Nail Telocytes: Identification, Potential Physiological Function, and Role in Pathology: A Reappraisal of the So-Called Onychofibroblasts/Onychodermis.

ABSTRACT: Some authors have suggested that the fibroblasts of the nail mesenchyme (onychofibroblasts) can be distinguished from skin fibroblasts by their high expression of CD10. My 2015 study documented the presence of a relatively sparse CD34+/CD10+ dendritic subpopulation in the dermis and hypodermis of the matrix. For some time now, my hypothesis has been that these interstitial dendritic mesenchymal cells of the matrix correspond to telocytes. Telocytes have been described as peculiar interstitial dendritic cells present in the mesenchymal tissue of numerous organs, including the skin, but their presence and characteristics in the nail unit have not been explored. This study was undertaken to more comprehensively investigate the existence and characteristics of nail telocytes. A series of 20 normal adult nail units were examined with a combination of morphological and immunohistochemical analyses. The matrix dermis contained a sparse subpopulation of CD34+/CD10+ elongated telocytes with a higher density in the lunular region and, at this distal level, a change in their immunohistochemical profile, resulting in a progressive loss of CD34 expression. The matrix hypodermis showed CD34+/CD10+ telocytes in their classical elongated aspect, which acquired, especially in the distal fibromyxoid area of the thumb, an oval to round morphology with multiple intracytoplasmic vacuoles. The characteristic dynamic immunophenotypic profile of the dermal telocytes with a progressive distal loss of the defining molecule CD34 was equally observed in the distal hypodermis. The nail bed dermis was thick with a dense fibrous connective tissue. A reticular network of CD34-/CD10+ telocytes was present in the superficial dermis of the proximal nail bed. The mesenchymal cells of the deep part of the proximal nail bed dermis and the entire distal nail bed dermis were CD34-/CD10-. The adult nail mesenchyme is composed of 3 microanatomically distinct regions. Only the thumb has a distal hypodermis rich in mucinous material. The population of telocytes is relatively sparse compared with the fibroblastic population of the entire nail mesenchyme. The concept of onychodermis/onychofibroblasts is not valid. Nail telocytes have a dynamic immunohistochemical profile depending on whether they are located proximally or distally. The CD34+/CD10+ profile correlates with the onychogenic epithelial region, while the CD34-/CD10+ profile correlates with a spatial rearrangement of the nail epidermal bed.

Onychocytic Matricoma: A Clinical, Dermoscopic, and Pathological Analysis of 14 Cases.

ABSTRACT: Onychocytic matricoma (OCM) is a benign neoplasm of the nail matrix. Only 18 cases of this tumor have been reported in the literature to date. We retrospectively analyzed the clinical features of 14 patients with OCM. The most common clinical feature was longitudinal xanthopachyonychia (n = 9), followed by longitudinal leukopachyonychia (=3) and longitudinal pachymelanonychia (n = 2). The most common clinical findings identified following dermoscopy and analysis at high magnification of classical photographs were free-edge thickening of the nail plate without pitting (n = 14), longitudinal ridging (n = 7), round white clods (n = 7), white dots (n = 7), and filiform hemorrhages (n = 7), followed by oval and linear white clods (n = 5), fuzzy lateral border (n = 5), and red-purple blood clods (n = 3). Nail clipping histopathology showed a thickened nail plate with multiple, small, round-to-oval spaces. The tumor expressed immunopositivity for LEF-1. Dermoscopy of the nail plate and nail clipping histology provides useful information with regards to the differential diagnosis with subungual squamous cell carcinoma and nail melanoma. Ex vivo-in vivo correlation facilitates a better dermoscopic assessment of this unique underrecognized disease. However, the differential diagnosis between OCM and onychocytic carcinoma requires biopsy of the tumor. LEF-1 as an onychogenic marker can be used to resolve the differential diagnosis between OCM and subungual longitudinal acanthoma/seborrheic keratosis.

Plasma-based analysis of ERBB2 mutational status by multiplex digital PCR in a large series of patients with metastatic breast cancer.

Erb-b2 receptor tyrosine kinase 2 (ERBB2)-activating mutations are therapeutically actionable alterations found in various cancers, including metastatic breast cancer (MBC). We developed multiplex digital PCR assays to detect and quantify ERBB2 mutations in circulating tumor DNA from liquid biopsies. We studied the plasma from 272 patients with hormone-receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) MBC to detect 17 ERBB2 mutations using a screening assay. The assay was developed on the three-color Crystal dPCR™ naica® platform with a two-step strategy for precise mutation identification. We found that nine patients (3.3%) harbored at least one ERBB2 mutation. The mutation rate was higher in patients with lobular histology (5.9%) compared to invasive breast carcinoma of no special type (2.6%). A total of 12 mutations were found with the following frequencies: L755S (25.00%), V777L (25.00%), S310Y (16.67%), L869R (16.67%), S310F (8.33%), and D769H (8.33%). Matched tumor samples from six patients identified the same mutations with an 83% concordance rate. In summary, our highly sensitive multiplex digital PCR assays are well suited for plasma-based monitoring of ERBB2 mutational status in patients with MBC.

Regorafenib in patients with advanced Ewing sarcoma: results of a non-comparative, randomised, double-blind, placebo-controlled, multicentre Phase II study.

BACKGROUND: The REGOBONE multi-cohort study explored the efficacy and safety of regorafenib for patients with advanced bone sarcomas; this report details the Ewing sarcoma (ES) cohort. METHODS: Patients with relapsed ES progressing despite prior standard therapy, were randomised (2:1) to receive regorafenib or placebo. Patients on placebo could crossover to receive regorafenib after centrally confirmed progression. The primary endpoint was the progression-free rate at 8 weeks. With one-sided α of 0.05, and 80% power, at least 14/24 progression-free patients at 8 weeks were needed for success. RESULTS: From September 2014 to November 2019, 41 patients were accrued. 36 patients were evaluable for efficacy: 23 on regorafenib and 13 on placebo. Thirteen patients (56%; one-sided 95% CI [37.5%-[)) were progression-free at 8 weeks on regorafenib vs. 1 (7.7%; 95% CI [0.4%-[) on placebo. Median PFS was 11.4 weeks on regorafenib, and 3.9 weeks on placebo. Ten placebo patients crossed over to receive regorafenib after progression. The most common grade ≥3 regorafenib-related adverse events were pain (22%), asthenia (17%), thrombocytopenia (13%) and diarrhoea (13%). CONCLUSION: Although the primary endpoint was not met statistically in this randomised cohort, there is evidence to suggest that regorafenib might modestly delay tumour progression in relapsed ES after failure of prior chemotherapy.

Prone position versus usual care in hypoxemic COVID-19 patients in medical wards: a randomised controlled trial.

BACKGROUND: Benefit of early awake prone positioning for COVID-19 patients hospitalised in medical wards and who need oxygen therapy remains to be demonstrated. The question was considered at the time of COVID-19 pandemic to avoid overloading the intensive care units. We aimed to determine whether prone position plus usual care could reduce the rate of non-invasive ventilation (NIV) or intubation or death as compared to usual care alone. METHODS: In this multicentre randomised clinical trial, 268 patients were randomly assigned to awake prone position plus usual care (N = 135) or usual care alone (N = 132). The primary outcome was the proportion of patients who underwent NIV or intubation or died within 28 days. Main secondary outcomes included the rates of NIV, of intubation or death, within 28 days. RESULTS: Median time spent each day in the prone position within 72 h of randomisation was 90 min (IQR 30-133). The proportion of NIV or intubation or death within 28 days was 14.1% (19/135) in the prone position group and 12.9% (17/132) in the usual care group [odds ratio adjusted for stratification (aOR) 0.43; 95% confidence interval (CI) 0.14-1.35]. The probability of intubation, or intubation or death (secondary outcomes) was lower in the prone position group than in the usual care group (aOR 0.11; 95% CI 0.01-0.89 and aOR 0.09; 95% CI 0.01-0.76, respectively) in the whole study population and in the prespecified subgroup of patients with SpO2 ≥ 95% on inclusion (aOR 0.11; 95% CI 0.01-0.90, and aOR 0.09; 95% CI 0.03-0.27, respectively). CONCLUSIONS: Awake prone position plus usual care in COVID-19 patients in medical wards did not decrease the composite outcome of need for NIV or intubation or death. Trial registration ClinicalTrials.gov Identifier: NCT04363463 . Registered 27 April 2020.

Development of sensitive and robust multiplex digital PCR assays for the detection of ESR1 mutations in the plasma of metastatic breast cancer patients.

BACKGROUND: Early detection of ESR1 mutations is a key element for better personalization of the management of patients with HR+/HER2- Metastatic Breast Cancer (MBC). Analysis of circulating tumor DNA from liquid biopsies is a particularly well-suited strategy for longitudinal monitoring of such patients. MATERIALS AND METHODS: Using the naica® three-color digital PCR platform, we developed a screening assay allowing the detection of 11 ESR1 mutations and designed a sequential strategy for precise mutation identification. We then applied this strategy in the analysis of plasma circulating cell-free DNA from 109 HR+/HER2- MBC patients and performed a double-blind comparison study on a subset of patients with the multiplex assay used at the Institut Curie (IC) for the PADA-1 study. RESULTS: Thirty-one patients (28.4%) harboured at least one ESR1 mutation, with the following frequencies: D538G (41.03%), Y537S (25.64%), E380Q (10.26%), Y537N (10.26%), "(536-540)" (7.69%), Y537C (2.56%), and L536R (2.56%). The presence of ESR1 mutation(s) was significantly associated with liver metastases (p = 0.0091). A very good agreement (91%) was observed with the IC assay. CONCLUSION: Our assays have proven to be robust and highly sensitive and are very well-suited for monitoring ESR1 mutations in the plasma of MBC patients.

Management and outcomes of adolescent and young adult sarcoma patients: results from the French nationwide database NETSARC.

BACKGROUND: The initial management of patients with sarcoma is a critical issue. We used the nationwide French National Cancer Institute-funded prospective sarcoma database NETSARC to report the management and oncologic outcomes in adolescents and young adults (AYAs) patients with sarcoma at the national level. PATIENTS AND METHODS: NETSARC database gathers regularly monitored and updated data from patients with sarcoma. NETSARC was queried for patients (15-30 years) with sarcoma diagnosed from 2010 to 2017 for whom tumor resection had been performed. We reported management, locoregional recurrence-free survival (LRFS), progression-free survival (PFS), and overall survival (OS) in AYA treated in French reference sarcoma centers (RSC) and outside RSC (non-RSC) and conducted multivariable survival analyses adjusted for classical prognostic factors. RESULTS: Among 3,227 patients aged 15-30 years with sarcoma diagnosed between 2010 and 2017, the study included 2,227 patients with surgery data available, among whom 1,290 AYAs had been operated in RSC, and 937 AYAs in non-RSC. Significant differences in compliance to guidelines were observed including pre-treatment biopsy (RSC: 85.9%; non-RSC 48.1%), pre-treatment imaging (RSC: 86.8%; non-RSC: 56.5%) and R0 margins (RSC 57.6%; non-RSC: 20.2%) (p < 0.001). 3y-OS rates were 81.1% (95%CI 78.3-83.6) in AYA in RSC and 82.7% (95%CI 79.4-85.5) in AYA in non-RSC, respectively. Whereas no significant differences in OS was observed in AYAs treated in RSC and in non-RSC, LRFS and PFS were improved in AYAs treated in RSC compared to AYAs treated in non-RSC (Hazard Ratios (HR): 0.58 and 0.83, respectively). CONCLUSIONS: This study highlights the importance for AYA patients with sarcoma to be managed in national sarcoma reference centers involving multidisciplinary medical teams with paediatric and adult oncologists.

Onychomatricoma: a clinicopathological, immunohistochemical, and molecular study of 10 cases highlighting recurrent RB1 deletion and the potential diagnostic value of LEF-1.

AIMS: Onychomatricoma (OM), an uncommon benign fibroepithelial neoplasm of the nail unit, is sometimes diagnostically challenging for clinicians and pathologists. OM consistently expresses CD34, but no specific immunohistohemical markers or recurrent genetic alterations have been identified to date. Recent studies have suggested that Wnt signalling is a key molecular characteristic of OM. METHODS AND RESULTS: Ten cases were analysed: four classical OM including two with pleomorphic cells; two superficial acral fibromyxoma-like variants of OM; three micropapilliferum variants of OM including one with pleomorphic cells; and one proliferating variant of OM. Immunohistochemically, the spindle cells were positive with CD34 (n = 10) and CD99 (n = 1), with focal reactivity for CD10 (n = 5). The epithelial component of the tumours expressed immunopositivity for LEF-1. Using array comparative genomic hybridization (aCGH), we demonstrated that all OM, including its variants that were tested (n = 8), harboured a few copy number alterations with losses of whole or part of chromosome 13 including the RB1 gene (n = 8) and chromosome 16 (n = 6). CONCLUSION: We report a recurrent loss of RB1 (13q) as a possible driver molecular event in OM indicating a relationship between OM and other lesions of the spectrum of the so-called '13q/RB1' family of tumours. We did not identify a role for the Wnt/beta-catenin signalling pathway, as has been proposed in a recent study. LEF-1 could be a potential sensitive and specific marker of OM and should be used in the differential diagnosis between OM, superficial acral fibromyxoma, and the CD34-positive fibrosing family of tumours.

Patterns of care and outcome of CIC-rearranged sarcoma patients: A nationwide study of the French sarcoma group.

BACKGROUND: CIC-rearranged sarcomas (CIC-RS) represent the most frequent subset of "Ewing-like" undifferentiated small round cell sarcomas. These tumors tend to be more aggressive than Ewing sarcomas. Moreover, treatment strategy can differ according to teams. The primary aim of this retrospective study was to describe the characteristics, treatments, and outcome for patients with CIC-RS included in the French NETSARC+ database. METHODS: Pediatric and adult patients from 13 French centers with a diagnosis of CIC-RS were registered from October 2008 to March 2021. Patients and tumors characteristics were collected from the national network NETSARC+ database (http://netsarc.sarcomabcb.org). CIC-RS diagnosis was pathologically and molecularly confirmed with a central review by expert pathologists. Two groups of patients were studied: those treated as classical Ewing sarcomas (cohort EwS) and those treated as high-grade soft tissue sarcomas (cohort STS) according to ESMO and/or EpSSG guidelines. Survival was calculated using the Kaplan-Meier method and the log-rank test was used to compare survival. RESULTS: Among 79 patients, the male/female sex ratio was 0.7 and the median age at diagnosis was 27 years (range 2-87). With a median follow-up of 37 months, 39 patients died of the disease. Median overall survival from diagnosis was 18 months, with no significant difference between both cohorts (p = 0.9). Nevertheless, when focusing on patients with metastatic disease at diagnosis (N = 21), all patients from cohort STS died of disease while some patients from cohort EwS were still alive and in complete remission. CONCLUSION: FSG experience confirms the aggressive clinical course of CDS patients regardless of chemotherapy regimen.

Are There Signs of Enthesitis in Nail Psoriasis? An Immunohistological Study of Nail Psoriasis With and Without Psoriatic Arthritis.

ABSTRACT: The concept of nail psoriasis as an entheseal-driven disease has essentially been formulated on the basis of radiological findings because it is usually not possible to obtain the tissue directly from the joints. The aim of this retrospective study was to evaluate the histological features of isolated nail psoriasis with and without distal interphalangeal psoriatic arthritis (PsA), focusing on the question as to whether the fascia and adipose tissue surrounding the apex of the nail unit genuinely show an inflammatory infiltrate. In support of the nail-enthesitis theory, an ongoing inflammatory infiltrate could be expected. An immunohistochemical study was performed to evaluate the distribution and phenotype of the inflammatory infiltrate in nail psoriasis with and without PsA. This study did not show an inflammatory infiltrate in the fascia connecting the nail to the extensor tendon. CD8 and CD4 subsets were present in equal number in the nail dermis of nail psoriasis with or without PsA, which is a similar distribution to that seen in psoriatic synovium while skin psoriasis is characterized by a dermal predominance of CD4 T lymphocytes. Because of this study and recent microanatomic studies of the normal nail unit, it is possible to move away from a purely anatomic explanation of the strong association between nail psoriasis and PsA and to propose immunological factors as contributory. This study provides support for the hypothesis that CD8+ T cells play a crucial role in the pathogenesis of nail psoriasis through a pathogenic pathway similar to that of PsA and contrasting with that of the skin.

Trastuzumab Deruxtecan in HER2-Positive Metastatic Breast Cancer Patients with Brain Metastases: A DESTINY-Breast01 Subgroup Analysis.

DESTINY-Breast01 (NCT03248492) evaluated trastuzumab deruxtecan (T-DXd; DS-8201) in patients with heavily pretreated HER2-positive metastatic breast cancer (mBC). We present a subgroup of 24 patients with a history of treated brain metastases (BM), a population with limited treatment options. In patients with BMs, the confirmed objective response rate (cORR) was 58.3% [95% confidence interval (CI), 36.6%-77.9%], and the median progression-free survival (mPFS) was 18.1 months (95% CI, 6.7-18.1 months). In patients without BMs (n = 160), cORR was 61.3% and mPFS was 16.4 months. Eight patients (47.1%) experienced a best overall intracranial response of partial response or complete response. Seven patients (41.2%) had a best percentage change in brain lesion diameter from baseline consistent with stable disease. Two patients (8.3%) with BMs and two (1.3%) without BMs experienced progression in the brain. The safety profile of T-DXd was consistent with previous studies. The durable clinical activity of T-DXd in this population warrants further investigation. SIGNIFICANCE: Advances in treating HER2-positive metastatic breast cancer have greatly improved patient outcomes, but intracranial progression remains an important risk for which few therapeutic options are currently available. T-DXd demonstrated durable efficacy in patients with stable, treated BMs. This article is highlighted in the In This Issue feature, p. 2711.

Does awake prone positioning prevent the use of mechanical respiratory support or death in COVID-19 patients on standard oxygen therapy hospitalised in general wards? A multicentre randomised controlled trial: the PROVID-19 protocol.

INTRODUCTION: COVID-19 is responsible of severe hypoxaemia and acute respiratory distress syndrome (ARDS). Prone positioning improves oxygenation and survival in sedated mechanically patients with ARDS not related to COVID-19. Awake prone positioning is a simple and safe technique which improves oxygenation in non-intubated COVID-19 patients. We hypothesised that early prone positioning in COVID-19 patients breathing spontaneously in medical wards could decrease the rates of intubation or need for noninvasive ventilation or death. METHODS AND ANALYSIS: PROVID-19 is an investigator-initiated, prospective, multicentre randomised, controlled, superiority trial comparing awake prone positioning to standard of care in hypoxaemic COVID-19 patients in 20 medical wards in France and Monaco. Patients are randomised to receive either awake prone position plus usual care or usual care alone with stratification on centres, body mass index and severity of hypoxaemia.The study objective is to compare the rate of treatment failure defined as a composite endpoint comprising the need for non-invasive ventilation (at two pressure levels) or for intubation or death, between the intervention group (awake prone position plus usual care) and the usual care (usual care alone) group at 28 days. ETHICS AND DISSEMINATION: The protocol and amendments have been approved by the ethics committees (Comité de protection des personnes Ouest VI, France, no 1279 HPS2 and Comité Consultatif d'Ethique en matière de Recherche Biomédicale, Monaco, no 2020.8894 AP/jv), and patients are included after written informed consent. The results will be submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04363463.

Early chest CT-scan in emergency patients affected by community-acquired pneumonia is associated with improved diagnosis consistency.

Chest CT-scan (CT) exceeds chest X-ray (CXR) to diagnose community-acquired pneumonia (CAP) but actual use and results remain unclear. We examine whether CT performed at ED visit improved ED diagnosis of CAP as compared to a final diagnosis of CAP at hospital discharge (gold standard diagnosis for the study), and how it impacts relevant clinical outcomes. This retrospective monocenter observational study was based on the analysis of the hospital database. Patients with a diagnosis of CAP in the ED (ICD-10 codes: J110, J111, from J12- to J18-, J440, J690, U0710, and U0711) were included. We compared ED patients who were diagnosed with CAP using CXR and CT. We measured diagnostic consistency, duration of ED visit, percentage of CXR and CT during hospital stay, hospital length-of-stay, ICU admission, and in-hospital mortality. Multivariate analysis was adjusted for CRB65 score by multiple logistic regression analysis for binary outcomes and by multivariate analysis of variance for continuous outcomes. We included 994 ED patients with an initial diagnosis of CAP (751 receiving CXR, 243 receiving CT). CT prescription in the ED increased over time ( P < 0.001). In patients admitted after ED, CT improved diagnosis consistency for CAP [88.2% vs. 80.9%; difference 7.3% (95% confidence interval 1.2-13.3%)] with a trend for lower hospital length-of-stay [10.2 vs. 12.2 days; difference -2.0 (95% confidence interval -3.9 to -0.1)], but not ICU admission ( P = 0.09) and in-hospital mortality ( P = 0.056). Diagnosis of patients admitted with CAP improved when CT was obtained at ED visit. These results should be reproduced at a larger scale to test whether early CT conserves healthcare resources.

Microvascular injuries, secondary edema, and inconsistencies in lung vascularization between affected and nonaffected pulmonary segments of non-critically ill hospitalized COVID-19 patients presenting with clinical deterioration.

PURPOSE: We aimed to better understand the pathophysiology of SARS-CoV-2 pneumonia in non-critically ill hospitalized patients secondarily presenting with clinical deterioration and increase in oxygen requirement without any identified worsening factors. METHODS: We consecutively enrolled patients without clinical or biological evidence for superinfection, without left ventricular dysfunction and for whom a pulmonary embolism was discarded by computed tomography (CT) pulmonary angiography. We investigated lung ventilation and perfusion (LVP) by LVP scintigraphy, and, 24 h later, left and right ventricular function by Tc-99m-labeled albumin-gated blood-pool scintigraphy with late (60 mn) tomographic albumin images on the lungs to evaluate lung albumin retention that could indicate microvascular injuries with secondary edema. RESULTS: We included 20 patients with confirmed SARS-CoV-2 pneumonia. All had CT evidence of organizing pneumonia and normal left ventricular ejection fraction. No patient demonstrated preserved ventilation with perfusion defect (mismatch), which may discard a distal lung thrombosis. Patterns of ventilation and perfusion were heterogeneous in seven patients (35%) with healthy lung segments presenting a relative paradoxical hypoperfusion and hypoventilation compared with segments with organizing pneumonia presenting a relative enhancement in perfusion and preserved ventilation. Lung albumin retention in area of organizing pneumonia was observed in 12 patients (60%), indicating microvascular injuries, increase in vessel permeability, and secondary edema. CONCLUSION: In hospitalized non-critically ill patients without evidence of superinfection, pulmonary embolism, or cardiac dysfunction, various types of damage may contribute to clinical deterioration including microvascular injuries and secondary edema, inconsistencies in lung segments vascularization suggesting a dysregulation of the balance in perfusion between segments affected by COVID-19 and others. SUMMARY STATEMENT: Microvascular injuries and dysregulation of the balance in perfusion between segments affected by COVID-19 and others are present in non-critically ill patients without other known aggravating factors. KEY RESULTS: In non-critically ill patients without evidence of superinfection, pulmonary embolism, macroscopic distal thrombosis or cardiac dysfunction, various types of damage may contribute to clinical deterioration including 1/ microvascular injuries and secondary edema, 2/ inconsistencies in lung segments vascularization with hypervascularization of consolidated segments contrasting with hypoperfusion of not affected segments, suggesting a dysregulation of the balance in perfusion between segments affected by COVID-19 and others.

Recently developed drugs for the treatment of drug-resistant tuberculosis: a research and development case study.

Two drugs with novel mechanisms of action, the diarylquinoline bedaquiline and the nitroimidazole delamanid-as well as pretomanid from the same class of drugs as delamanid-have recently become available to treat drug-resistant tuberculosis (DR-TB) after many decades of little innovation in the field of DR-TB treatment. Despite evidence of improved efficacy and reduced toxicity of multidrug regimens including the two agents, access to bedaquiline and delamanid has been limited in many settings with a high burden of DR-TB and consistently poor treatment outcomes. Aside from regulatory, logistic and cost barriers at country level, uptake of the novel agents was complicated by gaps in knowledge for optimal use in clinical practice after initial market approval. The main incentives of the current pharmaceutical research and development paradigm are structured around obtaining regulatory approval, which in turn requires efficacy and safety data generated by clinical trials. Recently completed and ongoing clinical trials did not answer critical questions of how to provide shorter, less toxic treatment DR-TB treatment regimens containing bedaquiline and delamanid and improve patient outcomes. Voluntary generation of evidence that is not part of this process-yet essential from a clinical or policy perspective-has been left to non-sponsor partners and researchers, often without collaborative efforts to improve post-regulatory approval access to life-saving drugs. Additionally, these efforts are currently not recognised in the value chain of the research and development process, and there are no incentives to make this critical research happen in a coordinated way.