Improving accuracy of outcome prediction for infants born extremely preterm using a digital tool: Translating 'NIC-PREDICT' into clinical practice, the first steps.

BACKGROUND: Many clinicians overestimate mortality and disability rates in infants born extremely preterm. We developed a digital tool ('NIC-PREDICT') that predicts infant mortality and survival with and without major disability in infants born 23-27 weeks' gestation. AIMS: To determine if clinicians could use NIC-PREDICT accurately, and if their perceptions of infant outcomes improved after its release in 2021. MATERIALS AND METHODS: Midwives, nurses, obstetricians, neonatologists and paediatricians working in tertiary and non-tertiary hospitals in Victoria were asked to use NIC-PREDICT to estimate three mutually exclusive outcomes: (i) mortality; (ii) survival free of major disability; and (iii) survival with major disability for six different scenarios where a liveborn infant was offered survival-focused care after birth. The proportions who completed the survey (responded to all six scenarios) and the proportions able to provide 100% accurate results for all scenarios were determined. Estimates of the three outcomes were compared with true rates. RESULTS: A total of 85 clinicians responded: 70 (82%) completed the survey, with an overall accuracy of 76%. Overall, predictions of mortality were accurate (mean difference from true value 0.7% (95% confidence interval (CI) -0.7, 2.1) P = 0.33), as were predictions of survival without major disability (mean difference - 0.7 (95% CI -3.0, 1.7) P = 0.58). However, survival with major disability was overestimated by 4.9% ((95% CI 1.7, 8.0) P = 0.003). CONCLUSIONS: Most perinatal clinicians who responded used NIC-PREDICT correctly to estimate expected outcomes in infants born extremely preterm who are offered intensive care. Undue pessimism about survival with major disability remains an ongoing concern.

Canadian colorectal cancer screening programs: How do they measure up using the International Agency for Research on Cancer criteria for organized screening?

Background: Canada has one of the highest incidences of colorectal cancer (CRC) worldwide. CRC screening improves CRC outcomes and is cost-effective. This study compares Canadian CRC screening programs using essential elements of an organized screening program outlined by the International Agency for Research on Cancer (IARC). Methods: We collaborated with the Cancer Screening in 5 continents (CanScreen5) program, an initiative of IARC. Standardized data collection forms were sent to representatives of provincial and territorial CRC screening programs. Twenty-five questions were selected to reflect IARC's essential elements of an organized screening program. We performed a qualitative analysis of Canada's CRC screening programs and compared programs within Canada and internationally. Results: CRC screening programs exist in 10 provinces and 2 territories. None of the programs in Canada met all the essential criteria of an organized screening program outlined by IARC. Three programs do not send invitations to participate in screening. Among those that do, 4 programs do not include a stool test kit in the invitations. While all provinces met the essential elements for leadership, governance, finance, and access to essential services, there was more heterogeneity in the domains of service delivery as well as information systems and quality assurance. Conclusions: There is considerable heterogeneity in the design of CRC screening programs in Canada and worldwide. Programs should strive to meet all the essential IARC criteria for organized screening if local resources allow, such as issuing invitations and implementing systems to track and compare outcomes to maximize screening program quality, effectiveness, and impact.

Recent Updates on the Diagnosis and Management of Age-Related Macular Degeneration.

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the Western world, with a higher prevalence among Europeans and North Americans than that in Africans, Hispanics, and Asians. Advanced AMD is categorized as atrophic (dry) or exudative (wet/neovascular age-related macular degeneration [nAMD]). Dry AMD is characterized by progressive geographic atrophy of the retinal pigment epithelium and outer retinal layers, whereas nAMD is characterized by new vessels that invade the subretinal and/or subretinal pigment epithelium spaces. Existing treatments delay the onset of advanced AMD and reverses vision loss for a couple of years before atrophy usually decreases central visual acuity. We searched PubMed and Medline databases from January 1, 1980, to December 1, 2023, using the following search terms: macular degeneration, choroidal neovascularization, geographic atrophy, drusen, age-related maculopathy, AMD, ARMD, and anti-VEGF. Relevant articles in English (or English translations) were retrieved and reviewed. Bibliographies of the identified manuscripts were also reviewed to identify relevant studies. Age-related macular degeneration most commonly affects people older than 55 years. Visual prognosis varies, with advanced lesions (nAMD and geographic atrophy) leading to rapid, progressive loss of central vision and contrast sensitivity. Although AMD is not a life-threatening disease, reduced vision profoundly compromises quality of life and necessitates living assistance for many patients. Over the past 2 decades, advances in prevention (vitamin supplementation) and therapy (antivascular endothelial growth factor and complement inhibitor drugs) have reduced vision loss and blindness. Further research is needed to decrease the incidence of blindness in patients with advanced disease.

Efficacy of refrigerated gel packs for therapeutic hypothermia in neonatal retrieval: a retrospective cohort study.

OBJECTIVE: To determine the efficacy of refrigerated gel packs in achieving and maintaining target temperature in neonates receiving therapeutic hypothermia (TH) for hypoxic ischaemic encephalopathy during neonatal retrieval. DESIGN: Retrospective cohort study. SETTING: Paediatric Infant Perinatal Emergency Retrieval, Victoria, Australia. PATIENTS: 200 neonates treated with TH during retrieval between 1 January 2015 and 31 December 2020. INTERVENTIONS: Active cooling with refrigerated gel packs or passive cooling. MAIN OUTCOME MEASURES: The primary outcomes were the proportion of neonates who achieved therapeutic cooling rectal temperature (33-34°C) within 6 hours of birth and maintained target temperature range once TH was achieved. Secondary outcomes included need for respiratory support, inotropes, anticonvulsant therapy, sedation and survival at 7 days of life. RESULTS: 200 neonates received TH. Median gestational age was 39 weeks and median birth weight 3300 g. 120 (60%) were actively cooled with refrigerated gel packs and the remainder passively cooled. 121 neonates (61%) reached target temperature within 6 hours and 14 (7%) after 6 hours of birth. Of those who achieved target temperature, 38% were maintained in therapeutic cooling range for the remainder of the retrieval. CONCLUSIONS: Achieving and maintaining TH during neonatal retrieval with gel packs is challenging. Target temperature was not maintained in most neonates in this study. These findings support existing evidence favouring the use of servo-controlled cooling devices to optimise TH in the retrieval setting.

An in vitro study to determine the impact of lipid emulsion on partitioning of a broad spectrum of drugs associated with overdose.

Background: Intravenous lipid emulsion is recognised as a therapy for rescue in cases of local anaesthetic toxicity, but its use in reversing overdose or toxicity related to other drugs remains the subject of debate. This in vitro study sought to expand our understanding of the importance of partitioning in determining the impact of intravenous lipid emulsion on aqueous free drug concentrations. Methods: Twenty-seven drugs and associated metabolites were screened for the ability of intravenous lipid emulsion to reduce the amount of free drug in the aqueous phase, using specialised cassettes designed for this purpose. The relative amount of drug equilibrating across the membrane from plasma to phosphate-buffered saline was measured, using liquid chromatography-mass spectrometry, at a 6 h timepoint in plasma samples treated with intravenous lipid emulsion and paired, untreated controls. Results: The data obtained were plotted against measures of partition (LogP and cLogD7.4) and with log-transformed non-protein bound drug. There were significant inverse correlations between the capacity for intravenous lipid emulsion to reduce drug detected in the phosphate-buffered saline compartment and LogP and cLogD7.4, and a direct association with log [non-protein-bound drug]. However, a number of drugs showed substantial variance between different plasma samples. Conclusions: Modulation of free drug in the aqueous compartment is broadly predictable by the partition coefficient, although ramipril was identified to be an outlier in this regard. Further mechanistic and clinical exploration is merited to establish a standardised protocol for lipid emulsion therapy.

The Role of Widefield Optical Coherence Tomography Angiography in Assessing the Severity of Diabetic Retinopathy.

INTRODUCTION: Physicians need an accurate understanding of diabetic retinopathy (DR) severity to optimally manage patients. The aim of this prospective study is to correlate the severity of macular and peripheral retinal vascular abnormalities seen on widefield (WF) optical coherence tomography angiography (OCTA) with DR grading based on WF fundus photography. METHODS: The study included 150 eyes from 82 patients with treatment-naïve DR. All patients were imaged with WF fundus photography and swept-source WF OCTA. Quantitative and qualitative analyses of the foveal avascular zone (FAZ) size and shape, and measurement of capillary nonperfusion (CNP) areas, were performed from the OCTA images. The mixed-effects model was used to compare the DR grading from WF photography with the vascular changes seen on WF-OCTA, and Bonferroni correction was applied to the gradings. RESULTS: The mean [± standard deviation (SD)] age of patients was 55.5 (± 9.4) years. The WF-OCTA showed that an increasing size of the FAZ (from 0.442 (± 0.059) µm to 0.933 (± 0.086) µm) correlated with increasing severity of the DR (as determined with WF photography). The deep capillary plexus, FAZ size, and CNP areas in eyes with proliferative diabetic retinopathy (PDR) differed from those with mild nonproliferative diabetic retinopathy (NPDR) (p < 0.001). Most eyes with severe nonproliferative DR were found to have CNP in four quadrants [superficial capillary plexus (SCP) 60%, deep capillary plexus (DCP) 50%]. The WF-OCTA detected subtle neovascularization of the disc (NVD) in 7 eyes (10%) and neovascularization elsewhere (NVE) in 13 eyes (18%) that had been diagnosed with only moderate NPDR on WF photography. CONCLUSIONS: FAZ and CNP areas as measured by WF-OCTA correlate with DR severity. WF-OCTA can also detect subtle NVE and NVD that cannot be seen with fundus photography.

Fatal Presentation of Susac Syndrome in a Congenitally Deaf Patient With a Cochlear Implant.

OBJECTIVE: To report a fatal case of Susac syndrome in a congenitally deaf patient with a cochlear implant and a history of migraines, emphasizing the diagnostic challenges in patients with preexisting conditions. PATIENT: A 33-year-old male with congenital hearing loss, a cochlear implant, and chronic migraines who presented with mild subacute auditory disturbance and headaches that later progressed to severe encephalopathy. INTERVENTION: Explantation of a non-magnetic resonance imaging (MRI) compatible cochlear implant followed by MRI, fundoscopy, and the administration of immunosuppressive medications. MAIN OUTCOME MEASURES: Diagnosis was confirmed by characteristic MRI appearance and the presence of a hemi-retinal artery occlusion. RESULTS: After weeks of immunosuppressive treatment, the patient died of a global cerebral ischemic event of unknown origin. CONCLUSIONS: For patients with preexisting sensorineural hearing loss and cochlear implants, Susac syndrome poses a diagnostic challenge. Auditory disturbances in the absence of cochlear implant failure should prompt further evaluation for visual disturbances and encephalopathy. MRI and fundoscopy should be performed to detect other features of the disease.

Top 10 research priorities for congenital diaphragmatic hernia in Australia: James Lind Alliance Priority Setting Partnership.

OBJECTIVES: The Gaps in the Congenital Diaphragmatic Hernia (CDH) Journey Priority Setting Partnership (PSP) was developed in collaboration with CDH Australia, James Lind Alliance (JLA) and the Murdoch Children's Research Institute to identify research priorities for people with CDH, their families and healthcare workers in Australasia. DESIGN: Research PSP in accordance with the JLA standardised methodology. SETTING: Australian community and institutions caring for patients with CDH and their families. PATIENTS: CDH survivors, families of children born with CDH (including bereaved) and healthcare professionals including critical care physicians and nurses (neonatal and paediatric), obstetric, surgical, allied health professionals (physiotherapists, speech pathologists and speech therapists) and general practitioners. MAIN OUTCOME MEASURE: Top 10 research priorities for CDH. RESULTS: 377 questions, from a community-based online survey, were categorised and collated into 50 research questions. Through a further prioritisation process, 21 questions were then discussed at a prioritisation workshop where they were ranked by 21 participants (CDH survivors, parents of children born with CDH (bereaved and not) and 11 multidisciplinary healthcare professionals) into their top 10 research priorities. CONCLUSION: Stakeholders' involvement identified the top 10 CDH-related research questions, spanning from antenatal care to long-term functional outcomes, that should be prioritised for future research to maximise meaningful outcomes for people with CDH and their families.

How to be a good reviewer: A step-by-step guide for approaching peer review of a scientific manuscript.

Objectives: The peer review process is critical to maintaining quality, reliability, novelty, and innovation in the scientific literature. However, the teaching of scientific peer review is rarely a component of formal scientific or clinical training, and even the most experienced peer reviewers express interest in continuing education. The objective of this review article is to summarize the collective perspectives of experienced journal editors about how to be a good reviewer in a step-by-step guide that can serve as a resource for the performance of peer review of a scientific manuscript. Methods: This is a narrative review. Results: A review of the history and an overview of the modern-day peer review process are provided with attention to the role played by the reviewer, including important reasons for involvement in scientific peer review. The general components of a scientific peer review are described, and a model for how to structure a peer review report is provided. These concepts are also summarized in a reviewer checklist that can be used in real-time to develop and double-check one's reviewer report before submitting it. Conclusions: Peer review is a critically important service for maintaining quality in the scientific literature. Peer review of a scientific manuscript and the associated reviewer's report should assess specific details related to the accuracy, validity, novelty, and interpretation of a study's results. We hope that this article will serve as a resource and guide for reviewers of all levels of experience in the performance of peer review of a scientific manuscript.

Optimizing the conversion of phosphoenolpyruvate to lactate by enzymatic channeling with mixed nanoparticle display.

Co-assembling enzymes with nanoparticles (NPs) into nanoclusters allows them to access channeling, a highly efficient form of multienzyme catalysis. Using pyruvate kinase (PykA) and lactate dehydrogenase (LDH) to convert phosphoenolpyruvic acid to lactic acid with semiconductor quantum dots (QDs) confirms how enzyme cluster formation dictates the rate of coupled catalytic flux (kflux) across a series of differentially sized/shaped QDs and 2D nanoplatelets (NPLs). Enzyme kinetics and coupled flux were used to demonstrate that by mixing different NP systems into clusters, a >10× improvement in kflux is observed relative to free enzymes, which is also ≥2× greater than enhancement on individual NPs. Cluster formation was characterized with gel electrophoresis and transmission electron microscopy (TEM) imaging. The generalizability of this mixed-NP approach to improving flux is confirmed by application to a seven-enzyme system. This represents a powerful approach for accessing channeling with almost any choice of enzymes constituting a multienzyme cascade.

Voice Disorders and Hearing Loss May Be Additive Risk Factors for Depression in a National Cohort.

OBJECTIVES: Hearing loss (HL) (receptive communication impairment) is a known risk factor for depression. However, dysphonia (expressive communication impairment), has received little study. We study HL, self-reported voice disorder, and combined impairment as risk factors for depression in a large national cohort. METHODS: This was a cross-sectional epidemiologic study. Data were analyzed from the Korean National Health and Nutrition Examination Survey (KNHANES) cycles 2008-2012 and 2019-2020. KNHANES uniquely contains both audiometry and voice disorder data. HL (yes/no) was defined as ≥25 dB pure tone average. Voice disorder (yes/no) was defined by self-report. Depression (yes/no) was defined by physician diagnosis. Odds ratios for depression were calculated using multivariable logistic regressions with HL and voice disorder. RESULTS: 8,524 individuals aged 19 to 80 years old had complete data. The mean age was 57.3 years (SD = 13.4) and 64% were women. All regressions were controlled for age and sex. Those with HL, versus those without, had 1.27 times the odds (95% CI = 1.07-1.52, p = 0.007) of depression. Those with self-reported voice disorder, versus those without, had 1.48 times the odds (1.22-1.78, p < 0.001) of depression. Those with HL and self-reported voice disorder, versus those with neither, had 1.79 times the odds (1.27-2.48, p < 0.001) of depression. CONCLUSIONS: This study demonstrates independent relationships between HL and depression and self-reported voice disorder and depression. Combined HL and self-reported voice disorder had nearly 1.8 times the odds of depression. This is likely due to the grossly additive effect of difficulty with incoming and outgoing communication streams. LEVEL OF EVIDENCE: II Laryngoscope, 134:4060-4065, 2024.

Elective Surgery Trends and Outcomes of Nonagenarians and Centenarians in Otolaryngology-Head and Neck Surgery: A NSQIP Study.

OBJECTIVE: To describe types and outcomes of elective otolaryngological surgeries undergone by patients ≥90 years of age and to assess whether very old age is an independent risk factor for postsurgical complications and death. METHODS: The National Surgical Quality Improvement Program, a validated national prospective surgical outcomes database, was used to identify all patients aged 65 years and older who underwent elective otolaryngological procedures from 2011 to 2020. Study outcomes included minor complications, major life-threatening complications, and 30-day mortality. Predictors of outcomes, including frailty, were identified using univariable analyses and age was added into the final logistic regression models with stepwise selection. RESULTS: A total of 40,723 patients met inclusion criteria; 629 (1.5%) patients were ≥90 years of age. Of the 63,389 procedures, head and neck (67.6%) and facial plastics and reconstructive (15.0%) procedures were most common. The overall incidence of major life-threatening complications, minor complications, and death was 2.0%, 3.5%, and 0.4%, respectively. Age ≥90 was significantly associated with an increased risk for 30-day mortality, but not with major or minor postoperative complications. A high modified frailty index was significantly associated with an increased risk for major postoperative complications and death amongst patients ≥90 years. CONCLUSIONS: Elective otolaryngological surgery can be safe in relatively healthy nonagenarians and centenarians, though there is a small increased risk of 30-day mortality. Although older age can predispose patients to other comorbidities, age alone should not deter surgeons and patients from considering elective otolaryngological procedures. Frailty may be a better predictor for surgical outcomes. LEVEL OF EVIDENCE: IV Laryngoscope, 134:3989-3996, 2024.

Real-world experience of full-thickness traumatic macular hole among young patients.

OBJECTIVE: To describe the demographics, clinical, and imaging characteristics, and visual outcomes in young patients with full-thickness traumatic macular hole (TMH). METHODS: This retrospective hospital-based study included patients with full-thickness TMH who presented between August 2010 and June 2021. Demographic data, clinical findings, and imaging characteristics were extracted from an electronic medical record system. Regression analyses were performed to determine significant associations among variables and to identify predictors of visual outcomes. RESULTS: 144 (0.005%) patients among 2,834,616 were diagnosed with Full thickness TMH. The majority of them were male (89.58%; odds ratio [OR] = 6.71) and the holes were unilateral. The mean age at presentation was 23.37 ± 8.19 years. Ball were the most common cause of injuries (22.22%), followed by stick (14.58%) and firecracker (12.50%). The mean LogMAR visual acuity (VA) at presentation was 1.18 ± 0.72, with 25.69% of eyes having VA < 20/400. The mean minimum hole diameter was 619.34 ± 336.16 µm. Sub-retinal fluid was present in 44.44%, followed by intraretinal fluid in 34.03% of eyes. Macular holes closed after vitrectomy in 66.67% of eyes, with mean final VA of 1.07 ± 0.85. Baseline VA was a strong predictor of final VA (R2 = 0.677; p = 0.000168). CONCLUSION: Traumatic macular hole is a unilateral condition with significant visual impairment that is mainly seen in males during the third decade of life. Surgery is successful in most cases but improvements in VA are modest.

ASPSCR1-TFE3 reprograms transcription by organizing enhancer loops around hexameric VCP/p97.

The t(X,17) chromosomal translocation, generating the ASPSCR1::TFE3 fusion oncoprotein, is the singular genetic driver of alveolar soft part sarcoma (ASPS) and some Xp11-rearranged renal cell carcinomas (RCCs), frustrating efforts to identify therapeutic targets for these rare cancers. Here, proteomic analysis identifies VCP/p97, an AAA+ ATPase with known segregase function, as strongly enriched in co-immunoprecipitated nuclear complexes with ASPSCR1::TFE3. We demonstrate that VCP is a likely obligate co-factor of ASPSCR1::TFE3, one of the only such fusion oncoprotein co-factors identified in cancer biology. Specifically, VCP co-distributes with ASPSCR1::TFE3 across chromatin in association with enhancers genome-wide. VCP presence, its hexameric assembly, and its enzymatic function orchestrate the oncogenic transcriptional signature of ASPSCR1::TFE3, by facilitating assembly of higher-order chromatin conformation structures demonstrated by HiChIP. Finally, ASPSCR1::TFE3 and VCP demonstrate co-dependence for cancer cell proliferation and tumorigenesis in vitro and in ASPS and RCC mouse models, underscoring VCP's potential as a novel therapeutic target.

Effect-based monitoring of two rivers under urban and agricultural influence reveals a range of biological activities in sediment and water extracts.

Chemical contaminants, such as pesticides, pharmaceuticals and industrial compounds are ubiquitous in surface water and sediment in areas subject to human activity. While targeted chemical analysis is typically used for water and sediment quality monitoring, there is growing interest in applying effect-based methods with in vitro bioassays to capture the effects of all active contaminants in a sample. The current study evaluated the biological effects in surface water and sediment from two contrasting catchments in Aotearoa New Zealand, the highly urbanised Whau River catchment in Tamaki Makaurau (Auckland) and the urban and mixed agricultural Koreti (New River) Estuary catchment. Two complementary passive sampling devices, Chemcatcher for polar chemicals and polyethylene (PED) for non-polar chemicals, were applied to capture a wide range of contaminants in water, while composite sediment samples were collected at each sampling site. Bioassays indicative of induction of xenobiotic metabolism, receptor-mediated effects, genotoxicity, cytotoxicity and apical effects were applied to the water and sediment extracts. Most sediment extracts induced moderate to strong estrogenic and aryl hydrocarbon (AhR) activity, along with moderate toxicity to bacteria. The water extracts showed similar patterns to the sediment extracts, but with lower activity. Generally, the polar Chemcatcher extracts showed greater estrogenic activity, photosynthesis inhibition and algal growth inhibition than the non-polar PED extracts, though the PED extracts showed greater AhR activity. The observed effects in the water extracts were compared to available ecological effect-based trigger values (EBT) to evaluate the potential risk. For the polar extracts, most sites in both catchments exceeded the EBT for estrogenicity, with many sites exceeding the EBTs for AhR activity and photosynthesis inhibition. Of the wide range of endpoints considered, estrogenic activity, AhR activity and herbicidal activity appear to be the primary risk drivers in both the Whau and Koreti Estuary catchments.

Multiplexed DNA and Protease Detection with Orthogonal Energy Transfer on a Single Quantum Dot Scaffolded Biosensor.

Almost all pathogens, whether viral or bacterial, utilize key proteolytic steps in their pathogenesis. The ability to detect a pathogen's genomic material along with its proteolytic activity represents one approach to identifying the pathogen and providing initial evidence of its viability. Here, we report on a prototype biosensor design assembled around a single semiconductor quantum dot (QD) scaffold that is capable of detecting both nucleic acid sequences and proteolytic activity by using orthogonal energy transfer (ET) processes. The sensor consists of a central QD assembled via peptidyl-PNA linkers with multiple DNA sequences that encode complements to genomic sequences originating from the Ebola, Influenza, and COVID-19 viruses, which we use as surrogate targets. These are hybridized to complement strands labeled with a terbium (Tb) chelate, AlexaFluor647 (AF647), and Cy5.5 dyes, giving rise to two potential FRET cascades: the first includes Tb → QD → AF647 → Cy5.5 (→ = ET step), which is detected in a time-gated modality, and QD → AF647 → Cy5.5, which is detected from direct excitation. The labeled DNA-displaying QD construct is then further assembled with a RuII-modified peptide, which quenches QD photoluminescence by charge transfer and is recognized by a protease to yield the full biosensor. Each of the labeled DNAs and peptides can be ratiometrically assembled to the QD in a controllable manner to tune each of the ET pathways. Addition of a given target DNA displaces its labeled complement on the QD, disrupting that FRET channel, while protease addition disrupts charge transfer quenching of the central QD scaffold and boosts its photoluminescence and FRET relay capabilities. Along with characterizing the ET pathways and verifying biosensing in both individual and multiplexed formats, we also demonstrate the ability of this construct to function in molecular logic and perform Boolean operations; this highlights the construct's ability to discriminate and transduce signals between different inputs or pathogens. The potential application space for such a sensor device is discussed.

Hyperviscosity Syndrome Induced Bilateral Visual and Auditory Impairment in Therapy Resistant Waldenström Macroglobulinemia with MYD88 and CXCR4 Mutations.

Hyperviscosity syndrome (HVS) is an emergent complication of Waldenström macroglobulinemia (WM) characterized by visual, neurologic, and rarely auditory impairment. We report a 69-year-old female with MYD88 and CXCR4-mutant WM who developed HVS resulting in bilateral blindness and deafness associated with neurologic manifestations including confusion, severe generalized weakness, and imbalance. Ophthalmologic evaluation revealed bilateral central retinal vein occlusion (CRVO), diffuse retinal hemorrhages, macular edema, and serous macular detachments (SMD). Magnetic resonance imaging of the brain showed bleeding in the inner ears. Management was challenging as her WM was resistant to systemic therapies including bendamustine + rituximab (BR) and rituximab + bortezomib + dexamethasone (RVD). Bruton's tyrosine kinase inhibitors could not be used initially due to ongoing lower gastrointestinal bleeding. She required five total sessions of plasma exchange and was finally initiated on zanubrutinib, achieving a partial response. She also received intravitreal bevacizumab with rapid resolution of the retinal hemorrhages but with little improvement of the SMD. She had partial restoration of her hearing in the right ear and only slight improvement in her bilateral visual deficits. The management of HVS in frail, elderly patients with therapy-resistant WM can be challenging. In these cases, plasma exchange is required until an effective systemic therapy can be safely instituted. Genomic profiling is important in the management of WM as it can predict treatment resistance and guide therapeutic decisions.

Multivalent Display of Erythropoietin on Quantum Dots Enhances Aquaporin-4 Expression and Water Transport in Human Astrocytes In Vitro.

In mammalian cells, growth factor-induced intracellular signaling and protein synthesis play a critical role in cellular physiology and homeostasis. In the brain's glymphatic system (GS), the water-conducting activity of aquaporin-4 (AQPN-4) membrane channels (expressed in polarized fashion on astrocyte end-feet) mediates the clearance of wastes through the convective transport of fluid and solutes through the perivascular space. The glycoprotein erythropoietin (EPO) has been shown to induce the astrocyte expression of AQPN-4 via signaling through the EPO receptor and the JAK/STAT signaling pathway. Here, we self-assemble EPO in a multivalent fashion onto the surface of semiconductor quantum dots (QDs) (driven by polyhistidine-based self-assembly) to drive the interaction of the bioconjugates with EPOR on human astrocytes (HA). This results in a 2-fold augmentation of JAK/STAT signaling activity and a 1.8-fold enhancement in the expression of AQPN-4 in cultured primary HA compared to free EPO. This translates into a 2-fold increase in the water transport rate in HA cells as measured by the calcein AM water transport assay. Importantly, EPO-QD-induced augmented AQPN-4 expression does not elicit any deleterious effect on the astrocyte viability. We discuss our results in the context of the implications of EPO-nanoparticle (NP) bioconjugates for use as research tools to understand the GS and their potential as therapeutics for the modulation of GS function. More generally, our results illustrate the utility of NP bioconjugates for the controlled modulation of growth factor-induced intracellular signaling.

Sarcomatoid carcinoma of the common bile duct presenting as painless jaundice.

A woman in her 70s presented with painless jaundice and index biopsy of a common bile duct (CBD) mass obtained by endoscopic retrograde cholangiopancreatography was suspicious for malignant peripheral nerve sheath tumour. Treatment consisted of pancreaticoduodenectomy, and final pathology results were consistent with sarcomatoid carcinoma. Postoperative complications included pancreaticojejunal leak, surgical wound infection, bacteraemia, myocardial injury, and significant ulceration and stricturing of the oesophagus. 14 weeks post-pancreaticoduodenectomy, the patient was found to have a perforated viscus, gastroduodenal leak and diffuse small bowel ischaemia-the patient passed away following emergent laparotomy. We aim to add to the limited literature surrounding this rare CBD neoplasm.