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Regulatory harmonization and convergence have been identified as the key driver in promoting efficient evaluation of medicines, reducing workload, and supporting earlier access to medicines on the African continent. There has been great progress to date in enhancing regulatory harmonization and convergence on the African continent via the Regional Economic Communities (RECs) and with the establishment of the Africa Medicines Agency (AMA). In this article, the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA) Africa Regulatory Network (ARN) presents its perspective based on the available literature review and results from a survey conducted with innovative biopharmaceutical companies to gather experiences using regional joint assessment procedures (JAPs) in Africa, such as the East African Community Medicines Regulatory Harmonization (EAC-MRH), the West African Medicines Regulatory Harmonization (WA-MRH), and the Southern African Development Community Medicines Regulatory Harmonization (SADC-MRH) initiative through the ZAZIBONA Collaborative Procedure for Medicines Registration (ZaZiBoNa), and provides best practices in this evolving landscape. The article also assesses other collaborative registration pathways available to facilitating registration of pharmaceutical products in African countries, such as WHO Collaborative Registration Procedures (CRP), Swissmedic’s Marketing Authorisation for Global Health Products (MAGHP) and EU Medicines for All (EU-M4ALL). Benefits and challenges of each of the existing pathways are discussed in this article. Main benefits include building more expert capacity and improved collaboration amongst experts, as well as shorter review timelines in some cases. Key challenges include the lack of predictability in the adherence to procedural timelines as defined per guidelines, lengthy timeline to achieve national marketing authorization following joint assessment, the lack of dedicated personnel, administrative issues during the submission process as well as additional country-specific requirements on top of JAP-specific requirements. Our recommendations for improvements include harmonization of requirements across countries and regions and with international standards, appropriate resource allocation for JAP activities to ensure adherence to timelines, use of JAPs throughout the entire product lifecycle and all product categories, adequate use of digital technologies, and improved communication and transparency with applicants. These improvements will allow industry to better plan their filing strategies for the region which will lead to overall improved usability of the JAPs in Africa and enable faster patient access.

Abstract Background In the treatment of phenylketonuria (PKU), there was disparity between UK dietitians regarding interpretation of how different foods should be allocated in a low phenylalanine diet (allowed without measurement, not allowed, or allowed as part of phenylalanine exchanges). This led to variable advice being given to patients. Methodology In 2015, British Inherited Metabolic Disease Group (BIMDG) dietitians (n = 70) were sent a multiple-choice questionnaire on the interpretation of protein from food-labels and the allocation of different foods. Based on majority responses, 16 statements were developed. Over 18-months, using Delphi methodology, these statements were systematically reviewed and refined with a facilitator recording discussion until a clear majority was attained for each statement. In Phase 2 and 3 a further 7 statements were added. Results The statements incorporated controversial dietary topics including: a practical ‘scale’ for guiding calculation of protein from food-labels; a general definition for exchange-free foods; and guidance for specific foods. Responses were divided into paediatric and adult groups. Initially, there was majority consensus (≥86%) by paediatric dietitians (n = 29) for 14 of 16 statements; a further 2 structured discussions were required for 2 statements, with a final majority consensus of 72% (n = 26/36) and 64% (n = 16/25). In adult practice, 75% of dietitians agreed with all initial statements for adult patients and 40% advocated separate maternal-PKU guidelines. In Phase 2, 5 of 6 statements were agreed by ≥76% of respondents with one statement requiring a further round of discussion resulting in 2 agreed statements with a consensus of ≥71% by dietitians in both paediatric and adult practice. In Phase 3 one statement was added to elaborate further on an initial statement, and this received 94% acceptance by respondents. Statements were endorsed by the UK National Society for PKU. Conclusions The BIMDG dietitians group have developed consensus dietetic statements that aim to harmonise dietary advice given to patients with PKU across the UK, but monitoring of statement adherence by health professionals and patients is required.

Widespread peritoneal dissemination is common in patients with gynecologic or gastrointestinal cancers. Accumulating evidence of a central role for regional immunity in cancer control indicates that intraperitoneal immunotherapy may have treatment advantages. This study delineates immune mechanisms engaged by intraperitoneal delivery of a cell-based vaccine comprised of silicified ovarian cancer cells associated with enhanced survival. Vaccine trafficking from the site of injection to milky spots and other fat-associated lymphoid clusters was studied in syngeneic cancer models using bioluminescent and fluorescent imaging, microscopy, and flow cytometry. Spectral flow cytometry was used to phenotype peritoneal immune cell populations, while bioluminescent imaging of cancer was used to study myeloid and T cell dependency, systemic immunity, and vaccine efficacy in models of disseminated high-grade serous ovarian and DNA mismatch-repair proficient microsatellite-stable colorectal cancer. Following intraperitoneal vaccination of mice with ovarian cancer, vaccine cells were rapidly internalized by myeloid cells, with subsequent trafficking to fat-associated lymphoid clusters. Tumor clearance was confirmed to be T cell-mediated, leading to the establishment of local and systemic immunity. Combination immune checkpoint inhibitor and vaccine therapy in mice with advanced disease, characterized by an established suppressive tumor microenvironment, increased the number of mice with non-detectable tumors, however, change in tumor burden compared to vaccine monotherapy was not significant. Vaccination also resulted in tumor clearance in mouse models of metastatic colorectal cancer. This study demonstrates that intraperitoneal vaccine delivery has the potential to enhance vaccine efficacy by activating resident immune cells with the subsequent establishment of protective systemic anti-tumor immunity.

Introduction There are no established methods to identify children with atypical diabetes for further study. We aimed to develop strategies to systematically ascertain cases of atypical pediatric diabetes using electronic medical records (EMR).Research design and methods We tested two strategies in a large pediatric hospital in the USA. Strategy 1: we designed a questionnaire to rule out typical diabetes and applied it to the EMR of 100 youth with diabetes. Strategy 2: we built three electronic queries to generate reports of three atypical pediatric diabetes phenotypes: unknown type, type 2 diabetes (T2D) diagnosed

Abstract Introduction In Germany, the estimation of the disease burden of respiratory syncytial virus (RSV) in older adults is limited. This makes it challenging for public health decision-makers to develop evidence-based recommendations for newly available vaccines against RSV for individuals aged 60 years and older (60+). This study investigates publicly available data sources in Germany to address the current gaps in evidence regarding the burden of RSV. Methods Hospitalisation databases from the German Federal Statistical Office and national mortality statistic between 2000 and 2023, as well as regular surveillance reports from the national public health institute since 2014, were utilised to extract, combine and analyse data on RSV-related morbidity and mortality. These data were used to triangulate the age-specific burden of RSV. Results The data indicate that the number of RSV-related outpatient consultations ranges between 1,313,100 and 3,911,800 cases per season from 2014/2015 to 2022/2023 for all age groups, with approximately 13.0% of outpatient consultations occurring in adults 60+. The significant increase in hospitalisations over time suggests that heightened testing due to the coronavirus disease 2019 (COVID-19) pandemic revealed the underdetection of inpatient RSV cases in pre-pandemic seasons. In the most recent season recorded, 2022/2023, the data show 12,800 RSV-related hospitalisations in adults 60+ (24% of all RSV-related hospitalisations) and 1340 in-hospital deaths in adults 60+ (93% of all RSV-related deaths). Conclusion The comparison of pre- to post-pandemic seasons strongly suggest up to a sevenfold underdetection of RSV in individuals 60+, and the analysis of in-hospital mortality reveals higher mortality rates compared with the general German mortality statistics. These findings highlight the urgent need to improve surveillance and implement targeted prevention strategies to mitigate the impact of RSV in older adults.

We report the generation of a gene-edited human induced pluripotent stem cell (iPSC) line from an Alzheimer’s disease patient-derived iPSC line harbouring the PSEN1 H163R mutation. This line demonstrates pluripotent stem cell morphology, expression of pluripotency markers, and maintains a normal karyotype.

Background: The clinical presentation of neuroblastoma can widely vary but can include orthopaedic related complaints. Case details: We present two cases of neuroblastoma diagnosis after an initial presentation of an orthopaedic complaint of limp and hip pain. Both cases varied on laboratory markers and warning symptoms, leading to delays in final diagnosis. Conclusion: These cases demonstrate the importance of orthopaedic surgeons including neuroblastoma in the differential diagnosis of hip pain and limp.

Electrical impedance spectroscopy (EIS) stands as a widely employed characterization technique for studying muscular tissue in both physio/pathological conditions. This methodology commonly involves modeling tissues through equivalent electrical circuits, facilitating a correlation between electrical parameters and physiological properties. Within existing literature, diverse equivalent electrical circuits have been proposed, varying in complexity and fitting properties. However, to date, none have definitively proven to be the most suiTable for tissue impedance measurements. This study aims to outline a systematic methodology for EIS measurements and to compare the performances of three widely used electrical circuits in characterizing both physiological and pathological muscle tissue conditions. Results highlight that, for optimal fitting with electrical parameters relevant to tissue characterization, the choice of the circuit to be fitted closely hinges on the specific measurement objectives, including measurement parameters and associated physiological features. Naturally, this necessitates a balance between simplicity and fitting accuracy.

Abstract Background The recent outbreaks of Marburg virus disease (MVD) in Guinea and Ghana have become a major public health concern not only to the West African sub-region but a threat to global health. Main body of the abstract Given the poorly elucidated ecological and epidemiological dynamics of the Marburg virus, it would be imprudent to preclude the possibility of another pandemic if urgent efforts are not put in place. However, the prior emergence and impact of COVID-19 and other co-occurring epidemics may add ‘noise’ to the epidemiological dynamics and public health interventions that may be required in the advent of a MVD outbreak in Nigeria. Short conclusion Paying attention to the lessons learned from previous (and current) multiple epidemics including Avian Influenza, Yellow fever, Ebola virus disease, Monkeypox, Lassa fever, and COVID-19 could help avoid a potentially devastating public health catastrophe in Nigeria.

Abstract Background: The intersection of synthetic biology and biomaterials promises to enhance safety and efficacy in novel therapeutics. Both fields increasingly employ Boolean logic, which allows for specific therapeutic outputs (e.g., drug release, peptide synthesis) in response to inputs such as disease markers or bio‐orthogonal stimuli. Examples include stimuli‐responsive drug delivery devices and logic‐gated chimeric antigen receptor (CAR) T cells. In this review, we explore recent manuscripts highlighting the potential of synthetic biology and biomaterials with Boolean logic to create novel and efficacious living therapeutics. Main body: Collaborations in synthetic biology and biomaterials have led to significant advancements in drug delivery and cell therapy. Borrowing from synthetic biology, researchers have created Boolean‐responsive biomaterials sensitive to multiple inputs including pH, light, enzymes and more to produce functional outputs such as degradation, gel‐sol transition and conformational change. Biomaterials also enhance synthetic biology, particularly CAR T and adoptive T cell therapy, by modulating therapeutic immune cells in vivo. Nanoparticles and hydrogels also enable in situ generation of CAR T cells, which promises to drive down production costs and expand access to these therapies to a larger population. Biomaterials are also used to interface with logic‐gated CAR T cell therapies, creating controllable cellular therapies that enhance safety and efficacy. Finally, designer cells acting as living therapeutic factories benefit from biomaterials that improve biocompatibility and stability in vivo. Conclusion: By using Boolean logic in both cellular therapy and drug delivery devices, researchers have achieved better safety and efficacy outcomes. While early projects show incredible promise, coordination between these fields is ongoing and growing. We expect that these collaborations will continue to grow and realize the next generation of living biomaterial therapeutics.

PURPOSETo better understand the barriers to accessing standard-of-care radiation therapy (RT) for breast and cervical cancer in sub-Saharan Africa and their impact on outcomes.METHODSA comprehensive literature search was completed with a medical librarian. Articles were screened by title, abstract, and full text. Included publications were analyzed for data describing barriers to RT access, available technology, and disease-related outcomes, and further grouped into subcategories and graded according to predefined criteria.RESULTSA total of 96 articles were included: 37 discussed breast cancer, 51 discussed cervical cancer, and eight discussed both. Financial access was affected by health care system payment models and combined burdens of treatment-related costs and lost wages. Staffing and technology shortages limit the ability to expand service locations and/or increase capacity within existing centers. Patient factors including use of traditional healers, fear of stigma, and low health literacy decrease the likelihood of early presentation and completion of therapies. Survival outcomes are worse than most high- and middle-income countries and are affected by many factors. Side effects are similar to other regions, but these findings are limited by poor documentation capabilities. Access to palliative RT is more expeditious than definitive management. RT was noted to lead to feelings of burden, lower self-esteem, and worsened quality of life.CONCLUSIONSub-Saharan Africa represents a diverse region with barriers to RT that differ on the basis of funding, available technology and staff, and community populations. Although long-term solutions must focus on building capacity by increasing the number of treatment machines and providers, short-term improvements should be implemented, such as interim housing for traveling patients, increased community education to reduce late-stage diagnoses, and use of virtual visits to avoid travel.

Glaucoma is one of the leading causes of blindness worldwide. Decreased aqueous humor drainage causes an increase in intraocular pressure (IOP), which in turn damages the ganglion cells of the retina and optic nerve. A mouse model of glaucoma was used to examine the behavior of Myo/Nog (M/N) cells, which were previously shown to respond to cataract surgery and retinopathy induced by hypoxia, light damage, and intravitreal injection of human retinal pigment epithelial cells. M/N cells express the skeletal-muscle-specific transcription factor MyoD, the bone morphogenetic protein inhibitor Noggin, and brain-specific angiogenesis inhibitor 1 (BAI1). Glaucoma was induced by injecting microbeads into the anterior chamber (AC) of the right eye to obstruct the flow of aqueous humor into the trabecular meshwork. IOP was elevated within three days of addition of microbeads. Loss of retinal ganglion cells (RGCs) and thinning of the ganglion cell layer–nerve fiber layer (GCL-NFL) was observed in tissue sections by day 32. The injection of microbeads resulted in an increase in BAI1-positive (+) M/N cells in the trabecular meshwork, ciliary body, canal of Schlemm, cornea, and ganglion cell layer (GCL). M/N cells ingested microbeads. The effect of further increasing the population of M/N cells on IOP and RGC loss was determined by injecting BAI1+ cells isolated from the brain into the AC of both eyes. Exogenous M/N cells prelabeled with CellTracker™ Red were found in the same tissues as the endogenous population of M/N cells in eyes with and without elevated IOP. The addition of M/N cells did not significantly reduce IOP in bead-injected eyes. However, there were significantly more RGCs and the NFL was thicker in glaucomatous eyes with M/N cell supplementation than eyes injected with phosphate-buffered saline. The numbers of RGCs and NFL thickness were similar in glaucomatous and non-glaucomatous eyes after adding M/N cells. These results demonstrate that endogenous M/N cells respond to elevated IOP in the anterior and posterior segments in response to induction of glaucoma. M/N cells’ mitigation of RGC loss may reflect a neuroprotective effect within the retina, as opposed to a significant drop in IOP.

Abstract Background From January to May 2021 the alpha variant (B.1.1.7) of SARS-CoV-2 was the most commonly detected variant in the UK. Following this, the Delta variant (B.1.617.2) then became the predominant variant. The UK COVID-19 vaccination programme started on 8th December 2020. Prior to the Delta variant, most vaccine effectiveness studies focused on the alpha variant. We therefore aimed to estimate the effectiveness of the BNT162b2 (Pfizer-BioNTech) and the ChAdOx1 nCoV-19 (Oxford-AstraZeneca) vaccines in preventing symptomatic and asymptomatic infection with respect to the Delta variant in a UK setting. Methods We used anonymised public health record data linked to infection data (PCR) using the Combined Intelligence for Population Health Action resource. We then constructed an SIR epidemic model to explain SARS-CoV-2 infection data across the Cheshire and Merseyside region of the UK. Vaccines were assumed to be effective after 21 days for 1 dose and 14 days for 2 doses. Results We determined that the effectiveness of the Oxford-AstraZeneca vaccine in reducing susceptibility to infection is 39% (95% credible interval [34, 43]) and 64% (95% credible interval [61, 67]) for a single dose and a double dose respectively. For the Pfizer-BioNTech vaccine, the effectiveness is 20% (95% credible interval [10, 28]) and 84% (95% credible interval [82, 86]) for a single-dose and a double dose respectively. Conclusion Vaccine effectiveness for reducing susceptibility to SARS-CoV-2 infection shows noticeable improvement after receiving two doses of either vaccine. Findings also suggest that a full course of the Pfizer-BioNTech provides the optimal protection against infection with the Delta variant. This reinforces the need to complete the full course programme to maximise individual protection and reduce transmission.

Studying a prospective cohort, the authors develop and validate a predictive score for post-acute COVID-19 syndrome, also known as long-COVID. This score relies on an immunoglobulin signature and is independent of timepoint of blood sampling.

BackgroundClinical markers of cognitive decline in Parkinson's disease (PD) encompass several mental non-motor symptoms such as hallucinations, apathy, anxiety, and depression. Furthermore, freezing of gait (FOG) and specific gait alterations have been associated with cognitive dysfunction in PD. Finally, although low cerebrospinal fluid levels of amyloid-β42 have been found to predict cognitive decline in PD, hitherto PET imaging of amyloid-β (Aβ) failed to consistently demonstrate the association between Aβ plaques deposition and mild cognitive impairment in PD (PD-MCI).AimFinding significant features associated with PD-MCI through a machine learning approach.Patients and methodsPatients were assessed with an extensive clinical and neuropsychological examination. Clinical evaluation included the assessment of mental non-motor symptoms and FOG using the specific items of the MDS-UPDRS I and II. Based on the neuropsychological examination, patients were classified as subjects without and with MCI (noPD-MCI, PD-MCI). All patients were evaluated using a motion analysis system. A subgroup of PD patients also underwent amyloid PET imaging. PD-MCI and noPD-MCI subjects were compared with a univariate statistical analysis on demographic data, clinical features, gait analysis variables, and amyloid PET data. Then, machine learning analysis was performed two times: Model 1 was implemented with age, clinical variables (hallucinations/psychosis, depression, anxiety, apathy, sleep problems, FOG), and gait features, while Model 2, including only the subgroup performing PET, was implemented with PET variables combined with the top five features of the former model.ResultsSeventy-five PD patients were enrolled (33 PD-MCI and 42 noPD-MCI). PD-MCI vs. noPD-MCI resulted in older and showed worse gait patterns, mainly characterized by increased dynamic instability and reduced step length; when comparing amyloid PET data, the two groups did not differ. Regarding the machine learning analyses, evaluation metrics were satisfactory for Model 1 overcoming 80% for accuracy and specificity, whereas they were disappointing for Model 2.ConclusionsThis study demonstrates that machine learning implemented with specific clinical features and gait variables exhibits high accuracy in predicting PD-MCI, whereas amyloid PET imaging is not able to increase prediction. Additionally, our results prompt that a data mining approach on certain gait parameters might represent a reliable surrogate biomarker of PD-MCI.

Abstract Objectives The objective of this study was to evaluate the performance of non‐targeted hepatitis C virus (HCV) screening in emergency departments (EDs) and other healthcare settings in terms of patients identified with HCV infection and linked to HCV care. Methods In the Southern Appalachian region of the United States, we developed non‐targeted HCV screening and linkage‐to‐care programs in 10 institutions at different healthcare settings, including EDs, outpatient clinics, and inpatient units. Serum samples were tested for HCV antibodies, and if positive, reflexed to HCV ribonucleic acid (RNA) testing as a confirmatory test for active infection. Patients with positive RNA tests were contacted to link them to HCV care. Results Between 2017 and 2019, among 195,152 patients screened for HCV infection, 16,529 (8.5%) were positive by antibody testing, 10,139 (5.2% of screened patients and 61.3% of patients positive by antibody test) were positive by RNA testing, and 5778 (3.0% of screened patients and 57.0% of patients positive by RNA test) were successfully linked to HCV care. Among 83,645 patients screened in EDs, 9060 (10.8%) were positive by HCV antibody, and 5243 (6.3%) were positive by RNA test. Among patients positive by RNA testing, linkage to care was lower for patients screened in the ED (44.1%) compared with outpatient clinics (67.6%) (P

“Brain-predicted age” quantifies apparent brain age compared to normative neuroimaging trajectories. Advanced brain-predicted age has been well established in symptomatic Alzheimer disease (AD), but is underexplored in preclinical AD. Prior brain-predicted age studies have typically used structural MRI, but resting-state functional connectivity (FC) remains underexplored. Our model predicted age from FC in 391 cognitively normal, amyloid-negative controls (ages 18–89). We applied the trained model to 145 amyloid-negative, 151 preclinical AD, and 156 symptomatic AD participants to test group differences. The model accurately predicted age in the training set. FC-predicted brain age gaps (FC-BAG) were significantly older in symptomatic AD and significantly younger in preclinical AD compared to controls. There was minimal correspondence between networks predictive of age and AD. Elevated FC-BAG may reflect network disruption during symptomatic AD. Reduced FC-BAG in preclinical AD was opposite to the expected direction, and may reflect a biphasic response to preclinical AD pathology or may be driven by inconsistency between age-related vs. AD-related networks. Overall, FC-predicted brain age may be a sensitive AD biomarker.

Among the issues on which health directions focus, fall risk is one of major importance since it affects patients hospitalized in both acute and rehabilitative hospitals. In this context, few publications have proposed a managerial approach aimed at (a) investigating several factors related to falls and (b) trying to acquire more knowledge and comprehension when analyzing the data collected. Consequently, this paper pursues such objectives by investigating data related to falls (and the recurrence of falls) registered in a rehabilitation hospital within the years 2020 and 2021. A multidisciplinary team (clinical staff and engineers) registered 238 first falls, and descriptive statistics were used to analyze the fall-related anamnestic and clinical data. Then, appropriate statistical analyses were used to compare the same data—this time distinguishing fallers/recurrent fallers—and, again, descriptive statistics were used to analyze the consequences of falls. The statistical analyses allowed us to gain insights into the fall mechanisms, the main places in which falls took place, the impacts of drugs, and fall consequences (e.g., the potential extra costs for the hospital). Moreover, the Morse and Stratify risk tools, state of consciousness, and fall containment measures were proven to be statistically significant features for distinguishing fallers and recurrent fallers, and they may be further investigated to define more accurate preventive measures within rehabilitation hospitals.

Hypothesis: In the care of acute myocardial infarction, ticagrelor attenuates post-ischemic myocardial damage and inhibits platelet activity to a greater extent than clopidogrel. Methods: Scholarly articles published in the last 10 years were compiled from a PubMed MeSH search focusing on acute coronary infarction and the antiplatelet therapies clopidogrel and ticagrelor. The databases used were PubMed, Google Scholar, Dynamed, and EBSCOhost. Eight articles were chosen based on subject matter related to the hypothesis, including cardioprotective effects, mortality benefits, platelet reactivity, angiographic effects, and electrocardiography changes. Results: Evidence from randomized clinical trials demonstrates that ticagrelor reduces infarct size, prevents remodeling, and reduces mortality rate after acute myocardial infarction to a greater extent than clopidogrel. However, some angiography studies show no difference between the two treatment regimes. Two articles show that ticagrelor is more effective in treating individuals with high platelet reactivity (HPR). In addition, there is some evidence of increased dyspnea and significant bleeding with ticagrelor. Discussion: Although there is growing evidence that ticagrelor is the better antiplatelet drug post-acute coronary infarction, more research needs to be done to determine the situations in which ticagrelor provides the optimal treatment regime in regards to cardioprotective effects, antiplatelet effects and an overall decrease in mortality. Conclusion: Ticagrelor was found to be superior to clopidogrel in relation to cardioprotective effects, mortality, and antiplatelet activity.

‘There is no justice for us...’: Van Hogendorp’s abolitionist play Kraspoekol (1800) as a trial against slavery Theatre plays in which social abuses are criticised often display striking parallels to the civic court. Both in trials and theatre performances the complaining party is positioned against someone who defends the accused person or issue, each propagating different viewpoints towards a case, whereupon a judge has to decide on the matter. In the early modern era, plays served as experimental sites to conduct (fictional) cases. When the theatre curtain comes down, the audience is incited to express its opinion on the case that was staged. The case that takes central stage in this article is the accusation of Dutch colonial slavery in Dirk van Hogendorp’s antislavery drama Kraspoekol, of de slaaverny (1800). This play was highly controversial and its performance in The Hague caused great tumult. Drawing on studies of early modern and contemporary theatre, this contribution will examine the interlace of Kraspoekol and legal practice by looking at accusations (by slaves and abolitionist characters) and defences (by slave master Kraspoekol). The article addresses how the combination of showing and phrasing injustice might encourage Kraspoekol’s audience to ascribe itself the role by the judge and to condemn not only the wrongful treatment of the characters of Kraspoekol, but the entire slavery institution.

BACKGROUND:Monoclonal free light chain (LC) proteins are present in the circulation of patients with immunoproliferative disorders such as light chain (AL) amyloidosis and multiple myeloma (MM). Light chain-associated amyloid is a complex pathology composed of proteinaceous fibrils and extracellular matrix proteins found in all patients with AL and in ~10-30% of patients who presented with MM. Amyloid deposits systemically in multiple organs and tissues leading to dysfunction and ultimately death. The overall survival of patients with amyloidosis is worse than for those with early stage MM. METHODS AND FINDINGS:We have developed a sensitive binding assay quantifying the recruitment of full length, patient-derived LC proteins by synthetic amyloid fibrils, as a method for studying their amyloidogenic potential. In a survey of eight urinary LC, both AL and MM-associated proteins were recruited by synthetic amyloid fibrils; however, AL-associated LC bound significantly more efficiently (p < 0.05) than did MM LCs. The LC proteins used in this study were isolated from urine and presumed to represent a surrogate of serum free light chains. CONCLUSION:The binding of LC to synthetic fibrils in this assay accurately differentiated LC with amyloidogenic propensity from MM LC that were not associated with clinical amyloid disease. Notably, the LC from a MM patient who subsequently developed amyloid behaved as an AL-associated protein in the assay, indicating the possibility for identifying MM patients at risk for developing amyloidosis based on the light chain recruitment efficacy. With this information, at risk patients can be monitored more closely for the development of amyloidosis, allowing timely administration of novel, amyloid-directed immunotherapies-this approach may improve the prognosis for these patients.

While previous research has indicated the utility of DNA barcoding in identifying spider species sampled from a localized region, the effectiveness of this method over a broader geographic scale and with denser taxon sampling has not yet been extensively considered. Using both new and published data from 1801 individuals belonging to 361 morphospecies, this study examined intra- and interspecific divergences for 19 genera that were each represented by at least 10 morphospecies. We particularly focused on increasing species-level sampling in order to better characterize levels of interspecific divergence within species-rich genera and to examine the prevalence of a “barcode gap” (discontinuity between intra- and interspecific divergences). Overall, the mean intraspecific divergence value was found to be 2.15%, the average maximum intraspecific divergence was 3.16%, while the mean divergence between nearest interspecific neighbours was 6.77%, demonstrating the typical presence of a barcode gap. Of the 66% of morphospecies that formed monophyletic sequence clusters, the majority (92.5%) possessed a barcode gap. We also examine possible biological explanations for the large proportion of paraphyletic and polyphyletic clusters and discuss the need for further taxonomic investigations. The overlap between intra- and interspecific divergences was not unexpected for some ‘species’, such as Pardosa groenlandica, since prior morphological studies have suggested that it is an example of a species complex. However, other cases of high intraspecific divergences may reflect cryptic species diversity, indicating the need for a taxonomic approach that combines both morphological and molecular methods. The list of the species, COI sequences, and source references used in the analysis is published as a dataset under doi: 10.3897/zookeys.16.239.app.A.ds. The list of analyzed species, mean and maximum intraspecific divergences, distances to the nearest neighbouring species in its genus, general localities, and lifestyle characteristics is published as a dataset under doi: 10.3897/zookeys.16.239.app.B.ds.