was associated with worse best-corrected visual acuity outcomes at the end of study, with a least-square mean difference in best-corrected visual acuity of 8.9 Early Treatment Diabetic Retinopathy Study letters between the quartiles with the lowest and highest CST variability at the final visit. Increased variability was also associated with a higher mean fraction of visits with the presence of fluid.

Conclusion:

More stable CST was associated with better visual outcomes at the end of treatment suggesting that CST variability may provide a more reliable prognostic marker of visual outcomes than the presence of fluid alone, with the potential to enhance the clinical care of neovascular age-related macular degeneration patients.
CHOROIDAL INVOLVEMENT IN HEREDITARY TRANSTHYRETIN AMYLOIDOSIS PATIENTS
Authors: Marta Ana , Marques João Heitor , Ferreira André , Coelho João , Beirão João Melo
Published: December 2021

Purpose:

To compare the choroidal characteristics between the eyes of patients with and without hereditary transthyretin amyloidosis.

Methods:

Case–control observational study with choroidal thickness and vasculature evaluation by optical coherence tomography with enhanced depth imaging protocol of the macula.

Results:

The study included 332 eyes: 166 eyes of hereditary transthyretin amyloidosis patients and 166 eyes of healthy patients. Mean age was similar between groups (P = 0.979). For hereditary transthyretin amyloidosis patients, on average, in all sectors analyzed (in the full 5 mm-width image [G] and also in 1-mm-width central [C], nasal [N], and temporal [T] sectors), there was a higher stromal area, a lower choroidal thickness, and a lower choroidal vascularity index, compared with the control group. The linear mixed models revealed no differences according to the systemic treatment groups.

Conclusion:

Hereditary transthyretin amyloidosis patients showed statistically significant differences in choroidal characteristics, compared with eyes without pathology. These age-related and statistically significant changes compared with the healthy eyes may help in the future to better monitor the systemic hereditary transthyretin amyloidosis disease and complement other systemic evaluations, including on clinical trials to analyze more objectively, the results of new therapies.
PREDICTED PROTEIN STRUCTURE VARIATIONS INDICATE THE CLINICAL PRESENTATION OF CYP4V2-RELATED BIETTI CRYSTALLINE DYSTROPHY
Authors: Chan Li-Wei , Sung Yu-Chi , Wu Dung-Chi , Chen Chien-Yu , Yang Chang-Hao , Yang Chung-May , Chen Pei-Lung , Chen Ta-Ching
Published: December 2021

Purpose:

To investigate the relationship between different CYP4V2 disease-causing variants and disease severity in Bietti crystalline dystrophy (BCD).

Methods:

Twenty-one subjects from 19 unrelated families with a clinical diagnosis of BCD were enrolled. A novel severity prediction score for BCD based on the predicted molecular impact of CYP4V2 variants was applied for grouping and subsequent analyses. The more severe variants led to less CYP4V2 protein function preservation and a higher severity prediction score.

Results:

All subjects harbored two alleles of CYP4V2 disease-causing variants, of which c.802–8_810del17insGC was the most prevalent (14/21, 66.67%) and c.1507G>C was novel. According to the severity score, the subjects were categorized into severe, moderate, and mild groups with different preservation of central vision (mean logMAR visual acuity 0.95 ± 0.82, 0.89 ± 1.22, and 0.56 ± 0.64, respectively). The patients with a lower severity score had slower disease progression.

Conclusion:

This is the first cohort study of BCD in Taiwan, and we established a novel BCD severity index based on the molecular impact of different CYP4V2 variants. More severe impairment of CYP4V2 protein led to a more severe disease course with earlier progression. Our results could be helpful in identifying a therapeutic window for patients with BCD.
RELATIONSHIP BETWEEN INTEGRITY OF HENLE FIBERS AND VISUAL ACUITY IN MYOPIC FOVEOSCHISIS
Authors: García-Ben Antonio , Baquero-Aranda Isabel , García-Basterra Ignacio , García-Campos José M.
Published: December 2021

Background:

To analyze the relationship between Henle fiber (HF) integrity and visual acuity in highly myopic eyes with foveoschisis.

Methods:

Three hundred and fifty-eight highly myopic eyes were included in this study and divided into three groups according to the Triton optical coherence tomography results. Group 1 included 19 eyes with myopic foveoschisis where the inner and outer retina were connected by a columnar structure in the HF layer at the foveolar area. Group 2 included 17 eyes with myopic foveoschisis where the columnar structure was disrupted in the HF layer at the foveolar area. Group 3 included 322 eyes without myopic foveoschisis or other ocular disease. Clinical and optical coherence tomography findings were obtained and compared.

Results:

Eyes with vitreomacular traction, arteriolar traction, and longer axial length were more likely to have myopic foveoschisis with intact columnar structure in the HF layer (odds ratio [OR], 12.84; P = 0.001; OR, 7.63; P = 0.04; OR, 2.03; P = 0.03) and with disrupted columnar structure in the HF layer (OR, 65.21; P = 0.001; OR, 6.60; P = 0.02; OR, 2.63; P = 0.01). Moreover, eyes with disrupted columnar structure in the HF layer presented a lower best-corrected visual acuity (P = 0.001), longer axial length (P = 0.001; P = 0.009), higher central foveolar thickness (P = 0.001; P = 0.02), and a higher prevalence of vitreomacular traction (P = 0.001; P = 0.04) than control or integrity HF eyes. Furthermore, worse best-corrected visual acuity was related to myopic foveoschisis with disrupted columnar structure in the HF layer (P < 0.01).

Conclusion:

The integrity of HF in patients with myopic foveoschisis appears to play an important role in visual acuity.
MACULAR PIGMENT OPTICAL DENSITY ASSESSED BY HETEROCHROMATIC FLICKER PHOTOMETRY IN EYES AFFECTED BY PRIMARY EPIRETINAL MEMBRANE
Authors: Cerino Luca , Aharrh-Gnama Agbeanda , Ruggeri Maria L. , Carpineto Paolo
Published: December 2021

Purpose:

To compare macular pigment optical density (MPOD) in healthy eyes versus eyes affected by primary epiretinal membrane (ERM) in different stages and to assess the relation between MPOD and optical coherence tomography findings.

Methods:

Prospective cross-sectional study of 62 eyes of 62 patients affected by unilateral primary ERM. Contralateral healthy eyes from the same patients were used as a control group. Main outcome measures were MPOD, ERM stage, central foveal thickness (CFT), outer nuclear layer thickness (ONLT), integrity of outer retinal bands, and presence of central bouquet abnormalities.

Results:

In the study group, mean CFT was 444 ± 75 μm and mean ONLT was 245 ± 40 μm, whereas in the control group, mean CFT was 230 ± 21 μm and mean ONLT was 102 ± 14 μm (P < 0.001). Mean MPOD was 0.86 ± 0.07 in eyes with ERM and 0.48 ± 0.09 in contralateral healthy eyes (P < 0.001). Macular pigment optical density was associated with CFT (P = 0.006) and ONLT (P < 0.001), whereas no significant associations were observed between MPOD and outer retinal bands integrity (P = 0.14) and central bouquet abnormalities (P = 0.08).

Conclusion:

Macular pigment optical density increased in eyes affected by primary ERM proportionally to CFT and, especially, ONLT. Probably, centripetal forces exerted by ERM contraction on the retinal surface lead to a progressive foveal packing of foveal Müller cells.
NONINVASIVE DIAGNOSTIC STRATEGY OF OCULAR TOXOCARIASIS BASED ON CLINICAL FEATURES
Authors: Jiang Zhaoxin , Sun Limei , Huang Li , Li Songshan , Hou Aohan , Zheng Shuxin , Ding Xiaoyan
Published: December 2021

Purpose:

To develop a noninvasive diagnostic strategy based on the clinical manifestations of ocular toxocariasis (OT) and evaluate its sensitivity and specificity.

Methods:

Patients with unilateral OT-like lesions were enrolled retrospectively and classified into OT and non-OT groups according to the immunologic diagnosis criterion of anti-OT immunoglobulin G. Nine clinical manifestations were recorded and compared between the groups. Among them, the retrolental membrane, branch-like vitreous strands, and retinal granulomas were the most common, which were further classified into three categories, including at least 1 of three signs, at least two of three signs, and all three signs positive. Diagnostic sensitivity and specificity were calculated for each strategy.

Results:

There were 105 immunologically confirmed patients with OT and 70 patients with non-OT uveitis/vitreoretinopathy. Retinal granulomas, retrolental membrane, and branch-like vitreous strands were significantly more frequent in OT patients than in non-OT patients. At least 1 of 3 signs positive strategy showed the highest sensitivity (100.0%) but the lowest specificity (62.0%). At least 2 of 3 signs positive strategies showed 80.0% sensitivity and 94.3% specificity. All 3 signs positive strategies had the lowest sensitivity (46.7%) and the highest specificity (100.0%). The cutoff point of this revealed an area under the curve of 0.85 and a 95% confidence interval of 0.79 to 0.91.

Conclusion:

A comprehensive strategy based on at least two out of three positive signs showed excellent sensitivity and specificity and could serve as a noninvasive and fast screening strategy for the clinical diagnosis of OT.
Assessing the Dental and Oral Health Needs at Vascular Anomalies Centers Across the United States
Authors: Mitra Shivani , Shen Daniel , Afshar Salim
Published: December 2021

Objective:

Patients with vascular anomalies often have serious oral health complications. We sought to capture nationwide vascular anomalies centers’ perspectives on the oral health and dental access of their patients.

Methods:

Eighty-one major multidisciplinary vascular anomalies centers across the United States were identified by online search. A 15-question survey was developed on Qualtrics and emailed to the centers. All survey responses were anonymous and self-reported.

Results:

Fifty-nine centers were included in our study and 27 (46%) responded to our survey. Twenty-five centers (92%) report seeing patients very often or somewhat often with oral health/dental related issues that require further care. Out of these 25 centers, 17 centers (68%) report being unable to easily meet the oral health needs of their patients. Eighteen out of 21 (86%) centers currently without an oral health professional at their center said having an oral health professional on their team would be valuable.

Conclusions:

There is a reported oral healthcare access gap for patients with vascular anomalies. Centers indicate a desire to closely work with dental professionals. There is a reported challenge in finding a dentist with adequate training or experience to care for patients with vascular anomalies. Increased efforts to educate community dental professionals on vascular anomalies care may help to bridge the gap.
Interaction between sodium-glucose co-transporter 2 and the sympathetic nervous system
Authors: Azzam Omar , Matthews Vance B. , Schlaich Markus P.
Published: December 2021

Purpose of review

Sodium-glucose co-transporter 2 (SGLT2) inhibitors have taken centre stage in research and therapeutic efforts to modulate hard clinical outcomes in patients with heightened cardiovascular and renal risk profiles. Sympathetic nervous system (SNS) activation is a prominent feature across several cardiovascular and renal disease states. This review reflects on the remarkable clinical impact of SGLT2 inhibitors on cardiorenal outcomes, and navigates the evidence for a proposed clinically relevant interaction between SGLT2 and the SNS.

Recent findings

SGLT2 inhibitors exert several pleiotropic effects beyond glucose-lowering. These include, but are not limited to, diuresis and natriuresis, blood pressure lowering, reduction in inflammation and oxidative stress, stimulation of erythropoiesis, and improvement in cardiac energetics. Treatment with SGLT2 inhibitors is associated with significant improvement in cardiorenal outcomes irrespective of diabetes status. In addition, evidence from preclinical studies points to a strong signal of a bidirectional temporal association between SGLT2 inhibition and reduction in SNS activation.

Ongoing preclinical and clinical trials aimed at unravelling the proposed interaction between SGLT and SNS will enhance our understanding of their individual and/or collective contributions to cardiovascular disease progression and guide future targeted therapeutic interventions.
Gene therapy for kidney disease: targeting cystinuria
Authors: Peek Jennifer L. , Wilson Matthew H.
Published: December 2021

Purpose of review

The aim of this study was to summarize recent findings in kidney gene therapy while proposing cystinuria as a model kidney disease target for genome engineering therapeutics.

Recent findings

Despite the advances of gene therapy for treating diseases of other organs, the kidney lags behind. Kidney-targeted gene delivery remains an obstacle to gene therapy of kidney disease. Nanoparticle and adeno-associated viral vector technologies offer emerging hope for kidney gene therapy. Cystinuria represents a model potential target for kidney gene therapy due to its known genetic and molecular basis, targetability, and capacity for phenotypic rescue.

Although gene therapy for kidney disease remains a major challenge, new and evolving technologies may actualize treatment for cystinuria and other kidney diseases.
COVID-19 in patients with glomerular disease
Authors: Turner-Stokes Tabitha , Edwards Helena , Lightstone Liz
Published: December 2021

Purpose of review

Managing patients with glomerular disease during the COVID-19 pandemic has been challenging, as the infection risk associated with immunosuppression must be balanced against the need to control severe glomerular disease that can lead to kidney failure. This review provides an overview of COVID-19 and the effectiveness of SARS-CoV-2 vaccination in patients with glomerular disease.

Recent findings

Registry data, although biased towards outcomes of hospitalized patients, suggest that the mortality from COVID-19 is higher in patients with glomerular disease than in the general population. Glucocorticoid use prior to SARS-CoV-2 infection is associated with adverse outcomes from COVID-19. Rituximab significantly attenuates serological responses to both natural infection and vaccination against SARS-CoV-2, although it is not clear whether this leads to adverse outcomes. Case reports of disease flares occurring after vaccination have been reported, but causality in any of these cases has yet to be proven and the absolute risk remains very small.

Patients with glomerular disease represent an at-risk group for severe COVID-19 disease and vaccination is key to reducing this risk. As immunosuppressed patients demonstrate an attenuated response to vaccination, the efficacy of a third primary dose followed by a subsequent booster is being investigated.
Cellular and molecular interrogation of kidney biopsy specimens
Authors: Eadon Michael T. , Dagher Pierre C. , El-Achkar Tarek M.
Published: December 2021

Purpose of review

Traditional histopathology of the kidney biopsy specimen has been an essential and successful tool for the diagnosis and staging of kidney diseases. However, it is likely that the full potential of the kidney biopsy has not been tapped so far. Indeed, there is now a concerted worldwide effort to interrogate kidney biopsy samples at the cellular and molecular levels with unprecedented rigor and depth. This review examines these novel approaches to study kidney biopsy specimens and highlights their potential to refine our understanding of the pathophysiology of kidney disease and lead to precision-based diagnosis and therapy.

Recent findings

Several consortia are now active at studying kidney biopsy samples from various patient cohorts with state-of-the art cellular and molecular techniques. These include advanced imaging approaches as well as deep molecular interrogation with tools such as epigenetics, transcriptomics, proteomics and metabolomics. The emphasis throughout is on rigor, reproducibility and quality control.

Although these techniques to study kidney biopsies are complementary, each on its own can yield novel ways to define and classify kidney disease. Therefore, great efforts are needed in order to generate an integrated output that can propel the diagnosis and treatment of kidney disease into the realm of precision medicine.
Mitochondrial deacetylase Sirt3 in vascular dysfunction and hypertension
Authors: Dikalov Sergey , Dikalova Anna
Published: December 2021

Purpose of review

Hypertension is a multifactorial disorder involving perturbations of the vasculature, the kidney, and the central nervous system. Hypertension represents a major risk factor for stroke, myocardial infarction, and heart failure. Despite treatment with multiple drugs, 37% of hypertensive patients remain hypertensive, likely due to the mechanisms contributing to blood pressure elevation that are not affected by current treatments. This review focuses on recently described novel role of mitochondrial deacetylase Sirt3 in vascular dysfunction and hypertension.

Recent findings

In the past several years, we have shown that the mitochondria are dysfunctional in hypertension; however, the role of mitochondria in the pathogenesis of hypertension remains elusive. We recently showed that patients with essential hypertension have decreased levels of the mitochondrial deacetylase Sirt3 leading to hyperacetylation of mitochondrial proteins. There is likely a causative role. Indeed, genetic deletion of Sirt3 in mice promotes vascular dysfunction and hypertension. Sirt3 depletion promotes endothelial dysfunction, increases smooth muscle cell hypertrophy, instigates vascular inflammation, and induces age-dependent hypertension.

Sirt3 is critical for vascular cell homeostasis, however, multiple risk factors impair Sirt3 leading to mitochondrial dysfunction and vascular dysregulation which contribute to hypertension and end-organ injury. Targeting Sirt3 may represent novel therapeutic approach to improve treatment of vascular dysfunction and reduce hypertension.
Paediatric alternative payment models: emerging elements
Authors: Gratale Daniella , Viveiros Janet , Boyer Katie
Published: December 2021

Purpose of review

The aim of this study was to summarize emerging elements of paediatric alternative payment models (APMs), identify strategies to address barriers in implementing paediatric APMs and share policy approaches.

Recent findings

The unique health needs of children and adolescents must be considered as paediatric value-based care and APMs are developed. The longer time period for achieving cost savings, relatively few existing model tests and challenges with cross-sector data-sharing and pooled financing are barriers to the adoption of paediatric APMs. The Integrated Care for Kids (InCK) model and some state-based efforts are testing whether an integrated service delivery model combined with paediatric APMs can reduce expenditures and improve care and outcomes. However, the relative paucity of models makes it difficult to identify the most effective strategies and overall impact of paediatric APMs.

Emerging paediatric APMs include the following key elements: developmentally appropriate approaches, paediatric-specific quality and cost measures, a focus on primary care, special considerations for children with complex healthcare needs and cross-sector integration of data, workforce and financing. A variety of strategies, rooted in cross-sector partnerships, can be pursued to address implementation barriers and ultimately support paediatric care transformation.
Clinical and public policy interventions to address food insecurity among children
Authors: Brochier Annelise , Garg Arvin , Peltz Alon
Published: December 2021

Purpose of review

This article describes the impacts of food insecurity (FI) on child health, outlines clinical and public policy interventions to mitigate FI in children, and defines new paradigms in population health to ameliorate the harmful effects of FI in children.

Recent findings

Rates of FI among children have dramatically increased with the onset of the COVID-19 pandemic, with particular adverse impact on low-income children. Population health innovations in screening, referral, and social service integration offer new opportunities to address FI.

Despite advances in clinical practice and public policy, FI remains a persistent issue for many US children. Clinicians and policymakers have opportunities to leverage clinical and community-based integration to improve service delivery opportunities to ameliorate childhood hunger and racial and socioeconomic inequity in the United States.
The COVID-19 pandemic and its potential enduring impact on children
Authors: Irwin Margaret , Lazarevic Bojan , Soled Derek , Adesman Andrew
Published: December 2021

Purpose of review

The COVID-19 pandemic has ushered in great and rapid change in our society. Although children are somewhat less likely to get infected or have severe symptoms from COVID-19, they are being adversely affected by this global public health emergency in many direct and indirect ways. This review focuses on the major areas in which children and adolescents are suffering, and how pediatricians can anticipate and optimize child healthcare and support as the COVID-19 pandemic and its aftermath continues.

Recent findings

This review provides preliminary insights into the physical, psychological, educational, developmental, behavioral, and social health implications of the pandemic on the pediatric population, highlighting both the pandemic's current and potential future impact on children.

The COVID-19 pandemic has and will likely continue to adversely affect many different aspects of children's health and well-being. It is important for pediatricians to be aware of these consequences of COVID-19 and take steps to help their patients now and in the future. Because the virus continues to ravage many parts of the world, continued research is needed to identify and evaluate any additional COVID-related challenges and concerns that adversely impact the growth and development of children.
Antineutrophilic cytoplasmic antibody-associated vasculitis and the kidney
Authors: Balani Shanthi , Kizilbash Sarah J. , Kouri Anne M.
Published: December 2021

Purpose of review

The purpose of this review is to highlight recent studies that have emerged on the topic of ANCA-associated vasculitis with some historical context. The review also discusses how the adult data is relevant to pediatric patients.

Recent findings

Pediatric studies on AAV are lacking. Therapies targeted to the inflammatory cascade specifically implicated in AAV, such as MPO inhibitors and complement mediators, are emerging. The PEXIVAS study recently called into question the routine use of plasma exchange (PLEX) in severe AAV, with no difference in ESKD or mortality found between patients who did or did not receive PLEX. Longer maintenance duration of nearly 48 months is preferred as compared with shorter duration in patients who are not on dialysis because of higher relapse rates in children with AAV.

Current treatment in AAV includes corticosteroids, rituximab, and cyclophosphamide for induction. Maintenance therapy commonly consists of azathioprine or rituximab. Plasma exchange (PLEX) is no longer recommended for induction therapy for AAV but some experts still consider this as an option for patients who are not responding to therapy or have severe disease at presentation. However, emerging novel therapies may be on the horizon.
EURO-MUSCULUS/USPRM Dynamic Ultrasound Protocols for Shoulder
Authors: Ricci Vincenzo , Chang Ke-Vin , Güvener Orhan , Mezian Kamal , Kara Murat , Leblebicioğlu Gürsel , Stecco Carla , Pirri Carmelo , Ata Ayşe Merve , Dughbaj Muhammad , Jain Nitin B. , Özçakar Levent
Published: December 2021

In this dynamic protocol, ultrasound examination of the shoulder using different maneuvers is described for several/relevant shoulder problems. Scanning videos are coupled with real-time patient examination videos for better understanding. The authors believe that this practical guide prepared by an international consensus of several experts (EURO-MUSCULUS: European Musculoskeletal Ultrasound Study Group and USPRM: Ultrasound Study Group of ISPRM [International Society of Physical and Rehabilitation Medicine]) will help musculoskeletal physicians perform a better and uniform/standard approach.
Renal function and associated mortality risk in adults commencing HIV antiretroviral therapy in Zimbabwe
Authors: Drak Douglas , Shamu Tinei , Heron Jack E. , Chimbetete Cleophas , Dahwa Rumbi , Gracey David M.
Published: December 2021

Background:

People with HIV (PWH) in sub-Saharan Africa appear to have a higher incidence of renal disease than other global regions but data are limited. This renal impairment may be associated with an increased mortality risk.

Aims:

To define the prevalence of renal disease and explore its association with mortality risk in a cohort from Zimbabwe commencing antiretroviral therapy (ART) for HIV infection.

Methods:

A retrospective study of all patients aged at least 18 years, commenced on ART for HIV infection at the Newlands Clinic in Harare, Zimbabwe between January 2007 and September 2019 was conducted. Data were extracted from electronic medical records. Patients with no baseline creatinine measurement were excluded. Baseline characteristics were assessed as potential predictors for mortality by Cox proportional hazard regression.

Results:

Three thousand and thirty-nine patients were eligible for inclusion. Most were female (62.1%), with a median age of 36 years (IQR 30–43). At baseline, 7.3% had an estimated glomerular filtration rate (eGFR) 90 ml/min per 1.73 m2 or less and 11.4% had proteinuria. Over a median follow-up period of 4.6 years (IQR 2.5–6.9), the mortality rate was 8.7%. One half of deaths (49.2%) occurred within the first year. In multivariable analysis, a baseline eGFR between 60 and 90 ml/min per 1.73 m2 [hazard ratio 2.22, 95% confidence interval (CI) 1.46–3.33, P < 0.001] and proteinuria (hazard ratio 2.10, 95% CI 1.35–3.27, P < 0.001) were associated with increased mortality risk.

Conclusion:

Baseline renal impairment was common. Both a reduced eGFR or proteinuria were independently associated with a doubling of mortality risk. These should serve as markers in the clinical setting of at-risk patients.
Impact of nucleos(t)ide reverse transcriptase inhibitor resistance on dolutegravir and protease-inhibitor-based regimens in children and adolescents in Kenya
Authors: Kingwara Leonard , Inzaule Seth C. , Momanyi Lazarus , Jordan Michael R. , Nyanya Winnie , Bowen Nancy , Oramisi Violet , Kiiru John Ndemi , Ngugi Catherine
Published: December 2021

We assessed the impact of using dolutegravir or a protease inhibitor with an inactive nucleoside-reverse transcriptase inhibitor (NRTI) in children and adolescents. We observed high-levels of viral suppression among those on tenofovir–lamivudine–dolutegravir even in presence of an inactive NRTI backbone but lower levels among those on protease inhibitors, especially those retained on an inactive abacavir. Although tenofovir may be recycled with dolutegravir, more studies are needed to determine if abacavir can be reused with dolutegravir or protease inhibitors.
Infusion Reactions After Receiving the Broadly Neutralizing Antibody VRC01 or Placebo to Reduce HIV-1 Acquisition: Results From the Phase 2b Antibody-Mediated Prevention Randomized Trials
Authors: Takuva Simbarashe , Karuna Shelly T. , Juraska Michal , Rudnicki Erika , Edupuganti Srilatha , Anderson Maija , De La Grecca Robert , Gaudinski Martin R. , Sehurutshi Alice , Orrell Catherine , Naidoo Logashvari , Valencia Javier , Villela Larissa M. , Walsh Stephen R. , Andrew Philip , Karg Carissa , Randhawa April , Hural John , Gomez Lorenzo Margarita M. , Burns David N. , Ledgerwood Julie , Mascola John R. , Cohen Myron , Corey Lawrence , Mngadi Kathy , Mgodi Nyaradzo M. ,   the HVTN 703/HPTN 081 and HVTN 704/HPTN 085 Study Teams
Published: December 2021

Background:

The antibody-mediated prevention (AMP) studies (HVTN 703/HPTN 081 and HVTN 704/HPTN 085) are harmonized phase 2b trials to assess HIV prevention efficacy and safety of intravenous infusion of anti-gp120 broadly neutralizing antibody VRC01. Antibodies for other indications can elicit infusion-related reactions (IRRs), often requiring premedication and limiting their application. We report on AMP study IRRs.

Methods:

From 2016 to 2018, 2699 HIV-uninfected, at-risk men and transgender adults in the Americas and Switzerland (704/085) and 1924 at-risk heterosexual women in sub-Saharan Africa (703/081) were randomized 1:1:1 to VRC01 10 mg/kg, 30 mg/kg, or placebo. Participants received infusions every 8 weeks (n = 10/participant) over 72 weeks, with 104 weeks of follow-up. Safety assessments were conducted before and after infusion and at noninfusion visits. A total of 40,674 infusions were administered.

Results:

Forty-seven participants (1.7%) experienced 49 IRRs in 704/085; 93 (4.8%) experienced 111 IRRs in 703/081 (P < 0.001). IRRs occurred more frequently in VRC01 than placebo recipients in 703/081 (P < 0.001). IRRs were associated with atopic history (P = 0.046) and with younger age (P = 0.023) in 703/081. Four clinical phenotypes of IRRs were observed: urticaria, dyspnea, dyspnea with rash, and “other.” Urticaria was most prevalent, occurring in 25 (0.9%) participants in 704/085 and 41 (2.1%) participants in 703/081. Most IRRs occurred with the initial infusion and incidence diminished through the last infusion. All reactions were managed successfully without sequelae.

Conclusions:

IRRs in the AMP studies were uncommon, typically mild or moderate, successfully managed at the research clinic, and resolved without sequelae. Analysis is ongoing to explore potential IRR mechanisms.
Birth of a Healthy Baby 9 Years After a Surgically Successful Deceased Donor Uterus Transplant
Authors: Ozkan Omer , Ozkan Ozlenen , Dogan Nasuh Utku , Bahceci Mustafa , Mendilcioglu Inane , Boynukalin Kubra , Ongun Hakan , Kantarci Abdul Mecit , Yaprak Muhittin , Cengiz Melike , Hadimioglu Necmiye , Kafadar Yusuf Taner , Celik Kiymet
Published: December 2021

Objective:

To describe surgical procedures, previous failed pregnancies, methods for overcoming pregnancy failure and, most importantly, birth of a healthy infant, in a uterus transplantation from a deceased donor.

Background:

Majority of uterus transplants have involved live donors, but several advantages make deceased donor transplantation a practicable option, principally by eliminating surgical risks to the live donor.

Methods:

Uterus transplantation from a deceased donor was performed in September 2011 in Turkey. After 5 miscarriages, perfusion computed tomography revealed an obstructed blood-outflow. To overcome this blood flow obstruction, a saphenous vein graft was anastomosed between utero-ovarian and left ovarian vein with laparotomy. Follow-up computed tomography confirmed resolution of venous congestion and a decrease in uterine volume.

Results:

Following vascular augmentation surgery, fetal cardiac activity were observed 28 days after the first embryo transfer attempt. Preterm premature rupture of the membranes was diagnosed at 19 weeks’ gestation. Cesarean section was planned at 28 weeks’ gestation due to intrauterine growth restriction and suspected preeclampsia. A healthy 760 g male baby was delivered. The baby was discharged from the neonatal intensive care unit 79 days after delivery in good condition weighing 2475 g.

Conclusions:

Deceased donor uterus transplantation is a reasonable approach for treating uterine factor-related infertility. In case of recurrent miscarriages, regional vascular augmentation by arterial or venous supercharging may be required to overcome regional misperfused regions determined by imaging studies.
Shotgun Immunoproteomics for Identification of Nonhuman Leukocyte Antigens Associated With Cellular Dysfunction in Heart Transplant Rejection
Authors: Gates Katherine V. , Panicker Anjali J. , Biendarra-Tiegs Sherri M. , Vetr Nikolai G. , Lopera Higuita Manuela , Nelson Timothy J. , Pereira Naveen L. , Griffiths Leigh G.
Published: December 2021

Background.

The International Society for Heart and Lung Transplant consensus panel notes that too little data exist regarding the role of non-HLA in allograft rejection. We developed a novel shotgun immunoproteomic approach to determine the identities and potential roles non-HLA play in antibody-mediated rejection (AMR) in heart transplant recipients.

Methods.

Serum was collected longitudinally from heart transplant recipients experiencing AMR in the absence of donor-specific anti-HLA antibodies (n = 6) and matched no rejection controls (n = 7). Antidonor heart affinity chromatography columns were formed by recipient immunoglobulin G immobilization at transplantation, acute rejection, and chronic postrejection time points. Affinity chromatography columns were used to capture antigens from individual patient’s donor heart biopsies collected at transplantation. Captured proteins were subjected to quantitative proteomic analysis and the longitudinal response was calculated.

Results.

Overlap in antigen-specific response between AMR and non-AMR patients was only 8.3%. In AMR patients, a total of 155 non-HLAs were identified, with responses toward 43 high prevalence antigens found in ≥50% of patients. Immunofluorescence staining for representative high prevalence antigens demonstrated that their abundance increased at acute rejection, correlating with their respective non-HLA antibody response. Physiological changes in cardiomyocyte and endothelial cell function, following in vitro culture with patient immunoglobulin G, correlated with response toward several high prevalence antigens.

Conclusions.

This work demonstrates a novel high-throughput strategy to identify clinically relevant non-HLA from donor endomyocardial biopsy. Such a technique has the potential to improve understanding of longitudinal timing of antigen-specific responses and their cause and effect relationship in graft rejection.
Rapid fluoroquinolone resistance detection inPseudomonas aeruginosausing mismatch amplification mutation assay-based real-time PCR
Authors: Madden Danielle E. , McCarthy Kate L. , Bell Scott C. , Olagoke Olusola , Baird Timothy , Neill Jane , Ramsay Kay A. , Kidd Timothy J. , Stewart Adam G. , Subedi Shradha , Choong Keat , Fraser Tamieka A. , Sarovich Derek S. , Price Erin P.
Published: December 2021

Background

Antimicrobial resistance (AMR) is an ever-increasing global health concern. One crucial facet in tackling the AMR epidemic is earlier and more accurate AMR diagnosis, particularly in the dangerous and highly multi-drug resistant ESKAPE pathogen,Pseudomonas aeruginosa.

Objectives

We aimed to develop two SYBR Green-based mismatch amplification mutation assays (SYBR-MAMAs) targeting GyrA T83I (gyrA248), and GyrA D87N, D87Y, and D87H (gyrA259). Together, these variants cause the majority of fluoroquinolone (FQ) AMR inP. aeruginosa.

Methods

Following assay validation, thegyrA248 andgyrA259 SYBR-MAMAs were tested on 84 clinicalP. aeruginosaisolates from Queensland, Australia, 45 of which demonstrated intermediate/full ciprofloxacin resistance according to antimicrobial susceptibility testing.

Results

Our two SYBR-MAMAs correctly predicted an AMR phenotype in the majority (84%) of isolates with intermediate/full FQ resistance. Importantly, all FQ-sensitive strains were predicted to have a sensitive phenotype. Whole-genome sequencing confirmed 100% concordance with SYBR-MAMA genotypes.

Conclusions

Our GyrA SYBR-MAMAs provide a rapid and cost-effective method for same-day identification of FQ AMR inP. aeruginosa. An additional SYBR-MAMA targeting the GyrB S466Y/S466F variants would increase FQ AMR prediction to 91%. Clinical implementation of our assays will permit more timely treatment alterations in cases where decreased FQ susceptibility is identified, leading to improved patient outcomes and antimicrobial stewardship.
Data-Driven Real-Time Strategic Placement of Mobile Vaccine Distribution Sites
Authors: Mehrab Zakaria , Wilson Mandy L. , Chang Serina , Harrison Galen , Lewis Bryan , Telionis Alex , Crow Justin , Kim Dennis , Spillmann Scott , Peters Kate , Leskovec Jure , Marathe Madhav V.
Published: December 2021

Abstract

The deployment of vaccines across the US provides significant defense against serious illness and death from COVID-19. Over 70% of vaccine-eligible Americans are at least partially vaccinated, but there are pockets of the population that are under-vaccinated, such as in rural areas and some demographic groups (e.g. age, race, ethnicity). These unvaccinated pockets are extremely susceptible to the Delta variant, exacerbating the healthcare crisis and increasing the risk of new variants. In this paper, we describe a data-driven model that provides real-time support to Virginia public health officials by recommending mobile vaccination site placement in order to target under-vaccinated populations. Our strategy uses fine-grained mobility data, along with US Census and vaccination uptake data, to identify locations that are most likely to be visited by unvaccinated individuals. We further extend our model to choose locations that maximize vaccine uptake among hesitant groups. We show that the top recommended sites vary substantially across some demographics, demonstrating the value of developing customized recommendation models that integrate fine-grained, heterogeneous data sources. In addition, we used a statistically equivalent Synthetic Population to study the effect of combined demographics (eg, people of a particular race and age), which is not possible using US Census data alone. We validate our recommendations by analyzing the success rates of deployed vaccine sites, and show that sites placed closer to our recommended areas administered higher numbers of doses. Our model is the first of its kind to consider evolving mobility patterns in real-time for suggesting placement strategies customized for different targeted demographic groups. Our results will be presented at IAAI-22, but given the critical nature of the pandemic, we offer this extended version of that paper for more timely consideration of our approach and to cover additional findings.
Whole genome sequencing identifies common and rare structural variants contributing to hematologic traits in the NHLBI TOPMed program
Authors: Wheeler Marsha M. , Stilp Adrienne M. , Rao Shuquan , Halldórsson Bjarni V. , Beyter Doruk , Wen Jia , Mikhaylova Anna V. , McHugh Caitlin P. , Lane John , Jiang Min-Zhi , Raffield Laura M. , Jun Goo , Sedlazeck Fritz J. , Metcalf Ginger , Yao Yao , Bis Joshua B. , Chami Nathalie , de Vries Paul S. , Desai Pinkal , Floyd James S. , Gao Yan , Kammers Kai , Kim Wonji , Moon Jee-Young , Ratan Aakrosh , Yanek Lisa R. , Almasy Laura , Becker Lewis C. , Blangero John , Cho Michael H. , Curran Joanne E. , Fornage Myriam , Kaplan Robert C. , Lewis Joshua P. , Loos Ruth J.F. , Mitchell Braxton D. , Morrison Alanna C. , Preuss Michael , Psaty Bruce M. , Rich Stephen S. , Rotter Jerome I. , Tang Hua , Tracy Russell P. , Boerwinkle Eric , Abecasis Goncalo , Blackwell Thomas W. , Smith Albert V. , Johnson Andrew D. , Mathias Rasika A. , Nickerson Deborah A. , Conomos Matthew P. , Li Yun ,   NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Þorsteinsdóttir Unnur , Magnússon Magnús K. , Stefansson Kari , Pankratz Nathan D. , Bauer Daniel E. , Auer Paul L. , Reiner Alex P.
Published: December 2021

Genome-wide association studies (GWAS) have identified thousands of single nucleotide variants and small indels that contribute to the genetic architecture of hematologic traits. While structural variants (SVs) are known to cause rare blood or hematopoietic disorders, the genome-wide contribution of SVs to quantitative blood cell trait variation is unknown. Here we utilized SVs detected from whole genome sequencing (WGS) in ancestrally diverse participants of the NHLBI TOPMed program (N=50,675). Using single variant tests, we assessed the association of common and rare SVs with red cell-, white cell-, and platelet-related quantitative traits. The results show 33 independent SVs (23 common and 10 rare) reaching genome-wide significance. The majority of significant association signals (N=27) replicated in independent datasets from deCODE genetics and the UK BioBank. Moreover, most trait-associated SVs (N=24) are within 1Mb of previously-reported GWAS loci. SV analyses additionally discovered an association between a complex structural variant on 17p11.2 and white blood cell-related phenotypes. Based on functional annotation, the majority of significant SVs are located in non-coding regions (N=26) and predicted to impact regulatory elements and/or local chromatin domain boundaries in blood cells. We predict that several trait-associated SVs represent the causal variant. This is supported by genome-editing experiments which provide evidence that a deletion associated with lower monocyte counts leads to disruption of an S1PR3 monocyte enhancer and decreased S1PR3 expression.