This Research Topic aims to bring attention to the latest advancements in the study of cell death and the clearance of dead cells. Although extensive research has been conducted on understanding the signalling pathways involved in cell death, less is known about the mechanisms that drive the recruitment of macrophages towards dead cells and the efficient engulfment of cell corpses. As evidenced by numerous clinical trials investigating drugs that target cell death in various diseases, there is comparatively less emphasis on targeting the clearance of dead cells. This Research Topic explores novel aspects of research in cell death and dead cell removal, strategies for controlling it during inflammatory disease and highlights the importance of understanding the complex mechanisms driving dead cell clearance in health and disease.Pontejo et al. present their recent findings that chemokines important for attracting macrophages to clear dead cells can bind to phosphatidylserine (PS) exposed on dead cells. Their proposed “breadcrumb” model suggests that upon cell death, cellular debris is dispersed in a gradient-like manner around the dead cell. Supporting this concept, they highlighted a previous study that showed that certain chemokines could bind to PS exposed on cellular debris. The chemokine-PS binding is, therefore, a potent mechanism to attract macrophages to the site of the dead cell’s body, thus aiding in its clearance.Yuan et al. describe the importance of ubiquitin complexes in various aspects of cell death signalling and during the removal of dead cells. They review the key ubiquitin systems regulating these processes and stress the need to further investigate the role of ubiquitination and deubiquitinases in dead cell clearance.McHugh et al. proposes CDK9 inhibition as a promising strategy for developing novel anti-inflammatory therapy. The inhibition of this transcriptional cyclin-dependent kinase was found to significantly reduce the production of pro-inflammatory cytokines by macrophages following LPS infection. Importantly, this reduction in cytokine production occurred without any significant increase in cell death or impairment of macrophages’ phagocytic function. Conversely, overexpressing CDK9 in THP-1 cells led to increased pro-inflammatory cytokine production compared to wild-type cells. These findings suggest that it may be possible to interfere with transcriptional processes using CDK9 inhibition without impacting macrophages’ essential cellular functions.An alternative strategy for managing inflammatory diseases involves suppressing the production of pro-inflammatory cytokines without directly modulating cell death or dead cell clearance. A study conducted by Ge et al. provide a comprehensive overview of the role of various cellular systems in dead cell clearance and its association with infection and inflammatory disorders.Controlling the clearance of dead cells is crucial for maintaining tissue homeostasis and perturbation of this process can lead to pathological conditions. This is especially relevant in autoimmune diseases such as rheumatoid arthritis, diabetes, multiple sclerosis, and systemic lupus erythematosus, where impaired dead cell removal has been implicated. Tanzer’s minireview highlights the different steps involved in dead cell removal, from engulfment to digestion, and emphasises the potential areas where these processes can be disrupted. Additionally, the review highlights the potential impact of dead cell cargo on the macrophage programming that occurs during dead cell clearance.In order to successfully treat inflammatory and infectious diseases by regulating cell death and dead cell removal, it is crucial to have a precise understanding of the underlying mechanisms. Our Research Topic has unveiled the complex nature of dead cell removal, revealing key knowledge gaps that necessitate further exploration. A comprehensive understanding of cell death and clearance is crucial for gaining precise insights into the underlying molecular mechanisms that drive inflammation, cancer, autoimmune disorders, and infectious diseases. This knowledge is essential for developing successful therapeutic targets and advancing our ability to control these diseases.


Bone marrow failure syndromes are a heterogeneous group of diseases. With the major advancements in diagnostic tools and sequencing techniques, these diseases may be better classified and therapies may be further tailored. Androgens, a historic group of drugs, were found to stimulate hematopoiesis by enhancing the responsiveness of progenitors. These agents have been used for decades to treat different forms of bone marrow failure. With the availability of more effective pathways to treat BMF, androgens are less used currently. Nevertheless, this group of drugs may serve BMF patients where standard therapy is contraindicated or not available. In this article, we review the published literature addressing the use of androgens in BMF patients and we make recommendations on how to best use this class of drugs within the current therapeutic landscape. Aplastic anemia (AA) is a term used to describe a group of heterogeneous syndromes that affect hematopoiesis and result in bone marrow failure . It can In the early days, the management of AA patients consisted of supportive transfusions in addition to other interventions with questionable efficacy  . The firThe body building action of androgens and their euphoric action on the brain led to widespread illicit use of AAS. Hence, all AAS were designated as class III controlled substances. Nevertheless, these agents have shown significant benefits in a number of disorders. Testosterone was first discovered in 1935 and found to have effects on both reproductive (androgenic) and non-reproductive tissues (anabolic). It has been used in different catabolic states due to its anabolic effects through nitrogen fixation and as such protein synthesis . VirilizA randomized trial compared anti-lymphocyte globulin (ALG)  showed 76% vs. 31% survival respectively at two years (p <0.002) . AnotherCongenital bone marrow failure syndromes are a heterogeneous group of cytopenias associated with various congenital defects and cancer predisposition. HSCT is the only curative treatment for the hematological complications related to these diseases, but many patients are ineligible and androgens are considered the main non-transplant modality to treat these patients. Early studies of using androgens in these patients showed favorable responses . OxymethFanconi anemia is the prototype of inherited bone marrow failure syndromes characterized by a number of mutations leading to genetic instability and multiple cancer susceptibility with frequent incidence of marrow failure and myelodysplasia –32. ClinTelomeres are essential for genomic stability but their length decreases with each cellular division. Dyskeratosis congenita (DC) is the prototype of telomeropathies. Androgens improve blood counts and reduce transfusion frequency in telomeropathies. Some studies have shown improvement in telomere length as well –41, althThe exact mechanism of action of androgens in stimulating hematopoiesis remains unknown, however it seems that the use of supra-physiological doses of androgens cause erythropoiesis expansion. This is in contrast to hematinic supplements  where excess supply will not cause excessive response in hematopoiesis. Earlier studies showed that androgens enhance the responsiveness of erythroid progenitors to erythropoietin and possibly enhance the growth of pluripotent and committed granulocyte/macrophage progenitors . Some ofThe diagnostic armamentarium is expanding with the use of new and more comprehensive sequencing and molecular techniques. These new diagnostic tools help to better delineate these syndromes and to identify more patients with cryptic alterations who may not benefit from immunosuppression. A number of innovative ideas and approaches  to address the unmet needs of these patients are in ongoing trials. Bone marrow failure patients who are not candidates for transplant  and patients with the non-severe forms are usually defaulted to non-transplant medical interventions. In affluent countries, a number of non-transplant options are available for this group of patients. However, in restricted resources countries these novel options are not readily available. Androgens are considered a classic old group of medications that can stimulate hematopoiesis and as such used for this group of disorders when modern resources are not available or have failed already. Androgens result in hematologic responses (transient in some patients however) in most patients with FA and telomeropathies but does not alter nor affect the risk of clonal evolution. A number of pros and cons have to be considered when a decision is made to treat a BMF patient with non-transplant modalities including the use of androgens. Factors linked to a potential better response to androgens include higher residual cellularity, mild to moderate cytopenia, toxin induced BMF, women with lower absolute neutrophil count, the use of higher dose of androgens and rapid improvement of counts after androgen initiation , 13, 14.- As a bridge to transplant in patients with symptomatic FA and telomeropathies- Older SAA patients, not candidate for HSCT and failed standard immunosuppression therapy (IST) and thrombopoietin mimetic (TPO) or TPO inaccessible- Patients with renal failure precluding the use of calcineurin inhibitors and failed TPO mimetic or TPO inaccessible- Multiply relapsed patients after failing standard lines of therapy- PNH patients with no access to complement inhibitors and parallel existing AA (AA/PNH overlap)Currently, there are no published trials looking into the safety, efficacy and different dosages of various AAS formulations to guide the clinicians’ choice when treating BMF patients. New trials looking into these issues are warranted.MA, RE, and MN designed and performed the research. MN wrote the first draft. All authors contributed to the article and approved the submitted version.


The effect of social preferences, such as altruism and trust, on economic development is widely recognized. However, the reciprocal impact, i.e., how individuals experience the economic environment and how this shapes their social preferences, has remained largely under-explored. This study sheds light on this reciprocal effect, revealing an intriguing macroeconomic impact on individuals’ social preferences. By harnessing the Global Preference Survey data and a non-linear regression model, our findings highlight an interesting trend: there is a discernible decrease in individuals’ social preference as they experience enhanced economic conditions, and this effect is more pronounced for males. This crucial revelation underscores the importance for researchers and policymakers to take into account the prospective attenuation of social preferences in the pursuit of economic well-being. For centuries, the field of social sciences has observed human behavior, and the behavior observed has not simply been understood as a function of pure self-interest and rational economic motives alone. This perspective—emphasized by behavioral economists—was even advocated by Adam Smith, who in his seminal work, “The Theory of Moral Sentiments”, delved deeply into the social behaviors of humans and the existence of social preferences . DespiteThe importance of social preferences in economic activities is indisputable. Studies by economists and social science researchers have consistently shown that social preferences are significant drivers of economic development. For instance, trust has been found to effectively encourage cooperation ,18 and iIn considering the significant role of social preferences in economic development, an intriguing question emerges: What factors shape individuals’ social preferences? What contributes to the emergence of cross-national variations in social preferences? Previous research has attempted to answer these questions and yielded insightful findings. For instance, a nation’s historical memory and culture have been found to influence its inhabitants’ social preferences; in the case of African nations, trust levels have decreased post the slave trade ,30, whilWhile it is established that social preferences are shaped by various factors and play a vital role in economic growth and development, whether economic development reciprocally influences and shapes social preferences remains an open question. This is primarily due to data scarcity and methodological limitations. This paper attempts to fill this knowledge gap, following the seminal works , and by Our findings largely align with the conclusions derived from Li and Zhang , yet we This paper significantly enriches the existing literature in two primary ways. Firstly, it discerns a novel determinant of social preference, namely the macroeconomic environment, thereby broadening our understanding of social preference formation. This research notably pushes the envelope of traditional behavioral economics, which typically views social preferences as inherent and unchanging. Secondly, it posits a bidirectional association between social preference and economic development, emphasizing how a flourishing economy could modulate individuals’ social preferences. These advancements render this study an essential stepping stone toward a more comprehensive comprehension of the intersection between economic dynamics and social behavior.The remainder of this paper is organized as follows: In this study, we adopted the methodological framework established by Malmendier and Nagel  to thoroGDP per capita metric. Our methodology involves computing a weighted average of each individual’s past macroeconomic environments, with each individual denoted as i and residing in country j, as articulated in Equation Aij, which was meticulously compiled by Falk et al. . This suOur investigation hones in on social preferences—specifically, altruism, positive reciprocity, negative reciprocity, and trust. We would like to underscore that the GPS applies distinct methodologies to assess these participant preferences. Altruism was evaluated through a self-reported question complemented by a donation game. Positive reciprocity was ascertained through a self-report question and a gift exchange game, while negative reciprocity was measured by multiple self-reporting questions. Trust was gauged via a solitary self-reporting question. This multi-faceted approach involved assigning weights to each question, particularly when multiple questions assess the same preference. This thorough methodology was underpinned by a meticulous experimental validation procedure. Furthermore, these measures, as part of the complete GPS dataset, were standardized to a mean of 0 and a standard deviation of 1. Further insights into the construction of these measures are available in Falk et al. . For a sGDP per capita and consumption per capita records were drawn from the Penn World Table (PWT) [GDP data became available in their respective countries due to gaps in early GDP per capita data in the PWT dataset.Finally, country-level historical real le (PWT) . The finAs Positive reciprocity, reflecting the inclination to repay the kindness of others, remains impervious to the macroeconomic environment  ,54 variaGDP. The outcomes of our regression analysis, by leveraging this alternative measure, are detailed in In order to rigorously examine the robustness of our results, we adopted an alternative approach, deploying the variable of per capita consumption of residents as a surrogate measure for the economic environment. The rationale behind this choice is that residents’ personal consumption level might directly and intuitively influence their perceptions of the economic situation more than GDP to per capita consumption, the significance of negative reciprocity was considerably diminished. However, the impact on altruistic preference and trust remained robust and statistically significant. This reinforces the strength and credibility of our initial findings.Upon meticulous scrutiny of our regression results, it becomes evident that with the switch of the economic environment variable from After incorporating this additional analysis, it fortifies our confidence in concluding that the macroeconomic environment an individual experiences indeed exerts a substantial and meaningful impact on their altruistic preferences and levels of trust. This refined understanding underscores the importance of considering macroeconomic influences when interpreting and predicting individuals’ social preferences, further informing our insights into the nuanced interplay between economic environments and human behavior.A pertinent question meriting further exploration is the precedence of economic environments and social preferences—does a past economic environment influence people’s social preferences, or is it the other way around? Although our non-linear regression technique and multi-country comparative methodology offer a better understanding of this causality, we have implemented an additional predictive regression for added assurance. This involves regressing individual social preferences against the future economic landscape of the individual’s resident country. If a significant relationship between social preferences and future economy emerges, and is consistent with the correlation observed with past economic conditions, it becomes challenging for us to decipher the causal relationship. However, if a variation is noted—for instance, if a past economic environment resulted in increased distrust (as shown in our primary results) and trust is positively linked with the future economic scenario—we can infer a more substantial conclusion. This could suggest that a positive past economic environment cultivated the distrust, rather than such distrust fostering an improved economic environment.In conclusion, our core findings illustrate a discrepancy between the influence of past economic environments on social preferences and the predictability of social preferences on future economic situations. This substantiates the initial query regarding causality, affirming that our investigation establishes causation rather than mere correlation.We further extend the baseline analyses in A careful inspection of It is crucial to mention here that our study does not merely identify these gender-based discrepancies in response to the macroeconomic environment; it also invites us to reflect on their broader societal and economic implications. The subtle, yet significant, ways in which gender mediates the relationship between the macroeconomic environment and social preferences offer valuable insights. These insights could inform future research and policy decisions, enriching our understanding of the dynamics of social preference formation in varying economic circumstances, thereby advancing this vital field of study.In our subsequent heterogeneity analysis, we cast a spotlight on the unique political systems of each studied nation. We enhanced the original regression model by incorporating an interaction term between a country’s Democracy Index  and its A closer examination reveals a significantly positive interaction between the Democracy Index and the economic environment when it comes to trust (notwithstanding its primary negative effect). This implies that, in a more democratic polity, the negative impact of a robust economic environment on reducing trust is diminished. When considered in conjunction with our previous discussions regarding the ’trust-trap’ theory of economic development, a theory asserting that, while economic development requires trust, an improved economy paradoxically reduces trust and thus hampers development; thus, democracies appear to be less vulnerable than non-democratic countries. This observed phenomenon suggests that encouraging political democratization could be a potent strategy in mitigating the detrimental effects of the trust trap. This study thereby underscores the intricate interplay between political structures and economic realities, suggesting the need for integrated, multi-faceted policy approaches.This investigation has utilized a widely used and validated data source ,59,60: tOur findings align with and arguably broaden the validity of several existing hypotheses and the results presented in the academic literature. For instance, a study by Piff et al. (2018) established a correlation between higher social status (which is often associated with superior economic circumstances) and diminished ethical behavior coupled with heightened self-interest . The autConversely, there is a body of research proposing that prosperous economic conditions might engender higher levels of trust and altruism. Eriksson and Simpson (2014) found a positive association between economic security and interpersonal trust, indicating that a stable economy could boost trust among its populace . HoweverThe implications of these insights are manifold and hold considerable significance for our understanding of human behavior within a macroeconomic context. This research elucidates that individual social preferences are not static but evolve in response to the broader economic environment. An individual’s altruism and trust are revealed to be not merely personal traits but complex adaptive responses to economic circumstances. As such, this study significantly extends the boundaries of existing research on behavioral economics, which typically perceives social preferences as innate and invariable.From a policy perspective, our findings shed light on the potential effects of macroeconomic policies on societal behaviors. Policymakers might need to consider the implications of economic policies on social preferences, especially trust and altruism, and how these changes could, in turn, influence the economy and societal dynamics. For instance, understanding that improved economic conditions may diminish altruistic tendencies could guide policies that encourage charitable giving and social responsibility. Policymakers might need to devise strategic incentives to maintain or enhance altruism, thereby promoting societal well-being, in periods of economic prosperity. Similarly, the revelation that heightened economic conditions may reduce trust levels warrants attention. Trust is a fundamental building block of economic transactions and social cooperation ,65,66, aIn conclusion, this study has unveiled a novel dimension of how macroeconomic conditions influence individual social preferences. The insights offer a fresh perspective on the dynamic interplay between economic environments and human behaviors, suggesting that an individual’s social preferences are a product of both their personal characteristics and their economic experiences. It is our hope that these findings will prompt further investigation into this underexplored territory and inform more nuanced and effective economic and social policies.


While advantages of seeing with two eyes  were noted many centuries ago by ancient Greek scholars including Klaudios Ptolemaios (c. 100–c. 178CE), those of hearing with two ears  were not reported until the end of the 18th century Wells, , 1802. GOne benefit of binaural hearing is that it aids in the recognition of a sound. In a natural acoustic environment, the detection and perception of a sound of interest can be masked by a background noise Gelfand, . A spatiAsim et al. demonstrated in the rat midbrain that neurophysiological responses of an ensemble of neurons to a sound could be suppressed by a preceding sound and the effect was only mildly dependent on local excitation/inhibition. Such a suppressive effect could be reduced by a spatial separation between the sounds, which was reminiscent of SRM. Fan et al. measured responses to diotic and dichotic tone-in-noise stimuli from individual neurons in the midbrain of awake rabbits and revealed that BMLD was related more to interaural correlation between sounds at the two ears than to ITD or ILD. Using a modeling/simulation approach, Smith et al. trained an artificial neural network to yield a BMLD performance that matched the performance of human listeners. Functions of inner nodes of the model resembled interaural correlation functions observed in animal neurophysiological studies, suggesting that BMLD is dependent on interaural correlation.SRM and BMLD were investigated in five studies in this Research Topic. Biberger and Ewert extended such investigations to more complex environments by examining how factors such as room reverberation affected detection and quality perception of a target sound in the presence of colocalized or spatially separated maskers. Encke and Dietz characterized the interaural statistics of tone-in-noise stimuli, providing a basis for future studies of the relationship between these statistics and SRM.Previous investigations of masking and SRM have been conducted only under anechoic conditions and have not considered stimulus statistics. Understanding how sound localization is affected by hearing loss and other disorders can not only help develop clinical approaches to deal with such problems, but also provide insights into mechanisms underlying normal binaural hearing. Four studies in this Research Topic examined how sound localization was affected by aging, stroke, tinnitus, and replacement of natural acoustic stimulation by electrical stimulation generated by cochlear implants (CIs).Eddins et al. used electroencephalography to demonstrate that the processing of ITD was more heavily dependent on the activation of the contralateral than the ipsilateral auditory cortex. This asymmetry along with across-hemisphere differences in response waveform over specific time windows was reduced with age, which may be among the factors affecting the sensitivity to ITD in older adults. Dietze et al. found that lesions of specific brain regions caused by ischemic stroke impaired sound lateralization, with the impairment manifested in different ways depending on lesion sites. Specifically, brainstem lesions caused compressed and distorted response choices in lateralization, thalamic lesions led to a shift of perceived auditory space, and cortical lesions resulted in strong effects on lateralization of stimuli contralateral to the lesion. Long et al.s' study on sound-localization abilities in listeners with tinnitus showed that tinnitus percepts could affect localization of tones but not words. Future work is needed to determine the structure(s) within the auditory pathway that is/are responsible for such interference.Previous studies have reported worsening of sound localization abilities in aging populations  to ITD were dependent on the temporal precision of spiking of inputs to the LSO from lower brainstem structures. In comparison to neural inputs to the LSO driven by acoustic stimulation, those driven by electrical stimulation  exhibited hyper precision and low jitter, which led to reduced sensitivity to ITD in olivary neurons. This finding suggests that localization ability based on ITD can be improved by introducing jitter into stimulation generated by CIs.The acuity of sound-source localization, especially that based on ITD cues, is known to be significantly reduced in individuals with bilateral CIs  cues received by the two ears. Six studies in this Research Topic investigated effects of perturbation of this integration on speech perception.Yoon and Morgan revealed that consonant recognition was possible even if large amounts of spectral information were missing at individual ears, as long as complementary information could be integrated across ears. This finding suggests that effective bimodal hearing  can be achieved when the implanted ear is provided with information within a frequency range that complements rather than overlaps that of the contralateral ear. Anderson et al. used a vocoder to simulate CI processing and manipulate the dynamic range of speech at each ear to create a “better ear” and a “poorer ear”. Decreasing the dynamic range in one ear led to increased binaural interference for single words, whereas for dichotic double word presentations, this manipulation led to increased word fusion and blending. These findings suggest that increased binaural fusion due to dynamic range asymmetry can result in abnormal fusion and interference.Two studies used simulation to create asymmetries of inputs in normal-hearing listeners. Oh et al. demonstrated in listeners with hearing aids that there was significant inter-subject variation in binaural pitch fusion, i.e., fusion of sounds with different pitches across ears. Broad binaural fusion was correlated with a reduced ability to use voice fundamental frequency differences in speech recognition in the presence of background talkers. This correlation was also observed in normal-hearing listeners, suggesting that underlying mechanisms are of central rather than peripheral origin. Burg et al. examined listening effort in users of bilateral CIs. They found that listening effort increased when a poorer ear was used in addition to a better ear, suggesting negative consequences of binaural integration when asymmetries in hearing are present between ears.Abnormal fusion does occur in listeners with hearing loss and can lead to binaural interference as well as difficulties with speech understanding in a noisy environment. Dolhopiatenko and Nogueira demonstrated that decoding of selective auditory attention could be obtained in bimodal CI users using electroencephalography signals, despite the presence of stimulus artifacts from the CI in these signals. Chou et al. developed an algorithm based on a biologically inspired network to process both special and directional acoustic information driven by the two ears. This algorithm is able to segregate sounds based on spatial and spectral information and may also have applications in the development of hearing devices or software. Methods used in both studies provide researchers an opportunity to explore how binaural integration contributes to neural processing.Two other studies developed new methods with potential application for future studies of binaural integration. Nisha et al. showed in listeners with hearing loss that auditory training using stimuli delivered in a virtual acoustic space improved spatial acuity of sound localization. Ding et al. examined the detection of a binaural gap, i.e., a period without correlation between acoustic signals received by the two ears, in listeners with normal hearing. Performance was correlated with the sensitivity to temporal fine structure of monaural acoustic stimulation, and this correlation was reduced by musical training. Sanchez Jimenez et al. used the ferret as a model system to study plastic changes in sound-localization behaviors following unilateral conductive hearing loss. They found that training facilitated recovery of sound localization abilities. Recovery could generalize to more naturalistic listening conditions, so long as the target sounds provided sufficient spatial information.Another emerging area of research is about how binaural hearing and underlying mechanisms are shaped by auditory experience. The current Research Topic explored some exciting directions in the field of binaural hearing using both normal and disordered/clinically relevant systems. These studies provide new knowledge about functions and underlying mechanisms of some established binaural phenomena. They also show how binaural hearing can be shaped by auditory experience and provide new applications of electrophysiological tools and computational models. Despite these advances, many important questions remain to be answered. For instance, how does the brain use spatial along with temporal and spectral cues to stream and group information to form cohesive individual acoustic images? Conversely, how is this information used to segregate multiple acoustic images, as in the cocktail party effect? A multidisciplinary approach is needed to address these questions and help understand how the auditory scene is analyzed by the brain. Human psychoacoustical and animal behavioral experiments can improve our understanding of binaural hearing at the functional level. Neurophysiological recordings along with neurostimulation, and neuropharmcological or molecular/genetic manipulation conducted in normal and disordered systems may reveal key binaural components through gain-of-function and loss-of-function analyses. Mathematical models will be critical for simulating binaural components not easily measured/manipulated using experimental techniques. Taken together, multiple approaches integrated across studies as well as within studies will pave the way for future advances in the study of binaural hearing.HZ: Conceptualization, Writing—original draft, Writing—review & editing. YZ: Conceptualization, Writing—original draft, Writing—review & editing. LR: Conceptualization, Writing—original draft, Writing—review & editing.


Carbon fibre-reinforced polyetheretherketone (CFR-PEEK) plates represent an exciting development within trauma and orthopaedic surgery, offering advantages including radiolucency, material properties similar to bone, and lack of localised tissue reaction. As more call for trials examining their use, there is no data available as to the acceptability of these implants to patients. This study aimed to therefore examine the acceptability of CFR-PEEK plates to patients undergoing fracture surgery.This was a prospective cross-sectional survey of patients undergoing surgery for a fracture of the ankle, distal femur, distal radius, or proximal humerus. Once a decision had been made to pursue operative fixation with a plate, patients were provided with descriptions of both CFR-PEEK and stainless steel and titanium metal implants alongside the current clinical evidence. All patients undertook a questionnaire examining their views as to the advantages and disadvantages of CFR-PEEK plates, and whether they would be happy to participate in a trial comparing both.Ninety-nine patients were happy to participate . Eighty-seven patients reported that they would want a CFR-PEEK implant for their fracture, and 76 reported that they would be willing to participate in an RCT comparing their use. Commonly reported advantages included radiolucency, low weight and biocompatibility. Disadvantages reported included cost and concerns regarding durability.This study demonstrates that CFR-PEEK implants would be acceptable to patients undergoing fracture surgery, with high numbers of patients stating that they would be willing to participate in a randomised study examining their use.The online version contains supplementary material available at 10.1007/s00590-023-03473-6. Carbon fibre-reinforced polyetheretherketone (CFR-PEEK) plates are an exciting prospect in the field of Orthopaedic surgery, possessing numerous advantageous including: radiolucency—enabling accurate fracture reduction and healing monitoring; a modulus of elasticity nearer to bone when compared to metal implants; decreased artefact in magnetic resonance imaging—allowing accurate assessment of co-existing soft tissue injuries following the management of fractures, and an absence of immune response to the implant that may result in localised inflammatory reactions , 2.A recent systematic review found that whilst the utility of CFR-PEEK implants appears promising, there is little high level evidence to justify transition to their routine use . Just twWhilst the usage of CFR-PEEK implants is an exciting prospect, there is a requirement for further studies in the form of large randomised controlled trials to demonstrate their non-inferiority prior to routine adoption in extremity fracture fixation. Patient and public involvement (PPI) is a key feature of planning any large randomised controlled trial, and thus far there have been no studies examining the acceptability of these implants to the population at risk .The aim of the presented study was therefore to examine the acceptability of CFR-PEEK implants compared to traditional metal implants in patients undergoing operative fixation of extremity fractures.We conducted a prospective cross-sectional survey of patients undergoing operative fixation of extremity fractures at our level one trauma centre. This study received Institutional review board approval (number #0258). Inclusion criteria were restricted to adult patients with fractures of the ankle, distal femur, distal radius and proximal humerus; given that these are the body areas where the use of these plates has been previously examined in the literature . ExclusiPatients were approached after a decision for open reduction and internal fixation (ORIF) had been made via a discussion between the patient and an Orthopaedic clinician who was independent to the study. Upon agreement to participate in the study patients were provided with an information leaflet summarising the current literature surrounding the implant in the body area they had injured. They were also provided with a table of summary of the advantages and disadvantages of the CFR-PEEK and traditional metal implants, alongside images of the fixation devices and a physical example of each device Appendix 1). Following this they were provided with a questionnaire assessing their opinion on the perceived advantages and disadvantages of the two plating systems, whether they would be willing to receive a carbon implant instead of a metal implant, and whether they would have been willing to participate in an RCT comparing the use of CFR-PEEK plates with metal (stainless steel/titanium) plating systems . Assumptions for parametric analysis were met and therefore continuous data were analysed using an unpaired two-tailed p = 0.01). There was no difference in acceptability when comparing gender or site of injury. In terms of decision-making as to the ideal implant for their fixation, 70 patients stated that they would favour their surgeon made this decision, whilst 29 stated they would prefer to decide this once adequate information had been provided. This could not be predicted by age, gender nor site of injury.Ninety-nine patients were happy to partake in the study and completed the questionnaire. This included 64 females and 35 males, with a mean age of 50 (range 18–95). Sixty patients had sustained a fracture to their ankle, twenty-four to their distal radius, ten to their proximal humerus, and five to their distal femur. All patients approached felt that the patient information leaflet provided them with sufficient information to understand the differences between the metal and CFR-PEEK plates. Following review of the information 86 patients indicated that they would prefer to have their injuries stabilised with a CFR-PEEK plate, with just 13 preferring the use of a conventional metal plate. Regarding entry into a potential RCT examining the difference between the two fixation devices, 76 patients stated that they would be happy to be recruited to participate, with just 23 opting against. Patients who stated that they were willing to participate in an RCT were noted to be significantly younger than those who would not , radiolucency (n = 52), and biocompatibility (n = 10). Responses regarding perceived advantages are summarised in Table n = 26), distrust in a new technology (n = 16), and concerns regarding durability (n = 5).Patients were provided with the opportunity to provide free text responses to their perceived advantages and disadvantages of the CFR-PEEK plating system, compared to traditional metal implants. When assessing advantages of this system, responses were received from 96 patients, with 43 patients reporting a single advantage, 50 reporting two advantages, and four reporting three advantages. The most common advantages noted were the reduced weight of the implants Below is the link to the electronic supplementary material.


Background: Inpatient malnutrition is a key determinant of adverse patient and healthcare outcomes. The engagement of patients as active participants in nutrition care processes that support informed consent, care planning and shared decision making is recommended and has expected benefits. This study applied patient-reported measures to identify the proportion of malnourished inpatients seen by dietitians that reported engagement in key nutrition care processes. Methods: A subset analysis of a multisite malnutrition audit limited to patients with diagnosed malnutrition who had at least one dietitian chart entry and were able to respond to patient-reported measurement questions. Results: Data were available for 71 patients across nine Queensland hospitals. Patients were predominantly older adults  and female (n = 46) with mild/moderate (n = 50) versus severe (n = 17) or unspecified severity (n = 4) malnutrition. The median length of stay at the time of audit was 7 days (IQR 13). More than half of the patients included had two or more documented dietitian reviews. Nearly all patients (n = 68) received at least one form of nutrition support. A substantial number of patients reported not receiving a malnutrition diagnosis (n = 37), not being provided information about malnutrition (n = 30), or not having a plan for ongoing nutrition care or follow-up (n = 31). There were no clinically relevant trends between patient-reported measures and the number of dietitian reviews or severity of malnutrition. Conclusions: Malnourished inpatients seen by dietitians across multiple hospitals almost always receive nutritional support. Urgent attention is required to identify why these same patients do not routinely report receiving malnutrition diagnostic advice, receiving information about being at risk of malnutrition, and having a plan for ongoing nutrition care, regardless of how many times they are seen by dietitians. Malnutrition is a well-documented predictor of adverse patient-reported and healthcare outcomes and carries a heavy healthcare burden worldwide ,2. It isDespite increased attention to malnutrition screening and diagnosis, in many settings malnutrition is often underdiagnosed and undertreated ,14. The Recent findings highlight that three in four inpatients with or at risk of malnutrition are not considered to require specialist care from a dietitian during their inpatient stay . This raClinician engagement of patients (or their carers) is a fundamental standard of care ,26. MalnThis study therefore applied patient-reported measures to identify the proportion of malnourished patients with at least one documented dietitian consultation that reported receiving a malnutrition diagnosis, receiving information about malnutrition, and having a plan for ongoing nutrition care.The Systematised Interdisciplinary Malnutrition Program for impLementation and Evaluation (SIMPLE) Phase II implementation program was a knowledge translation, quality assurance program aiming to scale and spread the initial SIMPLE program across hospitals in Queensland, Australia ,33,34,35This publication considers an exploratory subset analysis of a convenience sample of baseline audit data for SIMPLE Phase II hospitals ,17. DataAll measures were collected within the scope of routine clinical practice improvement under ethics committee approval as a quality assurance project (HREC/18/QPCH/318). Malnutrition was diagnosed by accredited practicing dietitians applying validated tools in line with local procedures. Validated diagnostic tools applied across settings were the Subjective Global Assessment (SGA B—moderate or C—severe), ICD10-AM criteria , and/or Mini Nutritional Assessment-Short Form (MNA-SF score 7 or less—unspecified severity) ,37,38. TFollowing feedback from participating sites as part of the pre-implementation context analysis, patient-reported measures were adapted from the initial SIMPLE program  17]. Re. Re17]. Trained dietitians, dietetics students under the supervision of a dietitian, and/or nutrition assistants (dietetics personnel) approached patients prior to discharge to apply a standardised peer audit tool after obtaining verbal consent. Sites were encouraged to use a “peer-reviewer” approach so that the audits were performed by dietetics personnel that were not the treating dietitian and to conduct audits on all patients in a ward, or if required, a random selection of patients. As a quality assurance activity, formal randomisation processes were not applied. A train the trainer approach utilised the SIMPLE champions network to support consistency of auditing. Supportive resources included a ward audit completion guide, data dictionary, and toolkit.Data were initially entered into Microsoft Excel by two members of the team and verified by a third person prior to statistical analysis undertaken using SPSS version 28. Continuous data were assessed for normality using the Shapiro–Wilk test. Due to the exploratory nature of the design and small numbers with no pre-determined power calculation, only descriptive statistical analyses were reported.After excluding patients not at risk of malnutrition, those without a diagnosis of malnutrition, patients not seen by a dietitian at least once, and those unable to answer patient-reported measures, 71 patients had data available for this subset analysis .The characteristics of included patients are described in Patient-reported measures for key components of the nutrition care process are provided in This study highlighted that almost all malnourished patients with at least 1 dietitian chart entry across 15 wards in 9 different hospitals in Queensland received oral nutrition support. However, it is perplexing as to why less than one in four of these patients reported receiving a malnutrition diagnosis, receiving information about being malnourished, and having a plan for ongoing nutrition care.Malnutrition is coded internationally as a disease or related health problem with a profound deleterious influence on patients, healthcare systems, and the broader community ,42,43. IAre the results above due to an unreasonable and overwhelming demand for dietitians to deliver comprehensive, individualised nutrition care for all inpatients screened at risk of malnutrition prior to their discharge? There is acknowledgement of the increasing demands on dietitians working in hospitals, even prior to the COVID-19 pandemic, and that systematised and interdisciplinary approaches may provide part of the solution ,21,46,47Another alternate hypothesis is that the messaging is simply lost in translation. Effective clinical communication is a prerequisite for patient engagement. Patient engagement is shaped by the relationship between the patient and care provider and is a fundamental component of good clinical practice . ResultsIt is not uncommon to observe cognitive deficits in older, malnourished patients, particularly when placed in unfamiliar environments with high cognitive loads. The sampling approach applied in this study excluded those who were obviously unable to appropriately respond to the patient-reported measures. However, formal evaluations of patient cognition were not undertaken.Another plausible explanation could simply be that older adults in hospitals routinely do not recall processes of engagement in their care. This is supported by the trends suggesting that those who reported receiving diagnostic information, receiving information about malnutrition, and having a plan for ongoing care were younger. However, if this is the case, a serious challenge is facing dietitians and the broader healthcare team. Are there more appropriate strategies to engage older patients in their nutrition care in such a way that they can recall such interactions? A balanced intervention would also need to ensure an equity of healthcare provision across ages .A counter-intuitive finding remains open for interpretation. Why did the findings demonstrate males as more likely to respond positively to the combined patient-reported measures? This appears in contrast to many studies suggesting females are more likely to engage in their healthcare . The stuThe findings of this study support recent qualitative works highlighting that malnutrition remains a misunderstood diagnosis by both healthcare professionals and older adults across different settings . There aAll these and many more questions cannot be explained by this study and consequently require ongoing exploration. Given the retrospective exploratory study design, it would be improper to invoke firm conclusions regarding the underlying factors contributing to the results. However, what is clear is that patients remain in the dark about their malnutrition status, intervention options, and care plan. As noted elsewhere, effective communication matters when it comes to the complex technical term of malnutrition . DietetiAs already noted, this study has considerable limitations, in particular the exploratory retrospective subset analysis. The results should be interpreted with some degree of caution. Whilst the initial patient-reported measures were developed by a team including a consumer with a lived experience of malnutrition, a more robust approach to the co-design of patient-reported measures could be another way to strengthen this work in the future. Similarly, the design did not allow for a consideration of the duration of time between dietitian consultation(s) and patient-reported measures, and so there may have been some influence on the accuracy of recall. The patient-reported measures were not specific to dietitians, and so whilst the findings demonstrate that dietitians are not communicating clearly about this, it seems clear than neither is the rest of the multidisciplinary team. Finally, the lack of a power calculation and small sample size precluded meaningful statistical analysis and so ongoing works are required to address this. The strengths lie in the multisite design and the ambitious approach to applying nutrition-focussed patient-reported measures in real-world settings.The findings demonstrate that malnourished patients seen by dietitians across fifteen wards in nine different hospitals routinely receive oral nutrition support. However, regardless of the number of times dietitians see these patients, patient-reported measures do not reflect patient engagement across key components of the nutrition care process. Further exploratory works are required to unpack the implications of this for dietetics personnel and those they care for.


Next-generation sequencing (NGS) and metabarcoding approaches are increasingly applied to wild animal populations, but there is a disconnect between the widely applied generalized linear mixed model (GLMM) approaches commonly used to study phenotypic variation and the statistical toolkit from community ecology typically applied to metabarcoding data. Here, we describe the suitability of a novel GLMM-based approach for analyzing the taxon-specific sequence read counts derived from standard metabarcoding data. This approach allows decomposition of the contribution of different drivers to variation in community composition  via interaction terms in the model random-effects structure. We provide guidance to implementing this approach and show how these models can identify how responsible specific taxonomic groups are for the effects attributed to different drivers. We applied this approach to two cross-sectional data sets from the Soay sheep population of St. Kilda. GLMMs showed agreement with dissimilarity-based approaches highlighting the substantial contribution of age and minimal contribution of season to microbiota community compositions, and simultaneously estimated the contribution of other technical and biological factors. We further used model predictions to show that age effects were principally due to increases in taxa of the phylum Bacteroidetes and declines in taxa of the phylum Firmicutes. This approach offers a powerful means for understanding the influence of drivers of community structure derived from metabarcoding data. We discuss how our approach could be readily adapted to allow researchers to estimate contributions of additional factors such as host or microbe phylogeny to answer emerging questions surrounding the ecological and evolutionary roles of within-host communities.NGS and fecal metabarcoding methods have provided powerful opportunities to study the wild gut microbiome. A wealth of data is, therefore, amassing across wild systems, generating the need for analytical approaches that can appropriately investigate simultaneous factors at the host and environmental scale that determine the composition of these communities. Here, we describe a generalized linear mixed-effects model (GLMM) approach to analyze read count data from metabarcoding of the gut microbiota, allowing us to quantify the contributions of multiple host and environmental factors to within-host community structure. Our approach provides outputs that are familiar to a majority of field ecologists and can be run using any standard mixed-effects modeling packages. We illustrate this approach using two metabarcoding data sets from the Soay sheep population of St. Kilda investigating age and season effects as worked examples. The ecological dynamics of within-host communities of parasites and commensal microbes can have dramatic effects on host health and fitness , 2. One Standard methodologies for investigating hypotheses concerning gut microbiota dynamics in the wild typically include the collection of fecal samples from selected study subjects and the application of NGS techniques for metabarcoding of informative bacterial genes for taxonomic assignment of sequenced reads . MicrobiThe application of mixed-effects models to microbiota data sets is not new. The “Hierarchical Modeling of Species Communities” approach uses latent variable modeling and random effects to model community compositions and has been previously used to examine urbanization effects on fungal environmental microbiota . SimilarAs gut microbes have such important effects on host physiology, behavior, and health, much research has sought to identify individual microbial taxa that are responsible for alterations of host phenotype and state. This has in many ways mirrored the goals of many genome-wide association study (GWAS) analyses, which have sought to identify particular genetic variants associated with phenotypes of interest, often with a goal of developing diagnostics or drug targets . HoweverAs previously discussed, host-associated microbiota often constitute hundreds or thousands of different taxa. Whenever we need to estimate a large ensemble of related parameters, a common statistical approach is to treat them as random variables from some distribution . To undeWhile fitting such random-effects models is known to improve parameter estimation owing to shrinkage, its biggest advantage is in allowing us to shift the questions we ask to the whole microbiota level, and partition complex and inter-related sources of variance. GLMM approaches have been used across other ecological and evolutionary contexts to estimate repeatability, relative levels of spatiotemporal variance , social To see how such a model can be structured, let us again return to the example of estimating the effect of season on the gut microbiota of a wild mammal . Consides) on total read count, h, where there are multiple samples per host), h,where position . For exaare taxa . With reContinuing with the above example, we can further use random-effect estimates from model outputs to explore which specific taxa are driving differential abundances between groups of interests , which is commonly of great interest in microbiome studies, but for which many existing methods may be affected by library size and normalization methods , 31. Differences , 32, 33)While the Poisson model accounts for variation in library size across samples, there has also been a shift in microbiota research toward explicitly compositional data analysis, which removes any effects of library size (other than in quantifying uncertainty) prior to analysis. The centered log-ratio (CLR) described by Aitchison  represenOvis aries) from the island of Hirta in the St. Kilda archipelago of the Outer Hebrides of Scotland. These animals are free-living and are part of a long-term study in which individuals have been marked and monitored longitudinally since 1985  and from the same individuals sampled in different seasons (2016). The 2013 samples were collected during the August catch and included 30 samples from lambs (around 4 months old) and 28 samples from older adults (ages 2–13 years). The 2016 samples were collected from a set of 36 females aged 1–13 years who were sampled in both spring (around the time of parturition) and then 3–4 months later in August. Microbial DNA was extracted from samples, amplified using bacterial 16S rRNA V4 region primers, and sequenced using the Ilumina MiSeq platform to generate 250 base pair (bp) paired-end reads. Sequences were processed using the DADA2 pipeline in R (v1.12.1) to call ASVs . Full details of sampling, sequencing, and data processing methods are provided in the electronic supplementary material . We condhttps://arsweeny.github.io/microbiome-glmm/. We applied separate GLMMs to the 2013 and 2016 data sets. First, an aggregate data set for each year was created from the sample metadata, taxonomic classifications for each ASV, and an ASV-by-sample abundance matrix . We use a Bayesian framework and fit GLMMs with Poisson errors and log links to each data set using the package “MCMCglmm”  on total read count, h, equivalent to sample here where hosts are sampled once each), ,where Models fit to 2016 data, which included samples from individual hosts of similar age sampled in both spring and summer of the same year (two samples per host), were specified as follows:s, binary factor: spring versus summer) on total read count, h, where there are multiple samples per host), h, where there are multiple samples per host), h,Here s) on total read count,  is a random effect describing variation in total read count among individual hosts ,  is a random effect accounting for library size by describing variation in mean read count in each sample , and h and r2 from GLMMs with Poisson error distributions. Using this formula, there is a portion of variance equal to 1 minus the sum variance of the model components, which represents variance arising from the Poisson distribution. Where multiple samples are present per individual (2016), repeatability of the community composition of ASVs can be estimated as the proportion of variance attributable to differential taxonomic composition across individuals divided by the sum of the variance explained by all other non-technical component terms estimating compositional effects Using this GLMM approach, we calculated the relative contributions to sources of variance in the data from both technical and biological model components. We followed Nakagawa and Schielzeth  for the We investigated differential abundances as outlined above. To extract information on specific bacterial taxa contributing to differential abundance across age groups or seasons, we used Poisson model outputs and subtracted the posterior distributions for each ASV between group levels . We used the resultant distribution to calculate a mean difference and the highest posterior density interval (HPDI) to estimate differential abundance for each ASV. For example, the mean of the posterior distribution for ASV1:summer minus that for ASV1:spring can be interpreted as the differential abundance of ASV between spring and summer. A difference can be considered robust when credible intervals do not span zero.F = 7.161, P < 0.001), with 11.34% of the variance in gut microbiota composition (R2) explained by differences between lambs and adults. PERMANOVA results for the 2016 data showed that group centroids for April and August are significantly distinct , but season only explains 2.81% (R2) of the observed variance.The gut microbiota communities of Soay sheep were dominated by two phyla, Firmicutes and Bacteroidetes , as has Poisson GLMMs from 2013 data showed comparable results to ordination approaches, where community composition differed substantially between age classes , we calculated differential abundances using the posterior distributions for each random-effect level of specific taxa across age classes . Our approach represents an important step forward for researchers interested in using meta-taxonomic approaches to understand variation in the community structure in complex, non-experimental settings. It allows the well-established power and flexibility of GLMM-based approaches to be harnessed to decompose drivers of variation in NGS-derived data on the taxonomic composition of samples. Our example analyses and tutorial provide very simple illustrations of how the approach can be used to estimate the contribution of host-related or environmental factors  to variation in the community structure of the gut microbiota. We show that results are comparable to those derived from widely applied ordination-based approaches and discuss the implications of observed variation in gut microbiota structure with age and season briefly below. However, these analyses are intended mainly as templates to help illustrate the approach, and barely scratch the surface of the types of important outstanding questions the method could be used to tackle with larger-scale data sets. Applying GLMMs to taxonomic-level sequence count data provides a rich toolkit from fields like quantitative genetics to dissect the contributions of different environmental and host factors to variation in community structure, with the potential to advance our understanding of community ecology, host–microbe or –pathogen interactions, and evolutionary dynamics.We have described a novel approach to analyze metabarcoding data derived from NGS using a GLMM framework, have illustrated this method using data describing variation in the gut microbiota community in wild sheep, and have provided a user guide for implementing multiple versions of this approach  diet components and align conceptually with approaches presented in this article (Beyond microbiota community analyses, approaches outlined in this manuscript are applicable more broadly to different types of metataxonomic data being collected across myriad systems and research disciplines. For example, there has been great interest in describing the dynamics of the parasite community as an ecosystem and understanding its influence on host health -62. A  article . GLMM ap article  while in


Despite the implementation of screening and early detection in many countries, the prostate cancer mortality rate remains high, particularly when the cancer is locally advanced. Targeted therapies with high efficacy and minimal harms should be particularly beneficial in this group, and several new approaches show promise. This article briefly analyses relevant clinical studies listed on ClinicalTrials.gov, combined with a short literature review that considers new therapeutic approaches that can be investigated in future clinical trials. Therapies using gold nanoparticles are of special interest in low-resource settings as they can localize and enhance the cancer-cell killing potential of X-rays using equipment that is already widely available. Prostate cancer is a disease that affects millions of men . GloballMen who die of prostate cancer do so because of metastatic spread from the original tumor, principally to the bone . These metastatic sites can in turn become secondary sites of metastatic spread, eventually resulting in incurable disease. In a large proportion of these men, it is likely that the disease has already spread by the time of diagnosis and initial treatment . Advanced prostate cancer is the term used to describe cases where the tumor has spread beyond the prostate and is usually divided into locally advanced (stage III) cancer, where the spread is confined to nearby tissues within the pelvis, and advanced (stage IV), where the cancer has spread to other parts of the body . LocallyThe ClinicalTrials.gov database is free-to-use and contains details of more than 450,000 privately and publicly funded clinical studies conducted in 221 countries ; an anal® Excel® for Microsoft 365 and JMP® Pro 17.1.0 running on Windows 10. Specific search terms were used in the query section of ClinicalTrials.gov. A comma-separated values (CSV) file of all studies meeting the query criteria was downloaded and analyzed using Microsoft®  was queried, and recent relevant articles were selected primarily based on their relevance to detection and/or treatment of locally advanced and/or lymph node involved prostate cancer. The literature review was not carried out systematically. Most of the information was obtained from review articles and their cited sources. In addition, manufacturers’ websites were scanned to determine if there were clinical trials in the pipeline.For the literature review, PubMedThe results from the ClinicalTrials.gov query and the literature review are considered separately.A query of [prostate cancer] in “condition or disease” and [lymph node metastases] in “other terms” on 18 May 2023 found 103 studies after removal of 60 studies where the eligibility criteria did not include locally advanced disease . A file The geographic distribution of the studies is shown in The status of the studies is shown in The start dates of the studies are shown in The phases of the studies are shown in The types of study designs are shown in A literature review of recent advances in the detection and treatment of prostate cancer revealed novel treatments that may not yet have reached the stage where they can be tested in clinical trials. This is not intended to be a systematic overview of the field, rather a brief up-to-date summary with an emphasis on prostate cancer that is locally advanced or confined to the lymphatics.Radiation therapy is often given as treatment for locally advanced prostate cancer. Areas of research include the combination of radiation therapy with androgen deprivation therapy and dose escalation and hypofractionation aimed at improving the precision and accuracy of radiation delivery in order to improve efficacy and reduce harm .Ongoing clinical trials include PACE-NODES, a phase III randomized trial of five-fraction prostate stereotactic body radiotherapy (SBRT) versus five-fraction prostate and pelvic nodal SBRT  and a piNanoparticle-enhanced radiotherapy (NERT) is a method of enhancing the therapeutic ratio of radiation therapy by the addition of nanoparticles that are located in or near the tumor cells . There aNano-radiopharmaceuticals177Lu]-PSMA-617 in men with metastatic prostate cancer [Radiolabeled nanoparticles have the potential to be used both for imaging and therapy, and several are under development. In particular, studies of prostate-specific membrane antigen (PSMA)-targeted radiopharmaceuticals are being conducted , includie cancer ,16. A coGadolinium-based nanoparticles®  is a polysiloxane-based nanoparticle containing approximately 15 gadolinium atoms in a particle of about 5 nanometers in diameter. The small size allows for selective accumulation in tumors after intravenous administration. The gadolinium allows MRI-contrast imaging and enhances the radiation-induced damage to tumors [AGuIXo tumors . One firo tumors ,20 and ao tumors . To dateo tumors , and theHafnium oxide particlesNBTXR3  is a radioenhancer composed of hafnium oxide crystalline nanoparticles . Eight cPSMA-targeted gold nanoparticlesGold nanoparticles (GNPs) are another avenue of research with promising pre-clinical results, particularly when functionalized with molecules that bind to prostate-specific membrane antigen (PSMA). After intravenous injection, these PSMA-GNP nanoparticles are selectively taken up by prostate cancer tumor cells and can be readily imaged using X-ray fluorescence . These nThere are some safety concerns regarding GNPs as they degrade slowly in vivo, leading to the possibility of cumulative toxicity, particularly in the liver and spleen . It has Oncolytic viruses specifically target cancer cells where they can replicate and infect nearby cancer cells without affecting normal tissue. Viruses in clinical development are either naturally occurring, non-pathogenic to humans, or genetically engineered . SeveralPrecision medicine uses molecular testing to identify specific genetic mutations and biomarkers in an individual patient’s cancer cells that can guide treatment decisions. Examples include alterations in androgen receptor signaling ; genomic alterations leading to activation of the PTEN-PI3K-AKT pathway (increases response to capivasertib); and disruption of the DNA repair pathway (enhances response to PARP inhibitors) .Prostate Health Index (PHI)PSA (prostate-specific antigen) screening is a well-established method to detect prostate cancer in men. However, limitations include a high rate of false-positive results and overdiagnosis, leading to overtreatment. This has led to the development of new techniques to improve prostate cancer detection accuracy. Some examples include:The PHI is a blood test that measures three forms of PSA to provide a more accurate assessment of prostate cancer risk and has been shown to improve prostate cancer detection accuracy, potentially reducing the number of unnecessary biopsies in up to a third of men .4Kscore TestThe 4Kscore is a blood test that measures four different PSA-related proteins to assess prostate cancer risk and can help distinguish between aggressive and non-aggressive prostate cancer, reducing the likelihood of overtreatment .MRI Fusion BiopsyAn MRI fusion biopsy combines MRI images with real-time ultrasound to improve prostate cancer detection accuracy and can help to decrease the overdetection of insignificant cancers .Liquid BiopsyA liquid biopsy is a blood test that detects circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) to help monitor prostate cancer progression and identify treatment resistance .PCA3 TestThe PCA3 is a urine test that measures the expression of the prostate cancer gene 3 (PCA3) to assess prostate cancer risk and therefore reduce the number of unnecessary biopsies .Prostate cancer is dependent on androgens for growth and progression. Several drugs are available that target androgen receptor signaling, including enzalutamide, apalutamide, and darolutamide. These drugs have been shown to improve survival in patients with metastatic prostate cancer and are being studied in men with locally advanced disease, particularly in combination with radiation therapy ,41, althOngoing clinical trials include ALADDIN, a randomized phase III trial of darolutamide vs. placebo  and APPR2+ ions into the cell when activated and is highly expressed in stage III/IV androgen-dependent prostate cancer. Pre-clinical studies indicate that pharmacologically induced Ca2+ cytotoxicity, which can be evoked by menthol, sensitizes cancer cells to standard therapies [TRPM8 , also known as the cold and menthol receptor 1 (CMR1), is an ion channel that allows entry of Caherapies ,46.A variety of immunotherapies are under development, including peptide-based cancer vaccines . AlthouActive surveillance is the monitoring of the patient with regular PSA tests and prostate biopsies but delaying treatment until the cancer shows signs of progression. This approach is probably most appropriate for men with low-risk prostate cancer, those with a limited life expectancy (such as the elderly), or in resource-limited settings . This seThe detection and eradication of locally advanced metastatic disease is clearly an important area of research, as the spread of tumor cells to local lymphatics is a strong prognostic indicator and predictor of death in the subsequent five years. It may therefore be surprising to find only 103 studies covering this topic from 1990 to date. However, there are several technical difficulties that need to be overcome before progress can be made, including identification of small clumps of metastatic cells within the pelvis and targeting treatment to these microscopic disease areas with minimal damage to normal tissues. Recent advances in precision medicine, androgen receptor targeting, immunotherapy, radiation therapy, and active surveillance may  improve therapy decisions for locally advanced prostate cancer. Note that it is important to test all treatments in adequately powered randomized clinical trials, as these provide the best evidence to inform clinical treatment guidelines. Unfortunately, the lack of such evidence means that many guidelines do not adequately take into account either the benefits or harms of treatments  and insSome of the shortcomings of current prostate cancer treatments include side effects of treatment ; limited effectiveness of treatment; resistance to treatment (leading to disease progression); and a lack of personalized treatment tailored to individual patient characteristics, biomarkers, and genetic profiling.Many of the studies in the review of clinical trials included a radiation intervention. The advantage of external beam radiation is that imaging is not necessary, as the treatment should target actively dividing cancer cells. However, the pelvis includes normal tissues at risk of damage from X-rays, including the lining of the gut. Several clinical trials are investigating more sensitive techniques such as PSMA PET scans  that can2+ cytotoxicity, as this opens the possibility of enhancing the effectiveness of conventional treatments using a substance as simple as menthol.Future trends in prostate cancer treatment include precision medicine, immunotherapy, targeted therapy using drugs that specifically target cancer cells’ genetic and molecular characteristics, liquid biopsy to monitor treatment response and detect treatment resistance, and artificial intelligence (AI) to analyze large data sets to identify personalized treatment options. Other new treatments being developed include oncolytic virus therapy and androgen receptor targeting. One particularly exciting area of research concerns pharmacological-induced CaOne of the more promising areas of research is the use of gold nanoparticles, which are being actively investigated for imaging, diagnosis, and treatment of disease . When liGold nanoparticles have additional advantages. They are non-toxic and can be produced in an environmentally friendly manner, potentially from acai berry or elderberry extracts  or direcMen recently diagnosed with locally advanced or advanced prostate cancer have many concerns about symptoms, treatment options, and the side-effects of treatments. Fundamentally, they want to have answers regarding their length and quality of life. While there is good advice available for coping with tiredness, pain, bladder problems, eating difficulties, etc., it is not currently possible to “see into the future” and predict what life will be like one year (or even one month) from now. However, examples from other areas of medicine have demonstrated that research produces therapies that can transform a disease from a dreaded killer to an annoying nuisance in a very short space of time. It is therefore worth maintaining a sense of optimism in the face of adversity, not only for oneself but also for the brothers, sons, nephews, and others who may face such a diagnosis in the future. It is this hope that drives the basic research and clinical trials that will provide evidence of the benefits and harms of new treatments, and eventually consign prostate cancer to a footnote in history alongside bubonic plague, chronic myelogenous leukemia, and COVID-19.This article has analyzed clinical trials and reviewed some of the recent advances in therapy decisions for locally advanced prostate cancer and shown that more clinical trials are needed, particularly in countries outside of North America and Europe. There are potentially many promising new technologies that need to be translated from bench to bedside to inform clinical guidelines and reduce global mortality from prostate cancer.


The human microbiota is a complex ecosystem that colonizes body surfaces and interacts with host organ systems, especially the immune system. Since the composition of this ecosystem depends on a variety of internal and external factors, each individual harbors a unique set of microbes. These differences in microbiota composition make individuals either more or less susceptible to various diseases, including cancer. Specific microbes are associated with cancer etiology and pathogenesis and several mechanisms of how they drive the typical hallmarks of cancer were recently identified. Although most microbes reside in the distal gut, they can influence cancer initiation and progression in distant tissues, as well as modulate the outcomes of established cancer therapies. Here, we describe the mechanisms by which microbes influence carcinogenesis and discuss their current and potential future applications in cancer diagnostics and management. Interestingly, only about one third of these bacterial taxa are shared among individuals  is associated with a variety of inflammatory, autoimmune, metabolic, and neoplastic diseases  may downregulate T cell response within the tumor, which could drive carcinogenesis of the gastrointestinal tract  via the toll-like receptor (TLR) 4—miRNA-21 signaling pathway  have a different gut microbiota than healthy individuals, and the presence of certain microbes in tumor tissue is associated with more advanced tumors , which prevents the apoptosis of damaged cells  is one of the most frequently mutated genes in human cancers, but its oncogenic potential in the colon remains relatively low in the absence of a specific gut microbial metabolite—gallic acid . However, when the colibactin levels are too low to stop the growth of all tumor cells, senescent cancer cells secrete growth factors that accelerate the growth of surrounding, unaffected cancer cells -17C in intestinal epithelial cells through TLR-MyD88-dependent signaling. This, in turn, restricts apoptosis via Bcl-2 and Bcl-xL and promotes cancer cell survival  to distant tissues via lymphatic and blood vessels. The underlying mechanisms are often associated with inflammation, require proteolytic enzymes, and involve the Wnt pathway. The spread of epithelial tumors depends on the EMT, which is critical for cancer cell migration and invasion of surrounding tissues. Both cancer cells and tumor stromal cells produce a wide range of matrix metalloproteinases (MMPs), most notably MMP2, MMP7, and MMP9  and translocating microorganism-associated molecular patterns (MAMPs) promotes chronic inflammation by releasing ROS and reactive nitrogen species (RNS) from resident phagocytes  7 in the colon mucosa -α, and IL-6  cells and even by some antibodies that enable tumor antigen recognition and cell lysis. While immune cells infiltrate solid tumors, oftentimes they are unable to mount an effective immune response. These impaired cells are attracted to the tumor or develop there in response to specific environmental conditions, locally produced cytokines or direct interactions with other cells, including cancer cells.Cells with immunosuppressive potential, particularly regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and tumor-infiltrating macrophages (TAMs), dominate the tumor microenvironment of patients with poor prognosis. Signaling through their bacterial or fungal sensors enhances their immunosuppressive activity, which further promotes carcinogenesis  from the gut and impairs the protective and tolerogenic functions of mucosal immunity for an extended period , and other structural components. After crossing the intestinal barrier, all of these factors can reach distant tissues and organs via lymphatic and systemic circulation . This enhanced anticancer immunity is driven by intratumoral CD4+ and CD8+ T cells that produce IFN-γ  or prevent (butyrate/propionate) inflammation. Butyrate both inhibits the immune response by inducing Tregs  or breach the integrity of the intestinal barrier   or sampling and processing methods. For example, most published studies examined urban populations from the so-called WEIRD  countries  are associated with increased cancer incidence and even predict poor prognosis in cancer patients  is heavily colonized by microbes  immunotherapy had enriched anabolic pathways compared to those who did not respond. Interestingly, these differences were particularly pronounced in the gut microbiome, whereas the oral microbiome of responders differed only slightly from that of non-responders  negates this effect  blocker ipilimumab and the PD-1 blocker nivolumab had a gut microbiome with increased abundances of ATBs have a negative effect on treatment outcomes of ICIs in solid tumors  is an essential part of the therapeutic armamentarium in oncology. Because ionizing radiation damages all living matter, RT is associated with marked changes in the microbiota in both humans and animal models  (Nood et al. The gut microbiota can be transferred from a healthy donor, directly impacting the gut microbial community of the recipient. FMT is used to restore gut microbial ecology in patients with H. pylori being established as a known human carcinogen (IARC Several microbes have long been associated with the development of cancer, with gen IARC . New bacAs we delve deeper into the intricate workings of host–microbe interactions, the potential for using this knowledge in clinical practice to improve cancer treatment and prevention becomes increasingly apparent. Several avenues of research are opening up for investigators in the basic and clinical sciences. In particular, research priority should be given to systematically investigating how the gut “immunological niche” interacts with nutritional and microbiological components and how the outcomes of these interactions reach distant tissues. Additionally, questions remain about how these early-life interactions between the host and the microbiota affect resistance to cancer later in life.Although applications are still limited in the clinical arena, recent publications indicate that the gut microbiota can serve as potential biomarkers, therapeutic targets, or means to improve existing therapies by increasing their efficacy or decreasing their toxicity. Current research is now focused on identifying microbes predicting therapeutic outcome or identifying patient subgroups suitable for individualized therapies.FMT presents a promising avenue for enhancing cancer therapy. However, before it can be used in clinical practice, we need to understand the underlying host-microbe interactions and tailor the approach to the specific cancer type and drug. While a single FMT is sufficient to correct acute dysbiosis in CDI, resolving long-term dysbiosis in chronic diseases such as cancer may require a different strategy. Therefore, in future studies, we may need to revise our approaches by focusing more on multiple FMTs or bacteriophage administration. The motivation behind this review was to combine concepts from different research areas to stimulate discussion among experts and open this complex and fascinating field to new researchers. We hope that this will ultimately accelerate progress toward new preventive and therapeutic interventions for cancer patients.


We address a controversy over use of the term “gene drive” to include both natural and synthetic genetic elements that promote their own transmission within a population, arguing that this broad definition is both practical and has advantages for risk analysis. There are some outside the genetics research community who argue that wide use of the term “gene drive” to encompass selfish genetic elements found either in extant organisms  or assembled in the laboratory (synthetic gene drives) will discourage the necessary scrutiny of risks that may be associated with the introduction of synthetic gene drives into free-living populations of target organisms3. Here we argue that the current definition is both scientifically sound and promotes good governance.Gene drive technologies are being considered as a new approach to address a variety of currently intractable global problems, including to prevent disease transmission, reduce crop loss, and preserve biodiversity1. Many of the original terms describing selfish genetic elements found in nature had mechanistic connotations, including preferential segregation, transmission ratio distortion, meiotic drive, genic meiotic drive, chromosomal meiotic drive, mitotic drive, neocentromere drive, centromere drive, B-chromosome drive, sex-chromosome drive, transposable elements, homing endonucleases, and genetic drive4. Today, biotechnology enables researchers to create genetic assemblies in the laboratory that mimic many of these types of natural drives. However, these synthetic, or engineered, drive systems can be purposefully designed to address particular goals, such as to reduce the prevalence of a target pest population or reduce the capacity of the target organisms to do harm. Drive mechanisms such as over-replication systems (e.g. homing), true meiotic drive systems (e.g. some toxin-antidote systems), and post-meiotic drive systems (e.g. cytoplasmic incompatibility) are currently a major focus of such research and development efforts4. The expression “gene drive” has emerged among applied geneticists as a useful generic term to refer to any type of transmission advantage2, encompassing a broad array of mechanisms utilized by both natural and synthetic selfish elements6.Researchers studying selfish genetic elements have coined many terms to describe specific phenomena and systems that result in asymmetric inheritance8, particularly with regard to regulatory policies and the ability to adequately assess potential risks. In this context, it has been argued that naturally occurring selfish elements and natural drive systems should not be included in the definition of gene drive9. To a great extent, the semantics are already established in that the term gene drive is currently in wide usage among the genetics research community. However, the concerns that have been raised are largely directed not to the scientific community but to the general public’s perception of synthetic gene drive technologies and to the ability of decision-makers to adequately evaluate them. Here we propose that an artificial distinction between natural and synthetic drive systems is not warranted, and indeed can be counterproductive to the common goal of effective risk assessment and informed decision-making about new synthetic gene drive technologies.There is ongoing debate about the novelty of synthetic gene drives4. The synthetic MEDEA gene drive system  simulates some ‘toxin-antidote’-type gene drive systems found widely in nature. Wolbachia (wPip) genes responsible for cytoplasmic incompatibility and asymmetric inheritance in Culex pipiens have been introduced into the genome of Anopheles gambiae as the potential basis for an engineered gene drive system in this mosquito10. Many Cas9-based synthetic gene drives configure the sequence-specific Cas9 DNA endonuclease in the same way as sequence-specific DNA-endonucleases referred to as homing endonucleases found in some pro- and eukaryotes. Not only does this configuration result in gene drive identical to that associated with homing endonucleases in nature but both gene drive systems rely on identical endogenous DNA repair mechanisms (homology directed repair) to achieve their transmission advantages. Another cogent example of the futility of any technical argument that natural and synthetic gene drives can be functionally distinguished is the recent success of a gene drive engineered to reduce the reproductive capacity of mice by using the naturally occurring t haplotype to spread inactivating mutations in a haplosufficient female fertility gene, thus effectively combining both natural and synthetic components within the same system11.Research advances make it increasingly less plausible to make any meaningful distinction between natural and synthetic drives. Many synthetic gene drive systems intentionally recapitulate the mechanisms used by naturally occurring selfish elements and thus are functionally the same or similar. For example, the first efforts to create synthetic gene drives using cloning technologies involved repurposing naturally occurring transposable elements and creating chimeric assemblies with drive characteristics similar to the original transposable elements9. Here, however, it is important to remember that natural gene drives also can be used to serve human intentions. Among the earliest envisioned uses of natural gene drives employing transposable elements, meiotic drive or underdominance mechanisms was to serve human purposes by reducing transmission of vector-borne diseases12. For example, Craig et al. clearly recognized the potential of periodic releases of Aedes aegypti containing sex-ratio distorting genes in urban areas to reduce the number of females below a level required for efficient disease transmission. Similarly, Curtis proposed the use of chromosome translocations to fix desirable genes in insect pest populations. While largely unsuccessful, these early attempts to harness natural gene drive systems inspired the development of synthetic gene drive technologies as new tools for vector control. More recently, a natural gene drive has intentionally been incorporated in a population suppression strategy for mice11.Another proposed rationale for distinguishing synthetic from natural gene drives is that synthetic drives are explicitly intended to serve human intentions, and therefore should not be considered as repurposed natural processes3. This presupposes that regulators will somehow equate naturalness with safety, a misconception that has been refuted elsewhere (e.g.13) and for which a multitude of obvious counterexamples exist , and therefore will not apply the same stringency of process. This supposition ignores the basic principles of methodologic rigor of risk analysis, which require case-by-case assessment of regulated biotechnology products whatever their composition. According to law, policy and/or regulation14, the testing and possibly the eventual use of synthetic gene drive systems is expected to be preceded by assessments of health risks, environmental risks, environmental and socioeconomic impacts, which will underpin decision-making at the various levels of societal organization.Concerns also have been raised that application of the term gene drive to natural systems will result in a false sense of safety that will confuse regulatory and political discussions about synthetic gene drive technologies and undermine appropriate governance of these new biotechnology applicationsWolbachia-mediated strategy for reducing transmission of arboviruses by Aedes mosquitoes is being studied as a means to predict the monitoring requirements for synthetic gene drive systems that similarly aim to reduce transmission of mosquito-borne pathogens15, which could contribute to more informed risk assessment and management.Informed decision-making will be best served by taking full advantage of the science, scholarship and knowledge related to both natural and synthetic gene drives. Because synthetic gene drive systems have yet to be deployed in natural settings, empirical field data on their fate in, and impact on, the receiving environment is lacking. However, the dynamics and evolutionary fate of many natural gene drive systems have been well studied and can provide an important knowledge base for predicting the behavior of similar synthetic drive systems. In the case of homing-based synthetic gene drives, for example, except for the use of a distinct but equally sequence-specific DNA endonuclease (Cas9/sgRNA), these systems are identical to and use the same cellular machinery to achieve drive as homing endonucleases found in nature. Exclusionary semantics in this case would have the unhelpful consequences of discouraging those engaged in technology development, assessment, and governance from using some 50 years of research on natural gene drives to support discussions and decision-making. As an example of such a comparative approach, experience with a self-sustaining 16. Creating an artificial barrier between natural and synthetic gene drives is not only difficult to justify scientifically, but could actively undermine good governance by discouraging the consideration of important information that will inform the modeling of long-term effects, enhance risk analysis, and reduce the possibility of unintended adverse consequences of new gene drive technologies.We agree with the proposition, originating in the basic genetics research community, that understanding how synthetic drives might spread and be altered over evolutionary time will be enhanced by studying how mechanistically similar naturally occurring drive systems behave in nature


Heparan sulfate is a crucial extracellular matrix component that organizes structural features and functional protein processes. This occurs through the formation of protein–heparan sulfate assemblies around cell surfaces, which allow for the deliberate local and temporal control of cellular signaling. As such, heparin-mimicking drugs can directly affect these processes by competing with naturally occurring heparan sulfate and heparin chains that then disturb protein assemblies and decrease regulatory capacities. The high number of heparan-sulfate-binding proteins that are present in the extracellular matrix can cause obscure pathological effects that should be considered and examined in more detail, especially when developing novel mimetics for clinical use. The objective of this article is to investigate recent studies that present heparan-sulfate-mediated protein assemblies and the impact of heparin mimetics on the assembly and function of these protein complexes. Intercellular signaling and correct structural organization are largely mediated by the extracellular matrix, which functions to organize macromolecules in a local and temporal manner. This is necessary for multicellular life ,2, and aFor this purpose, heparin-based drugs including heparin-mimicking drugs are actively being developed ,13,14. HHeparan sulfate molecules are important components of multicellular organisms that allow for the correct structural and functional organization of the extracellular matrix. Heparan sulfates interact with various proteins through both electrostatic and hydrogen-bonding interactions . These aOne of the key ways in which heparan sulfates directly regulate cellular processes is by modulating the activity of growth factors. Growth factors are signaling molecules that are involved in cell proliferation, differentiation and migration. Heparan sulfates are able to interact with these molecules, promoting the formation of signaling complexes that activate downstream signaling pathways. This is evidenced by the complex formation of FGFR1 and its ligand, which stabilizes the formation of a protein–protein complex . StructuThe indirect functional role of heparan sulfate on cellular signaling brings up two possible sources for a wide range of physiological diseases related to uncontrolled signaling. The first is mutations in the direct binding interfaces of proteins that affect ligand binding and subsequent protein diffusion . The cruThe second potential cause of disease is irregularities in enzymes that release heparan-sulfate-associated proteins from their structural supports, resulting in free ligand diffusion across the extracellular matrix. Heparanase is an extracellular matrix enzyme that functions to cleave heparan sulfate chains, where abnormal expression and function has been shown to cause uncontrolled cell signaling and remodeling of the extracellular matrix ,52. It wIn general, heparan-sulfate-mediated protein complex formation plays a critical role in regulating various cellular processes, including cell proliferation, differentiation and migration, by modulating the activity and localization of signaling proteins. Accordingly, the binding and retaining of proteins by heparan sulfates in the extracellular matrix adds a level of complexity to intercellular signaling that is often unaccounted for. As such, the precise mechanisms by which heparan sulfates interact with different proteins to control cellular processes are still not fully understood. Still, our current knowledge of irregularities in the structural integrity of GAG-mediated protein assemblies caused by intrinsic or extrinsic forces emphasizes the significance of heparan sulfate as a structural component. Prospective studies on protein systems in the extracellular matrix should consider possible effects of GAG ligands and the formation of larger protein assemblies that might affect cellular signaling and matrix organization.Heparan sulfate is a crucial component for multicellular life, and it interacts with many different signaling proteins and systems. Although heparan sulfate is a very unspecific ligand due to its overall strong negative charge, various heparin mimetics have been developed that constitute different classes, from basic small saccharides to polysulfated oligosaccharides and non-carbohydrate mimetics ,57. GeneAs heparan sulfates take part in the structurally organization of the extracellular matrix, inflammatory and fibrotic events are highly dependent on the present heparan sulfate composition and function. This includes the careful control of heparan sulfate modeling by enzymes and subsequent formation of protein assemblies that regulate proinflammatory and anti-inflammatory cytokines . This baFurthermore, cancer progression is often associated with abnormal remodeling of the immediate extracellular matrix, which allows for elevated cell proliferation and differentiation based on compromised control mechanisms. Synthetic heparin mimetics have recently been produced that show antithrombotic and inhibitory activity of various enzymes such as Heparanase, P-selectin and the integrin VLA-4 to drastically reduce metastatic activity; the heparin mimetic efficiently blocked melanoma cell binding to endothelial cells under blood flowing conditions . This waBeyond the direct effects of heparin mimetics on enzymes and signaling proteins, changes that affect general protein–heparan sulfate interactions and protein assemblies can alter signaling behavior. An example of this is the antagonist removal from the immediate surroundings of a cell surface ,66, whicIn any case, the underlying disease mechanisms in relation to heparan sulfate or heparin dependence have to be examined in order for appropriate drug development to occur. Heparin mimetics can function as inhibitors against extracellular matrix deconstruction and remodeling  16], as, as16],