Search

The western part of the Makran subduction zone (Iran) is currently experiencing active surface uplift, as attested by the presence of emerged marine terraces along the coast. To better understand the uplift recorded by these terraces, we investigated seven localities along the Iranian Makran and we performed radiocarbon, 230Th∕U and optically stimulated luminescence (OSL) dating of the layers of marine sediments deposited on top of the terraces. This enabled us to correlate the terraces regionally and to assign them to different Quaternary sea-level highstands. Our results show east–west variations in surface uplift rates mostly between 0.05 and 1.2 mm yr−1. We detected a region of anomalously high uplift rate, where two MIS 3 terraces are emerged, but we are uncertain how to interpret these results in a geologically coherent context. Although it is presently not clear whether the uplift of the terraces is linked to the occurrence of large megathrust earthquakes, our results highlight rapid surface uplift for a subduction zone context and heterogeneous accumulation of deformation in the overriding plate.

Background: In recent years, innovation in oncology has created new challenges for pricing and reimbursement systems. Oncology medicines with multiple indications face a number of access challenges: (1) the number of assessments and administrative burden; (2) aligning price to different values of the same product; (3) managing clinical uncertainty at time of launch; and (4) managing budget uncertainty. These challenges impact a range of stakeholders and can result in delayed patient access to life-saving treatments. Consequently, countries have taken steps to facilitate patient access. Methods: Drawing on the experience across Europe we have reviewed different mechanisms countries have adopted that address these challenges. These include approaches aimed directly at the issue, multi-year-multi-indication (MYMI) agreements (BE, NL), and other approaches to manage access: flexible access agreements for new indications with clinical uncertainty (UK); development of a new agreement for each new indication (IT); and immediate access for new indications and bundled assessments (DE). Results: MYMI agreements are valuable where existing rules mean that every indication faces the same upfront evaluation process that delays patient access. They are also useful in managing budget impact and uncertainty. Other approaches that adopt an indication-specific approach helps manage clinical uncertainty at the time of launch and realise different values for the same product. They can help align price to value, even though indication-based pricing does not exist. Bundled assessments reduce the administrative burden for stakeholders, and the benefits of immediate reimbursement is that patient access is not delayed. Conclusion: The challenges for medicines with multiple indications impact a range of stakeholders and can result in delayed patient access to life-saving treatments. MYMI agreements have created a more pragmatic approach to HTA for medicines with multiple indications to ensure both fast and broad patient access. Continued innovation in oncology will require further innovative approaches in pricing and reimbursement. It is important that policymakers, payers and manufacturers engage in early discussions and are willing to find new solutions to help accelerate patient access to innovative therapies.

An essential prerequisite for evolution by natural selection is variation among individuals in traits that affect fitness 1 . The ability of a system to produce selectable variation, known as evolvability 2 , thus markedly affects the rate of evolution. Although the immune system is among the fastest-evolving components in mammals 3 , the sources of variation in immune traits remain largely unknown 4,5 . Here we show that an important determinant of the immune system's evolvability is its organization into interacting modules represented by different immune cell types. By profiling immune cell variation in bone marrow of 54 genetically diverse mouse strains from the Collaborative Cross 6 , we found that variation in immune cell frequencies is polygenic and that many associated genes are involved in homeostatic balance through cell-intrinsic functions of proliferation, migration and cell death. However, we also found genes associated with the frequency of a particular cell type that are expressed in a different cell type, exerting their effect in what we term cyto-trans. The vertebrate evolutionary record shows that genes associated in cyto-trans have faced weaker negative selection, thus increasing the robustness and hence evolvability 2,7,8 of the immune system. This phenomenon is similarly observable in human blood. Our findings suggest that interactions between different components of the immune system provide a phenotypic space in which mutations can produce variation with little detriment, underscoring the role of modularity in the evolution of complex systems 9 ., (© 2024. The Author(s).)

Warming temperate winters are resulting in increased insect winter activity. With modern agroecosystems largely homogenous, characterised by low floral diversity, competitive interactions may arise between flower-visiting species, with potential implications for the ecosystem services they provide (e.g. biological control and pollination). Flower strips may be implemented during winter months to support flower-visiting insects and enhance ecosystem service provision. Employing field trials conducted in Brittany, France between 2019 and 2021 and laboratory cage experiments, the current study examined the impact of winter flower strips on aphid biological control performed by parasitoid wasps and the potential for competitive interactions between winter-active parasitoids and pollinators. Results revealed that parasitism rate was not enhanced by the presence of winter flower strips. This lack of effect was not the consequence of pollinator presence, and the current study found no effect of pollinator abundance on parasitism rate. Flower strips may thus be implemented during winter months to support nectar-feeding insects when floral resources are scarce, with no evidence of exploitative competition between pollinators and parasitoids, nor a detrimental impact on biological control provision., (© 2024. The Author(s).)

The role of postmating sexual selection as a potential reproductive barrier in speciation is not well understood. Here, we studied the effects of sperm competition and cryptic female choice as putative postmating barriers in two lamprey ecotypes with a partial reproductive isolation. The European river lamprey Lampetra fluviatilis is anadromous and parasitic of other fish species, whereas the brook lamprey Lampetra planeri is freshwater resident and nonparasitic. We measured sperm traits in both ecotypes and designed sperm competition experiments to test the occurrence of cryptic female choice. We also performed sperm competition experiments either at equal semen volume or equal sperm number to investigate the role of sperm velocity on fertilization success. We observed distinct sperm traits between ecotypes with a higher sperm concentration and a lower sperm velocity for L. planeri compared with L. fluviatilis . The outcomes of sperm competition reflected these differences in sperm traits, and there was no evidence for cryptic female choice irrespective of female ecotype. At equal semen volume, L. planeri males had a higher fertilization success than L. fluviatilis and vice versa at equal sperm number. Our results demonstrate that different sperm traits between ecotypes can influence the male reproductive success and thus gene flow between L. planeri and L. fluviatilis . However, postmating prezygotic barriers are absent and thus cannot explain the partial reproductive isolation between ecotypes., Competing Interests: All authors declare that they have no conflicts of interest., (© 2023 The Authors. Ecology and Evolution published by John Wiley & Sons Ltd.)

Background: In recent years, innovation in oncology has created new challenges for pricing and reimbursement systems. Oncology medicines with multiple indications face a number of access challenges: (1) the number of assessments and administrative burden; (2) aligning price to different values of the same product; (3) managing clinical uncertainty at time of launch; and (4) managing budget uncertainty. These challenges impact a range of stakeholders and can result in delayed patient access to life-saving treatments. Consequently, countries have taken steps to facilitate patient access. Methods: Drawing on the experience across Europe we have reviewed different mechanisms countries have adopted that address these challenges. These include approaches aimed directly at the issue, multi-year-multi-indication (MYMI) agreements (BE, NL), and other approaches to manage access: flexible access agreements for new indications with clinical uncertainty (UK); development of a new agreement for each new indication (IT); and immediate access for new indications and bundled assessments (DE). Results: MYMI agreements are valuable where existing rules mean that every indication faces the same upfront evaluation process that delays patient access. They are also useful in managing budget impact and uncertainty. Other approaches that adopt an indication-specific approach helps manage clinical uncertainty at the time of launch and realise different values for the same product. They can help align price to value, even though indication-based pricing does not exist. Bundled assessments reduce the administrative burden for stakeholders, and the benefits of immediate reimbursement is that patient access is not delayed. Conclusion: The challenges for medicines with multiple indications impact a range of stakeholders and can result in delayed patient access to life-saving treatments. MYMI agreements have created a more pragmatic approach to HTA for medicines with multiple indications to ensure both fast and broad patient access. Continued innovation in oncology will require further innovative approaches in pricing and reimbursement. It is important that policymakers, payers and manufacturers engage in early discussions and are willing to find new solutions to help accelerate patient access to innovative therapies., Competing Interests: No potential conflict of interest was reported by the author(s). E. Darquennes, D. Hemelsoet, J. Huismans, R.Normand & A. Roediger are employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ USA, who may own stock and/or hold stock options in the Company., (© 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

COVID-19, which is caused by SARS-CoV-2, can result in acute respiratory distress syndrome and multiple organ failure 1-4 , but little is known about its pathophysiology. Here we generated single-cell atlases of 24 lung, 16 kidney, 16 liver and 19 heart autopsy tissue samples and spatial atlases of 14 lung samples from donors who died of COVID-19. Integrated computational analysis uncovered substantial remodelling in the lung epithelial, immune and stromal compartments, with evidence of multiple paths of failed tissue regeneration, including defective alveolar type 2 differentiation and expansion of fibroblasts and putative TP63 + intrapulmonary basal-like progenitor cells. Viral RNAs were enriched in mononuclear phagocytic and endothelial lung cells, which induced specific host programs. Spatial analysis in lung distinguished inflammatory host responses in lung regions with and without viral RNA. Analysis of the other tissue atlases showed transcriptional alterations in multiple cell types in heart tissue from donors with COVID-19, and mapped cell types and genes implicated with disease severity based on COVID-19 genome-wide association studies. Our foundational dataset elucidates the biological effect of severe SARS-CoV-2 infection across the body, a key step towards new treatments.

Background: Metastasis is the major cause of death in patients with cancer. Myeloid skewing of hematopoietic cells is a prominent promoter of metastasis. However, the reservoir of these cells in the bone marrow (BM) compartment and their differentiation pattern from hematopoietic stem and progenitor cells (HSPCs) have not been explored., Methods: We used a unique model system consisting of tumor cell clones with low metastatic potential or high metastatic potential (met-low and met-high, respectively) to investigate the fate of HSPC differentiation using murine melanoma and breast carcinoma. Single-cell RNA sequencing (scRNA-seq) analysis was performed on HSPC obtained from the BM of met-low and met-high tumors. A proteomic screen of tumor-conditioned medium integrated with the scRNA-seq data analysis was performed to analyze the potential cross talk between cancer cells and HSPCs. Adoptive transfer of tumor-educated HSPC subsets obtained from green fluorescent protein (GFP)+ tagged mice was then carried out to identify the contribution of committed HSPCs to tumor spread. Peripheral mononuclear cells obtained from patients with breast and lung cancer were analyzed for HSPC subsets., Results: Mice bearing met-high tumors exhibited a significant increase in the percentage of HSPCs in the BM in comparison with tumor-free mice or mice bearing met-low tumors. ScRNA-seq analysis of these HSPCs revealed that met-high tumors enriched the monocyte-dendritic progenitors (MDPs) but not granulocyte-monocyte progenitors (GMPs). A proteomic screen of tumor- conditioned medium integrated with the scRNA-seq data analysis revealed that the interleukin 6 (IL-6)-IL-6 receptor axis is highly active in HSPC-derived MDP cells. Consequently, loss of function and gain of function of IL-6 in tumor cells resulted in decreased and increased metastasis and corresponding MDP levels, respectively. Importantly, IL-6-educated MDPs induce metastasis within mice bearing met-low tumors-through further differentiation into immunosuppressive macrophages and not dendritic cells. Consistently, MDP but not GMP levels in peripheral blood of breast and lung cancer patients are correlated with tumor aggressiveness., Conclusions: Our study reveals a new role for tumor-derived IL-6 in hijacking the HSPC differentiation program toward prometastatic MDPs that functionally differentiate into immunosuppressive monocytes to support the metastatic switch., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Background: Immunotherapies have revolutionized oncology, but their rapid expansion may potentially put healthcare budgets under strain. We developed an approach to reduce demand uncertainty and inform decision makers and payers of the potential health outcomes and budget impact of the anti-PD-1/PD-L1 class of immuno-oncology (IO) treatments., Methods: We used partitioned survival modelling and budget impact analysis to estimate overall survival, progression-free survival, life years gained (LYG), and number of adverse events (AEs), comparing "worlds with and without" anti-PD-1/PD-L1s over five years. The cancer types initially included melanoma, first and second line non-small cell lung cancer (NSCLC), bladder, head and neck, renal cell carcinoma, and triple negative breast cancer [1]. Inputs were based on publicly available data, literature, and expert advice., Results: The model [2] estimated budget and health impact of the anti-PD-1/PD-L1s and projected that between 2018-2022 the class [3] would have a manageable economic impact per year, compared to the current standard of care (SOC). The first country adaptations showed that for that period Belgium would save around 11,100 additional life years and avoid 6,100 AEs. Slovenia - 1,470 LYGs and 870 AEs avoided; Austria - respectively 4,200, 3,000; Italy - 19,800, 6,800. For Austria, the class had a projected share of about 4.5 % of the cancer care budget and 0.4 % of the total 2020 healthcare budget. For Belgium, Slovenia, and Italy - respectively 15.1 % and 1.1 %, 12.6 %, 0.6 %, and 6.5 %, 0.5 %., Conclusion: The Health Impact Projection (HIP) is a horizon scanning model designed to estimate the potential budget and health impact of the PD-(L)1 inhibitor class at a country level for the next five years. It provides valuable data to payers which they can use to support their reimbursement plans., Policy Summary: The model is a strategic tool which allows decisionmakers to assess the implications of policy decisions, such as additional investment, or accelerated access to IOs. It can drive tangible population health benefits by eliminating the questions around PD-(L)1 inhibitor spending and its related outcomes., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Cross-species differences form barriers to translational research that ultimately hinder the success of clinical trials, yet knowledge of species differences has yet to be systematically incorporated in the interpretation of animal models. Here we present Found In Translation (FIT; http://www.mouse2man.org ), a statistical methodology that leverages public gene expression data to extrapolate the results of a new mouse experiment to expression changes in the equivalent human condition. We applied FIT to data from mouse models of 28 different human diseases and identified experimental conditions in which FIT predictions outperformed direct cross-species extrapolation from mouse results, increasing the overlap of differentially expressed genes by 20-50%. FIT predicted novel disease-associated genes, an example of which we validated experimentally. FIT highlights signals that may otherwise be missed and reduces false leads, with no experimental cost.

The dramatic fall in the cost of DNA sequencing has revolutionized the experiments within reach in the life sciences. Here we provide an introduction for the domains of analyses possible using high-throughput sequencing, distinguishing between "counting" and "reading" applications. We discuss the steps in designing a high-throughput sequencing experiment, introduce the most widely used applications, and describe basic sequencing concepts. We review the various software programs available for many of the bioinformatics analysis required to make sense of the sequencing data. We hope that this introduction will be accessible to biologists with no previous background in bioinformatics, yet with a keen interest in applying the power of high-throughput sequencing in their research.

Olfactory ensheathing cells (OECs) play a crucial role during neurogenesis of primary olfactory neurons. Transplantation of OECs is considered as a promising new therapy for central nervous system repair. Nevertheless, OECs are constituted of distinct subpopulations and their role during neurogenesis is not clearly understood. In particular, OECs from the olfactory bulb (OB) constitute a heterogeneous, but not yet isolated and characterized, population of cells. In our study, flow cytometry analyses of primary OB cultures, based on cell surface expression of low-affinity nerve growth factor receptor (p75), reveal the presence of two distinct populations of OECs. Indeed, some of them express a high level of p75 (P75High) and the other a low level of p75 (P75Low). Effects of OB microenvironment were assessed, and we were able to show that fibroblasts mediate the induction of these two populations through the secretion of soluble factors. To characterize P75High and P75Low OECs, cells were sorted based on their differential expression of p75. Microarray analyses revealed that P75High OECs overexpress genes implicated in modulation of extracellular matrix and cell sorting, whereas P75Low OECs overexpress genes involved in regulation of the inflammatory response and axonal guidance. These results permit, for the first time, to isolate the two distinct subpopulations of OECs from OB, and suggest their specific role during neurogenesis., (Copyright © 2011 Wiley Periodicals, Inc.)

More than 500,000 inguinal herniorrhapies are performed each year in the United States. The traditional methods of hernia repair have demonstrated a low complication rate (< 1%). Recently, the success of laparoscopic cholecystectomy (complication rate < 2%) has generated enthusiasm for the application of laparoscopic techniques toward the management of other intra-abdominal pathologies. The initial reports concerning the efficacy and advantages of laparoscopic surgery are encouraging. However, the limited data available thus far precludes the answering of questions regarding perioperative morbidity. We present two cases of small bowel obstruction that occurred following uncomplicated laparoscopic herniorrhaphy. One occurred 2 weeks postoperatively and consisted of a herniation through the re-approximated peritoneum over the repair site. The second occurred 3 days postoperatively and was caused by herniation through a large (10 mm) trochar site. Surgical intervention involved exploratory laparotomy in the former and laparoscopic techniques in the latter. We suggest that the principles of solid abdominal closure are applicable to the relatively small peritoneal defects created during laparoscopic procedures. Additionally, awareness of this potential complication will aid in decreasing the morbidity of this and other laparoscopic surgeries.

Although gram-negative meningitis is rare in our hospital, between July, 1982 and July, 1983 clusters of cerebrospinal fluid (CSF) smears were reported positive for gram-negative bacilli. Fourteen specimens were obtained by diagnostic lumbar punctures, and one was obtained during a myelogram. No CSF cultures were positive, and a diagnosis of factitious meningitis was eventually established for each patient. Nonviable gram-negative bacilli were found in 6.7% of manometers, and 23.3% to 90% of the specimen tubes tested from the same lots of commercial lumbar puncture trays. It was estimated that there were between 44 and 333 organisms per specimen tube. Two lots of the commercial myelogram trays yielded nonviable gram-negative bacilli from 50% of the specimen tubes and 33.3% of the manometers tested. Retrospective review of laboratory records for 1982 and 1983 revealed 23 total CSF smears positive for gram-negative bacilli. No CSF grew gram-negative bacilli, and chart reviews confirmed a diagnosis of factitious meningitis in each case. In addition to the clusters of false-positive smears, this had occurred sporadically in both years. The problem did not recur after separate sterile tubes were provided for CSF collection. Physicians and laboratories should be aware that nonviable contaminants in commercial products may be a source of false-positive CSF gram-stained smears.

A low rate of seroconversion to hepatitis B vaccine is reported. This occurred in healthy hospital employees from two separate institutions. A total of 236 individuals were evaluated in this study and only 53% or 124 persons developed protective levels of antibody to hepatitis B surface antigen following a complete vaccine series. In one hospital, 30% of the vaccine recipients developed antibody but not to a protective level. Employees who received the entire series in the arm or in the arm and buttock (mixed) had a significantly greater number of responders than employees who received the entire series in the buttock (P less than .05). Recipients aged 50 to 59 years had a significantly lower response rate to the vaccine (P less than .05). There was no correlation with the vaccinee's sex or the timing of the second injection. Vaccine was noted to have frozen in one hospital and accounted for some loss of antigenicity. This failure to respond to the vaccine has necessitated the use of booster injections of vaccine and continued antibody monitoring.