The potential of 3rd-generation nanopore sequencing for B-cell clonotyping in lymphoproliferative disorders.

Lymphoid malignancies are characterized by clonal cell expansion, often identifiable by unique immunoglobulin rearrangements. Heavy (IGH) and light-chain gene usage offers diagnostic insights and enables sensitive residual disease detection via next-generation sequencing. With its adaptable throughput and variable read lengths, Oxford Nanopore thirdgeneration sequencing now holds promise for clonotyping. This study analyzed CD138+ plasma-cell DNA from eight multiple myeloma patients, comparing clonotyping performance between Nanopore sequencing, Illumina MiSeq, and Ion Torrent S5. We demonstrated clonotype consistency across platforms through Smith-Waterman local alignment of nanopore reads. The mean clonal percentage of IGH V and J gene usage in the CD138+ cells was 69% for Nanopore, 67% for S5, and 76% for MiSeq. When aligned with known clonotypes, clonal cells averaged a 91% similarity, exceeding 85%. In summary, Nanopore sequencing, with its capacity for generating millions of high-quality reads, proves effective for detecting clonal IGH rearrangements. This versatile platform offers the potential for measuring residual disease down to a sensitivity level of 10-6 at a lower cost, marking a significant advancement in clonotyping techniques.

Global disease burden of and risk factors for acute lower respiratory infections caused by respiratory syncytial virus in preterm infants and young children in 2019: a systematic review and meta-analysis of aggregated and individual participant data.

BACKGROUND: Infants and young children born prematurely are at high risk of severe acute lower respiratory infection (ALRI) caused by respiratory syncytial virus (RSV). In this study, we aimed to assess the global disease burden of and risk factors for RSV-associated ALRI in infants and young children born before 37 weeks of gestation. METHODS: We conducted a systematic review and meta-analysis of aggregated data from studies published between Jan 1, 1995, and Dec 31, 2021, identified from MEDLINE, Embase, and Global Health, and individual participant data shared by the Respiratory Virus Global Epidemiology Network on respiratory infectious diseases. We estimated RSV-associated ALRI incidence in community, hospital admission, in-hospital mortality, and overall mortality among children younger than 2 years born prematurely. We conducted two-stage random-effects meta-regression analyses accounting for chronological age groups, gestational age bands (early preterm, <32 weeks gestational age [wGA], and late preterm, 32 to <37 wGA), and changes over 5-year intervals from 2000 to 2019. Using individual participant data, we assessed perinatal, sociodemographic, and household factors, and underlying medical conditions for RSV-associated ALRI incidence, hospital admission, and three severity outcome groups (longer hospital stay [>4 days], use of supplemental oxygen and mechanical ventilation, or intensive care unit admission) by estimating pooled odds ratios (ORs) through a two-stage meta-analysis (multivariate logistic regression and random-effects meta-analysis). This study is registered with PROSPERO, CRD42021269742. FINDINGS: We included 47 studies from the literature and 17 studies with individual participant-level data contributed by the participating investigators. We estimated that, in 2019, 1 650 000 (95% uncertainty range [UR] 1 350 000-1 990 000) RSV-associated ALRI episodes, 533 000 (385 000-730 000) RSV-associated hospital admissions, 3050 (1080-8620) RSV-associated in-hospital deaths, and 26 760 (11 190-46 240) RSV-attributable deaths occurred in preterm infants worldwide. Among early preterm infants, the RSV-associated ALRI incidence rate and hospitalisation rate were significantly higher (rate ratio [RR] ranging from 1·69 to 3·87 across different age groups and outcomes) than for all infants born at any gestational age. In the second year of life, early preterm infants and young children had a similar incidence rate but still a significantly higher hospitalisation rate (RR 2·26 [95% UR 1·27-3·98]) compared with all infants and young children. Although late preterm infants had RSV-associated ALRI incidence rates similar to that of all infants younger than 1 year, they had higher RSV-associated ALRI hospitalisation rate in the first 6 months (RR 1·93 [1·11-3·26]). Overall, preterm infants accounted for 25% (95% UR 16-37) of RSV-associated ALRI hospitalisations in all infants of any gestational age. RSV-associated ALRI in-hospital case fatality ratio in preterm infants was similar to all infants. The factors identified to be associated with RSV-associated ALRI incidence were mainly perinatal and sociodemographic characteristics, and factors associated with severe outcomes from infection were mainly underlying medical conditions including congenital heart disease, tracheostomy, bronchopulmonary dysplasia, chronic lung disease, or Down syndrome (with ORs ranging from 1·40 to 4·23). INTERPRETATION: Preterm infants face a disproportionately high burden of RSV-associated disease, accounting for 25% of RSV hospitalisation burden. Early preterm infants have a substantial RSV hospitalisation burden persisting into the second year of life. Preventive products for RSV can have a substantial public health impact by preventing RSV-associated ALRI and severe outcomes from infection in preterm infants. FUNDING: EU Innovative Medicines Initiative Respiratory Syncytial Virus Consortium in Europe.

Examining the unmet needs of chronic wound patients with common mental disorders.

BACKGROUND: Common mental disorders (CMD) are highly morbid conditions not routinely screened for in chronic wound care. A comorbid psychiatric condition's influence on a patient with chronic wounds' quality of life (QoL) is unknown. This study investigates the implications of CMD on QoL in patients with chronic lower extremity (LE) wounds. METHODS: This cross-sectional study surveyed patients with chronic LE wounds evaluated in our multidisciplinary clinic between June-July 2022. Surveys included validated physical and social QoL questionnaires, including the Lower Extremity Functional Scale (LEFS), Patient-Reported Outcomes Measurement Information System (PROMIS-3a) Scale v2.0, 12-Item Short-Form (SF-12), and a screening tool for common mental disorders, the Self-Reporting Questionnaire 20 (SRQ-20). Data regarding patient demographics, comorbidities, psychiatric diagnoses, and wound care history were retrospectively collected. RESULTS: Of the 265 identified patients, 39 (14.7%) had documented psychiatric diagnoses, most often depression or anxiety. The diagnosed cohort had higher median SRQ-20 scores (6, IQR: 6 vs. 3, IQR: 5; P < 0.001) and a higher proportion of positive screens for CMD (30.8% vs. 15.5%; P = 0.020) than non-diagnosed patients. There were no differences in physical or social QoL in patients with and without a psychiatric diagnosis. However, individuals screening positively for CMD experienced significantly more pain (T-score 60.2 vs. 51.4, P = 0.0052) and reduced function (LEFS 26.0 vs. 41.0, P < 0.0000). CONCLUSION: This study illustrates that patients with chronic LE wounds experience potentially meaningful psychologic distress. Further, symptoms of a CMD (SRQ-20 ≥8), rather than a previous diagnosis, may influence pain and functional outcomes. These findings emphasize the potential relevance of psychological distress in this population and reinforce the need for further investigation of actionable responses to this apparent need.

COVID-19 nasopharyngeal swab and cribriform fracture.

Since the start of the pandemic, over 400 million COVID-19 swab tests have been conducted in the UK with a non-trivial number associated with skull base injury. Given the continuing use of nasopharyngeal swabs, further cases of swab-associated skull base injury are anticipated. We describe a 54-year-old woman presenting with persistent colourless nasal discharge for 2 weeks following a traumatic COVID-19 nasopharyngeal swab. A ß2-transferrin test confirmed cerebrospinal fluid (CSF) rhinorrhoea and a high-resolution sinus computed tomography (CT) scan demonstrated a cribriform plate defect. Magnetic resonance imaging showed radiological features of idiopathic intracranial hypertension (IIH): a Yuh grade V empty sella and thinned anterior skull base. Twenty-four hour intracranial pressure (ICP) monitoring confirmed raised pressures, prompting insertion of a ventriculoperitoneal shunt. The patient underwent CT cisternography and endoscopic transnasal repair of the skull base defect using a fluorescein adjuvant, without complications. A systematic search was performed to identify cases of COVID-19 swab-related injury. Eight cases were obtained, of which three presented with a history of IIH. Two cases were complicated by meningitis and were managed conservatively, whereas six required endoscopic skull base repair and one had a ventriculoperitoneal shunt inserted. A low threshold for high-resolution CT scanning is suggested for patients presenting with rhinorrhoea following a nasopharyngeal swab. The literature review suggests an underlying association between IIH, CSF rhinorrhoea and swab-related skull base injury. We highlight a comprehensive management pathway for these patients, including high-resolution CT with cisternography, ICP monitoring, shunt and fluorescein-based endoscopic repair to achieve the best standard of care.

Risk Factors for Failure of Final Anatomic Surgical Reattachment in Retinal Detachments From Combat Ocular Trauma.

BACKGROUND AND OBJECTIVE: The goal of this study was to determine the anatomic outcome of traumatic retinal detachment (RD) from combat ocular trauma. MATERIALS AND METHODS: Retrospective study of patients sustaining a traumatic RD in Operation Iraqi Freedom and Operation Enduring Freedom who were evacuated to Walter Reed Army Medical Center from 2001 to 2011. The Fisher exact test, Wilcoxon rank sum test, and Agresti and Coull methods were used for analyses. RESULTS: There were 143 eyes of 134 patients in which a traumatic RD developed, of a total of 890 eyes of 652 patients in the Walter Reed Ocular Trauma Database. Based on our results, predictors for failure to reattach the retina include maculaoff status (P = .0002), open-globe injury (P = .03), proliferative vitreoretinopathy postoperatively (P = .002), and presence of hyphema (P = .02). Intraocular foreign body and time to initial retinal surgery did not increase risk for failure. Thirty-four percent (34%) of eyes failed to be reattached. CONCLUSIONS: Traumatic RD due to injury sustained in a combat zone resulted in poor prognosis, with 82.09% of eyes with RD having a best-corrected visual acuity worse than 20/200. The anatomic success of RD repair was shown to be 65.71%, likely owing to the severity of the injuries, concomitant systemic injuries, and delayed surgical intervention. [Ophthalmic Surg Lasers Imaging Retina 2022;53:493-501.].

Historical and future trends in emergency pituitary referrals: a machine learning analysis.

PURPOSE: Acute pituitary referrals to neurosurgical services frequently necessitate emergency care. Yet, a detailed characterisation of pituitary emergency referral patterns, including how they may change prospectively is lacking. This study aims to evaluate historical and current pituitary referral patterns and utilise state-of-the-art machine learning tools to predict future service use. METHODS: A data-driven analysis was performed using all available electronic neurosurgical referrals (2014-2021) to the busiest U.K. pituitary centre. Pituitary referrals were characterised and volumes were predicted using an auto-regressive moving average model with a preceding seasonal and trend decomposition using Loess step (STL-ARIMA), compared against a Convolutional Neural Network-Long Short-Term Memory (CNN-LSTM) algorithm, Prophet and two standard baseline forecasting models. Median absolute, and median percentage error scoring metrics with cross-validation were employed to evaluate algorithm performance. RESULTS: 462 of 36,224 emergency referrals were included (referring centres = 48; mean patient age = 56.7 years, female:male = 0.49:0.51). Emergency medicine and endocrinology accounted for the majority of referrals (67%). The most common presentations were headache (47%) and visual field deficits (32%). Lesions mainly comprised tumours or haemorrhage (85%) and involved the pituitary gland or fossa (70%). The STL-ARIMA pipeline outperformed CNN-LSTM, Prophet and baseline algorithms across scoring metrics, with standard accuracy being achieved for yearly predictions. Referral volumes significantly increased from the start of data collection with future projected increases (p < 0.001) and did not significantly reduce during the COVID-19 pandemic. CONCLUSION: This work is the first to employ large-scale data and machine learning to describe and predict acute pituitary referral volumes, estimate future service demands, explore the impact of system stressors (e.g. COVID pandemic), and highlight areas for service improvement.

A biomarker assay to risk-stratify patients with symptoms of respiratory tract infection.

BACKGROUND: Patients who present to an emergency department (ED) with respiratory symptoms are often conservatively triaged in favour of hospitalisation. We sought to determine if an inflammatory biomarker panel that identifies the host response better predicts hospitalisation in order to improve the precision of clinical decision making in the ED. METHODS: From April 2020 to March 2021, plasma samples of 641 patients with symptoms of respiratory illness were collected from EDs in an international multicentre study: Canada (n=310), Italy (n=131) and Brazil (n=200). Patients were followed prospectively for 28 days. Subgroup analysis was conducted on confirmed coronavirus disease 2019 (COVID-19) patients (n=245). An inflammatory profile was determined using a rapid, 50-min, biomarker panel (RALI-Dx (Rapid Acute Lung Injury Diagnostic)), which measures interleukin (IL)-6, IL-8, IL-10, soluble tumour necrosis factor receptor 1 (sTNFR1) and soluble triggering receptor expressed on myeloid cells 1 (sTREM1). RESULTS: RALI-Dx biomarkers were significantly elevated in patients who required hospitalisation across all three sites. A machine learning algorithm that was applied to predict hospitalisation using RALI-Dx biomarkers had a mean±sd area under the receiver operating characteristic curve of 76±6% (Canada), 84±4% (Italy) and 86±3% (Brazil). Model performance was 82±3% for COVID-19 patients and 87±7% for patients with a confirmed pneumonia diagnosis. CONCLUSIONS: The rapid diagnostic biomarker panel accurately identified the need for inpatient care in patients presenting with respiratory symptoms, including COVID-19. The RALI-Dx test is broadly and easily applicable across many jurisdictions, and represents an important diagnostic adjunct to advance ED decision-making protocols.

Microsurgery for intracranial aneurysms: A qualitative survey on technical challenges and technological solutions.

Introduction: Microsurgery for the clipping of intracranial aneurysms remains a technically challenging and high-risk area of neurosurgery. We aimed to describe the technical challenges of aneurysm surgery, and the scope for technological innovations to overcome these barriers from the perspective of practising neurovascular surgeons. Materials and Methods: Consultant neurovascular surgeons and members of the British Neurovascular Group (BNVG) were electronically invited to participate in an online survey regarding surgery for both ruptured and unruptured aneurysms. The free text survey asked three questions: what do they consider to be the principal technical barriers to aneurysm clipping? What technological advances have previously contributed to improving the safety and efficacy of aneurysm clipping? What technological advances do they anticipate improving the safety and efficacy of aneurysm clipping in the future? A qualitative synthesis of responses was performed using multi-rater emergent thematic analysis. Results: The most significant reported historical advances in aneurysm surgery fell into five themes: (1) optimising clip placement, (2) minimising brain retraction, (3) tissue handling, (4) visualisation and orientation, and (5) management of intraoperative rupture. The most frequently reported innovation by far was indocyanine green angiography (84% of respondents). The three most commonly cited future advances were hybrid surgical and endovascular techniques, advances in intraoperative imaging, and patient-specific simulation and planning. Conclusions: While some surgeons perceive that the rate of innovation in aneurysm clipping has been dwarfed in recent years by endovascular techniques, surgeons surveyed highlighted a broad range of future technologies that have the potential to continue to improve the safety of aneurysm surgery in the future.

Globe and Adnexal Trauma Terminology Survey.

Importance: Ocular trauma terminology should be periodically updated to enable comprehensive capturing and monitoring of ocular trauma in clinical and research settings. Objective: To update terminology for globe and adnexal trauma. Design, Setting, and Participants: A 2-round modified Delphi survey was conducted from January 1 to July 31, 2021, using an expert panel, including 69 ophthalmologists identified through their membership in ophthalmology (globe and adnexal trauma) societies. Consensus was defined as at least 67% expert agreement. A steering committee developed questions after identifying gaps in the current terminology via a targeted literature review. Round 1 sought consensus on existing and newly proposed terminology, and round 2 focused on unresolved questions from round 1. Experts included ophthalmologists who had managed, on average, 52 globe or adnexal trauma cases throughout their careers and/or published a total of 5 or more globe or adnexal trauma-related peer-reviewed articles. Main Outcomes and Measures: Expert consensus on ocular and adnexal terms. Results: A total of 69 experts participated in and completed round 1 of the survey. All 69 participants who completed round 1 were asked to complete round 2, and 58 responses were received. Consensus was reached for 18 of 25 questions (72%) in round 1 and 4 of 7 questions (57%) in round 2. Existing Birmingham Eye Trauma Terminology system terminology achieved consensus of 84% (58 of 69 experts) in round 1 and 97% (56 of 58 experts) in round 2. Experts agreed on the need for further refinement of the definition of zones of injury (55 of 69 [80%]), as the zone affected can have a substantial effect on visual and functional outcomes. There was consensus that the mechanism of injury (52 of 69 [75%]) and status of the lacrimal canaliculi (54 of 69 [78%]), nasolacrimal ducts (48 of 69 [69%]), lens (46 of 58 [80%]), retina (42 of 58 [73%]), and central and paracentral cornea (47 of 58 [81%]) be included in the revised terminology. Conclusions and Relevance: There was consensus (defined as at least 67% expert agreement) on continued use of the existing Birmingham Eye Trauma Terminology system definitions and that additional terms are required to update the current ocular trauma terminology.

IgG4-related hypophysitis: a retrospective cohort study.

PURPOSE: IgG4-related hypophysitis (IgG4-RH) is a rare chronic inflammatory condition of the pituitary gland. This study reports the presentation, management and outcomes for patients with histologically proven IgG4-related hypophysitis. METHODS: A prospectively maintained electronic database was searched over a 14-year period from 1 January 2007 to 31 December 2020 at a single academic centre to identify all patients with a histological diagnosis of IgG4-RH. A retrospective case note review from electronic health records was conducted for each case to extract data on their presentation, management and outcomes. RESULTS: A total of 8 patients (5 male) with a median age of 51 years were identified. The most common presenting symptoms were headache (4/8; 50%), fatigue (3/8; 37.5%) and visual impairment (2/8; 25%). Three patients were initially treated with high-dose steroids aiming for reduction of the pituitary mass. However, ultimately all patients underwent transsphenoidal surgery. Post-operative changes included radiological reduction in pituitary mass in all patients that had imaging (7/7; 100%), improvement in vision (1/2; 50%), residual thick pituitary stalk (5/7; 71.4%), persistent anterior hypopituitarism (4/8; 50%) and panhypopopituitarism including diabetes insipidus (3/8; 37.5%). CONCLUSIONS: IgG4-RH is an increasingly recognised entity presenting with a variety of symptoms and signs. Clinical presentation is similar to other forms of hypophysitis. It is therefore important to consider IgG4-RH as a differential and to have a low threshold for pituitary biopsy, the diagnostic gold standard. The diagnosis of IgG4-RH will guide decisions for additional workup for IgG4-related disease, multi-disciplinary team involvement and follow-up.

Correlative Factors for Traumatic Brain Injury in Combat Ocular Trauma.

INTRODUCTION: Traumatic brain injury (TBI) remains a significant source of disability for active duty service members in both deployed and training settings as well as those who have left active service. Service members with ocular trauma are at risk for a TBI and should be screened appropriately. Early detection results in treatment to minimize long-term sequelae which can often be debilitating. This study is the first to evaluate different combat-related ocular injuries and their associations with TBI. MATERIALS AND METHODS: A secondary analysis of existing data was conducted from a prospective study of patients who sustained combat ocular trauma (COT) during Operation Iraqi Freedom (OIF) and Operation Enduring Freedom (OEF) between 2006 and 2020. Clinical data of a total of 88 participants were gathered and each case reviewed, including patient demographics, injury-related factors, history of TBI, and treatments rendered. All cases were then categorized to compare COT (n = 13) versus COT-T (Combat Ocular Trauma associated with TBI; n = 75). The Fisher's exact test was completed for each category to assess for predictive factors of TBI within the ophthalmic trauma cohort. Odds ratios were calculated with their 95% CI. RESULTS: When compared to COT, COT-T was significantly associated with closed globe injuries (56%; OR 4.24, 95% CI 1.08-16.67), blast injuries (89.3%; OR 3.72, 95% CI 0.93-14.9), multiple surgeries (89%; OR 2.51, 95% CI 0.57-11.08), anterior segment injuries (69.3%; OR 1.41, 95% CI 0.42-4.79), optic nerve injuries (24%; OR 1.05, 95% CI 0.26-4.25), orbital fractures (48%; OR 2.08, 95% CI 0.59-7.34), enucleation (17.3%; OR 2.52, 95% CI 0.300-21.08), the use of eye protection (68.6%; OR 2.18, 95% CI 0.57-8.32), and the need to undergo plastic surgery (78.7%; OR 2.30, 95% CI 0.66-8.02). Significant factors associated with COT included penetrating injury (30.8%; OR 0.027, 95% CI 0.07-1.08), posterior segment injuries (92%; OR 0.264, 95% CI 0.032-2.17), bilateral injuries (76.9%; OR 0.678, 95% CI 0.17-2.69), and bilateral blindness (7.7%; OR 0.857, 95% CI 0.092-7.99). CONCLUSIONS: Patients who have sustained combat-related ocular injuries, specifically blast injury, anterior segment injury, or an orbital fracture, were noted to be more likely to have also sustained a TBI. However, of the evaluated variables in predicting the co-occurrence of TBI, only closed globe injury was identified as statistically significant. Service members with injuries requiring multiple surgical procedures, reconstructive plastic surgery, or enucleation of an eye were also more likely to be diagnosed with a TBI, but these variables were not found to be predictive of TBI among ocular trauma patients. The presence of eye protection was not protective against TBI. Further studies are needed to find significant predictors of TBI in combat ocular trauma patients to assist in the early and accurate detection of TBI.

Acute myeloid leukemia exhibiting clonal instability during treatment: Implications for measurable residual disease assessments.

Next-generation sequencing (NGS) is an excellent methodology for measuring residual disease in acute myeloid leukemia and surveying several subclones simultaneously. There is little experience with interpretation of differential clonal responses to therapy. We hypothesized that differential clonal response could best be studied in patients with residual disease at the time of response evaluation. We performed targeted panel sequencing of paired diagnostic and first treatment evaluation samples in 69 patients with residual disease by morphology or measurable residual disease (MRD) level >0.02. Five patients had a rising clone at the time of evaluation. In a representative case, the rising clone was present only in the putative healthy stem cells (CD45lowCD34+CD38-CD123-CD7-) and not in the putative leukemic stem cells (CD34+CD38-CD123+CD7+) cells, thus indicating nonmalignant clonal hematopoiesis. In contrast, 17 of 43 evaluable patients exhibited a differential response in genes related to the leukemic clone. Twenty-six of 43 patients exhibited a clonal response that followed the overall treatment response. Patients with a differential response had better event-free survival (EFS) and overall survival (OS) than those in whom the clonal response followed the overall response (log-rank test, EFS: p = 0.045, OS: p = 0.050). This indicates that when following multiple leukemia-related clones, the less chemotherapy-responsive clone could, in some cases, have lower relapse potential, contrary to what is known when using standard mutation or fusion transcript-based disease surveillance. In conclusion, our results confirm the potential of refining MRD assessments by following multiple clones and warrants further studies on the precise interpretations of multiclone NGS-MRD assays.

Ophthalmic trauma: the top 100 cited articles in Ophthalmology journals.

OBJECTIVES: To analyze the top 100 cited papers on ophthalmic trauma. METHODS: A literature search of Ophthalmology journals within the ISI Web of Science database for the most cited papers related to ophthalmic trauma. RESULTS: The most cited articles were published between 1943 and 2013, the greatest number being published in 2000. Ophthalmology (45), Archives of Ophthalmology (17), and the American Journal of Ophthalmology (15) published most of the articles. The institutions with the highest number of publications were Wilmer Eye Institute (10) and Massachusetts Eye and Ear Infirmary (7). Sixty-seven percent of the articles originated from the USA. The most common type of trauma studied was non-open-globe injuries and the most frequent topic studied were pathological conditions secondary to trauma (34), particularly endophthalmitis (8), and optic neuropathy (6). Articles presenting a standardized classification system for eye injury received the highest average of citations per publication. Types of research most frequently cited were observational clinical studies (62) and epidemiological studies (30); the least frequent were clinical trials (2). CONCLUSION: This bibliographic study provides a historical perspective of the literature and identifies trends within the most highly influential papers on ophthalmic trauma. Many of these articles emerged within the past three decades and came from Ophthalmology journals that remain high impact to this day. Clinical trials have been difficult to conduct and are lacking, reflecting a critical need in ophthalmic trauma research, as most of our understanding of ophthalmic trauma comes from observational and epidemiological studies.

Outpatient Respiratory Management of Infants, Children, and Adolescents with Post-Prematurity Respiratory Disease: An Official American Thoracic Society Clinical Practice Guideline.

Background: Premature birth affects millions of neonates each year, placing them at risk for respiratory disease due to prematurity. Bronchopulmonary dysplasia is the most common chronic lung disease of infancy, but recent data suggest that even premature infants who do not meet the strict definition of bronchopulmonary dysplasia can develop adverse pulmonary outcomes later in life. This post-prematurity respiratory disease (PPRD) manifests as chronic respiratory symptoms, including cough, recurrent wheezing, exercise limitation, and reduced pulmonary function. This document provides an evidence-based clinical practice guideline on the outpatient management of infants, children, and adolescents with PPRD. Methods: A multidisciplinary panel of experts posed questions regarding the outpatient management of PPRD. We conducted a systematic review of the relevant literature. The Grading of Recommendations, Assessment, Development, and Evaluation approach was used to rate the quality of evidence and the strength of the clinical recommendations. Results: The panel members considered the strength of each recommendation and evaluated the benefits and risks of applying the intervention. In formulating the recommendations, the panel considered patient and caregiver values, the cost of care, and feasibility. Recommendations were developed for or against three common medical therapies and four diagnostic evaluations in the context of the outpatient management of PPRD. Conclusions: The panel developed recommendations for the outpatient management of patients with PPRD on the basis of limited evidence and expert opinion. Important areas for future research were identified.

Tunable and Cooperative Catalysis for Enantioselective Pictet-Spengler Reaction with Varied Nitrogen-Containing Heterocyclic Carboxaldehydes.

Herein we report an organocatalytic enantioselective functionalization of heterocyclic carboxaldehydes via the Pictet-Spengler reaction. Through careful pairing of novel squaramide and Brønsted acid catalysts, our method tolerates a breadth of heterocycles, enabling preparation of a series of heterocycle conjugated ß-(tetrahydro)carbolines in good yield and enantioselectivity. Careful selection of carboxylic acid co-catalyst is essential for toleration of a variety of regioisomeric heterocycles. Utility is demonstrated via the three-step stereoselective preparation of pyridine-containing analogues of potent selective estrogen receptor downregulator and U.S. FDA approved drug Tadalafil.

Kinetic Analysis of a Cysteine-Derived Thiyl-Catalyzed Asymmetric Vinylcyclopropane Cycloaddition Reflects Numerous Attractive Noncovalent Interactions.

Kinetic studies of a vinylcyclopropane (VCP) cycloaddition, catalyzed by peptide-based thiyl radicals, are described. Reactions were analyzed by using reaction progress kinetic analysis, revealing that ring-opening of the VCP is both rate- and enantio-determining. These conclusions are further corroborated by studies involving racemic and enantiopure VCP starting material. Noncovalent interactions play key roles throughout: both the peptide catalyst and VCP exhibit unproductive self-aggregation, which appears to be disrupted by binding between the catalyst and VCP. This in turn explains the requirement for the key catalyst feature, a substituent at the 4-position of the proline residue, which is required for both turnover/rate and selectivity.

Endophthalmitis: a bibliographic review.

PURPOSE: To analyze the 100 most cited articles pertaining to endophthalmitis using bibliometric analysis. METHODS: An all-time Web of Science literature search and refined to peer-reviewed articles in the field of ophthalmology with the keyword "endophthalmitis" was completed. Total citation count of articles published pertaining to endophthalmitis, topic, incidence rate, publishing journals, year published, language, country of origin, number of authors, names of the first and last authors, study type, and number of patients/eyes studied. RESULTS: The top 100 most cited articles pertaining to endophthalmitis had a mean citation count of 362.92, with a range of 175 to 3583. They were published in 20 peer-reviewed journals, with Ophthalmology publishing the most (n = 42). Thirteen different countries were represented, with the majority (n = 77) originating from the USA. The most common study type was clinical experiences (n = 52), though eight of the top ten were clinical trials. The number of patients varied widely, represented by a mean of 9680, but with a median of only 229. The majority (n = 67) examined the incidence of endophthalmitis which included 24 articles after anti-vascular endothelial growth factor injections, 18 after ocular surgeries/procedures, 15 after intraocular steroid injections, eight after chemotoxic drug use, and three after ocular injuries. CONCLUSION: This bibliographic study serves as a unique historical analysis of the top 100 cited scholarly articles pertaining to endophthalmitis with many of the articles related to post-procedural endophthalmitis.

Dysbiosis of the Urinary Bladder Microbiome in Cats with Chronic Kidney Disease.

Although feline urinary tract diseases cause high morbidity and mortality rates, and subclinical bacteriuria is not uncommon, the feline urinary microbiome has not been characterized. We conducted a case-control study to identify the feline urinary bladder microbiome and assess its association with chronic kidney disease (CKD), feline idiopathic cystitis (FIC), and positive urine cultures (PUCs). Of 108 feline urine samples subjected to 16S rRNA gene sequencing, 48 (44.4%) samples reached the 500-sequence rarefaction threshold and were selected for further analysis, suggesting that the feline bladder microbiome is typically sparse. Selected samples included 17 CKD, 9 FIC, 8 PUC cases and 14 controls. Among these, 19 phyla, 145 families, and 218 genera were identified. Proteobacteria were the most abundant, followed by Firmicutes. Notably, four major urotypes were identified, including two urotypes predominated by Escherichia-Shigella or Enterococcus and two others characterized by relatively high alpha diversity, Diverse 1 and Diverse 2. Urotype was associated with disease status (P value of 0.040), with the Escherichia-Shigella-predominant urotype being present in 53% of CKD cases and in all of the Escherichia coli PUC cases. Reflecting these patterns, the overall microbial composition of CKD cases was more similar to that of E. coli PUC cases than to that of controls (P value of <0.001). Finally, PUC cases had microbial compositions distinct from those of controls as well as CKD and FIC cases, with significantly lower Shannon diversity and Faith's phylogenetic diversity values. IMPORTANCE Despite the clinical importance of urinary diseases in cats, the presence of resident urine microbes has not been demonstrated in cats, and the role of these microbes as a community in urinary health remains unknown. Here, we have shown that cats with and without urinary tract disease harbor unique microbial communities in their urine. We found no evidence to suggest that the bladder microbiome is implicated in the pathogenesis of feline idiopathic cystitis, a disease similar to bladder pain syndrome/interstitial cystitis in humans. However, cats with chronic kidney disease had dysbiosis of their bladder microbiome, which was predominated by Escherichia-Shigella and had a community structure similar to that of cats with Escherichia coli cystitis. These findings suggest that chronic kidney disease alters the bladder environment to favor Escherichia-Shigella colonization, potentially increasing the risk of overt clinical infection.

Second surgery for progressive glioblastoma: a multi-centre questionnaire and cohort-based review of clinical decision-making and patient outcomes in current practice.

PURPOSE: Glioblastoma prognosis is poor. Treatment options are limited at progression. Surgery may benefit, but no quality guidelines exist to inform patient selection. We sought to describe variations in surgical management at progression, highlight where further evidence is needed, and build towards a consensus strategy. METHODS: Current practice in selection of patients with progressive GBM for second surgery was surveyed online amongst specialists in the UK and Europe. We complemented this with an assessment of practice in a retrospective cohort study from six United Kingdom neurosurgical units. We used descriptive statistics to analyse the data. RESULTS: 234 questionnaire responses were received. Maintaining or improving patient quality of life was key to decision making, with variation as to whether patient age, performance status or intended extent of resection was relevant. MGMT methylation status was not important. Half considered no minimum time after first surgery. 288 patients were reported in the cohort analysis. Median time to second surgery from first surgery 390 days. Median overall survival 815 days, with no association between time to second surgery and time to death (p = 0.874). CONCLUSIONS: This is the most wide-ranging examination of contemporaneous practice in management of GBM progression. Without evidence-based guidelines, the variation is unsurprising. We propose consensus guidelines for consideration, to reduce heterogeneity in decision making, support data collection and analysis of factors influencing outcomes, and to inform clinical trials to establish whether second surgery improves patient outcomes, or simply selects to patients already performing well.

Perspective: sensitive detection of residual lymphoproliferative disease by NGS and clonal rearrangements-how low can you go?

Malignant lymphoproliferative disorders collectively constitute a large fraction of the hematological cancers, ranging from indolent to highly aggressive neoplasms. Being a diagnostically important hallmark, clonal gene rearrangements of the immunoglobulins enable the detection of residual disease in the clinical course of patients down to a minute fraction of malignant cells. The introduction of next-generation sequencing (NGS) has provided unprecedented assay specificity, with a sensitivity matching that of polymerase chain reaction-based measurable residual disease (MRD) detection down to the 10-6 level. Although reaching 10-6 to 10-7 is theoretically feasible, employing a sufficient amount of DNA and sequencing coverage is placed in the perspective of the practical challenges when relying on clinical samples in contrast to controlled serial dilutions. As we discuss, the randomness of subsampling must be taken into account to accommodate the sensitivity threshold-in terms of both the required number of cells and sequencing coverage. As a substantial part of the reviewed studies do not state the depth of coverage or even amount of DNA in some cases, we call for increased transparency to enable critical assessment of the MRD assays for clinical implementation and feasibility.