People with early-onset colorectal cancer, under the age of 50, are more likely to experience diagnostic delay and to be diagnosed at later stages of the disease than older people. Advanced stage diagnosis potentially requires invasive therapeutic management at a time of life when these patients are establishing intimate relationships, raising families, building careers and laying foundations for financial stability. Barriers to timely diagnosis at primary care level have been identified but the patient perspective has not been investigated.Personal accounts of cancer care are increasingly accessed as rich sources of patient experience data. This study uses mixed methods, incorporating quantitative content analysis and qualitative thematic analysis, to investigate patients’ accounts of early-onset colorectal cancer diagnosis published on prominent bowel cancer support websites in the United Kingdom, Australia and New Zealand.n = 273) of diagnostic barriers at primary care level were thematically similar across the three countries. Patients perceived that GPs’ low suspicion of cancer due to age under 50 contributed to delays. Patients reported that their GPs seemed unaware of early-onset colorectal cancer and that they were not offered screening for colorectal cancer even when ‘red flag’ symptoms were present. Patients described experiences of inadequate information continuity within GP practices and across primary, specialist and tertiary levels of care, which they perceived contributed to diagnostic delay. Patients also reported tensions with GPs over the patient-centredness of care, describing discord related to symptom seriousness and lack of shared decision-making.Patients’ perceptions (Wider dissemination of information about early-onset colorectal cancer at primary care level is imperative given the increasing incidence of the disease, the frequency of diagnostic delay, the rates of late-stage diagnosis and the dissatisfaction with patient experience reported by patients whose diagnosis is delayed. Patient education about diagnostic protocols may help to pre-empt or resolve tensions between GPs’ enactment of value-based care and patients’ concerns about cancer. The challenges of diagnosing early-onset colorectal cancer are significant and will become more pressing for GPs, who will usually be the first point of access to a health system for this growing patient population.The online version contains supplementary material available at 10.1186/s12875-023-01967-0. Maybe it wouldn’t have though, because who gets bowel cancer at age 33?”The global incidence of colorectal cancer (CRC) in people aged under 50 is rising rapidly, in contrast to stable or declining rates of CRC in older adults –6. CRC oEoCRC takes longer to diagnose than traditional CRC , 11 and Data on healthcare-led barriers to timely EoCRC diagnosis –17 indicCurrent knowledge of diagnostic delay in EoCRC relies on surveys of EoCRC patient populations and quantitative analysis of patient records. As yet we have little understanding of how EoCRC patients perceive the quality of care they receive during their diagnostic phase and what they think about the actions of their GPs. This information will be of value in understanding the needs of this newly emerging patient population.What experiences and perceptions of health service barriers to diagnosis are reported by EoCRC patients in their online accounts of diagnosis? How do EoCRC patients who have experienced diagnostic delay characterise their interactions with GP services?We present our investigation of online patient reports of EoCRC diagnosis. We asked: Personal accounts of healthcare experiences published online are increasingly accessed as rich sources of patient-reported data , 21. TheThe study was designed and led by an experienced qualitative researcher with skills in the analysis of web-based patient accounts of personal experience. The research team comprised highly experienced researchers across clinical practice, social science, health systems research and qualitative and quantitative methods. Team members shared interests in identifying, characterising and responding to real-world complexities in the delivery of timely diagnosis to the newly emerging population of people with EoCRC.Websites hosted by three key charitable support organisations were selected as specific research settings: Bowel Cancer Australia,  Bowel CaThe study population was selected by criteria sampling rather than representative sampling. Personal accounts were excluded from the study if they were not written by people who were diagnosed under 50 years of age or if accounts solely comprised feedback on, or criticism of, a named institution or clinician.The study was granted ethical and scientific approval by the Macquarie University Human Research Ethics Committee (MQ HREC Reference No:52020666115757). The committee was satisfied that the use of the personal accounts as data matched the expectations of the individuals who published their accounts online in public domain sections of prominent cancer support websites.Eligible personal accounts of EoCRC published on the host websites as at February 2021 were collected as data. Each account was processed as a separate research text and downloaded into the NVivo 12 qualitative data analysis software program . Each text was de-identified and attributed a unique participant study number to be used on all study documents.Our mixed methods analysis of the personal accounts involved: quantitative description of the demographic and health status characteristics of the study population; quantitative content analysis to understand the frequency of topics and events of interest to the study; and qualitative thematic analysis to examine the descriptions and perceptions of the events that people reported in their narrative accounts.The qualitative analysis focused on three key categories of patient experience that are assessed in patient-reported experience measures (PREMs): clinical assessment; continuity of care; and interpersonal care. Sentence-by-sentence analysis organised parts of each text into these three categories. We then looked for topics and themes of EoCRC patient experience of diagnosis within each of these categories. One researcher led the thematic analysis with iterative review and consensus from co-authors.Though final decisions on themes were not based on numbers of references, cross-checking against the quantitative results was a useful mechanism for comprehending undue emphasis on isolated experiences or experiences only of interest to individual researchers. In particular, the quantitative results provided an important validating context for understanding the scope of negative and dissatisfying experiences comprised in the texts, given that the personal accounts also comprised reports of positive experiences and timely diagnosis.Across the three websites, 273 personal accounts met the inclusion criteria: 136 (50%) from UK, 116 (42%) from Australia and 21 (8%) from NZ. Over two-thirds were female (73%), and almost half were aged 30 to 39 years (48%). Two-thirds reported being married or in a relationship (66%) and over half reported being pregnant or having children under 18 years (55%), with the remainder not reporting.Overwhelmingly, the narrators reported a diagnosis of bowel or colon cancer (94%), with only 6% indicating rectal cancer. The majority was diagnosed at an advanced stage (III or IV) . When describing the status of their health, 22% gave no indication, 20% were in treatment, 42% were in complete remission, and 4% reported progression. For the most part comorbidities, family history and genetic mutations were not mentioned in the narratives, but these were recorded by 7, 16 and 9% of narrators, respectively. As shown in Table Table While the number of specialist referrals from primary care was not mentioned in 59% of narratives, there was only a single referral in 26% of narratives, while around 15% required two or more specialist referrals. Two-thirds of narratives did not mention the number of outpatient visits (66%), but 14% reported 5 or more such visits. Inpatient visits were mentioned in only 15% of narratives, with diagnosis occurring in the first hospitalisations in more than half of these (8%).The amount of time from first consultation to diagnosis was not mentioned in 39% of narratives; diagnosis took < 3 months in 21%, 3–12 months in 25%, and 1–5 years in 15%. Among the 40% of accounts that mentioned a duration of three or more months from initial consultation to diagnosis, 24% attributed the delay to missed diagnostic opportunity, while 71% did not report any reason.Once again, there is some variation in issues mentioned by patients in different countries. Possible differences include, for example, that: Australian narratives mentioned anaemia more frequently; NZ narratives less frequently mentioned CT scans or MRIs; Australian and NZ narratives more frequently mentioned that the patient had initiated a request for a diagnostic test (14–15%) compared to UK narratives (7%); and Australian narratives mentioned less time between first consult to diagnoses than NZ narratives, and more frequently mentioned a single specialist referral.Unsurprisingly, EoCRC patients’ accounts portrayed help-seeking experiences as satisfactory or positive when diagnosis was straightforward and timely, and characterised care as disappointing or frustrating when barriers to diagnosis were experienced. Our qualitative results suggest that patients experienced similar barriers to timely diagnosis at primary care level in all three countries of interest, despite variations in health systems with regards to clinical practice guidelines (CPGs), referral conventions and diagnostic testing protocols.In Table Patients in our study reported that anal bleeding and blood in stools were commonly attributed to haemorrhoids, persistent anaemia was managed as a dietary-related iron deficiency and ongoing symptoms of abdominal pain, bloating, bowel changes and fatigue were investigated and managed for IBS or other common gastrointestinal disorders as well as gynaecological conditions.A quarter of patients who reported delays of over three months conveyed frustration and dissatisfaction that their GPs had spent so much time focusing on common conditions and described their GP’s low suspicion of cancer as poor-quality care. These findings were largely consistent across the three countries of interest, supporting literature in all three countries that EoCRC patients who experience delays are dissatisfied with the diagnostic actions of their GPs when cancer investigations are not prioritised , 17, 26.This dissatisfaction amongst EoCRC patients points to the need for greater patient education of diagnostic protocols . Though A confounding aspect of our data was a seeming gender disbalance in clinical assessment; only female patients eventually diagnosed with EoCRC reported that their GPs diagnosed IBS. This finding may be influenced by the gender disproportion in our study population; while approximately the same number of women as men contract CRC under the age of 50,  three quSimilarly, only female patients reported that GPs discussed a psycho-emotional diagnosis such as stress, anxiety, and disordered eating. Women may be more likely than men to ask questions and discuss concerns in detail,  which maSeeing one GP over time has been associated with a marginally higher likelihood of early cancer diagnosis,  particulAspects of our data, however, challenge this explanation for GPs’ referral decisions. Patients with relevant family history of CRC and persistent symptoms identified as ‘red flags’  for CRC Patients also reported inadequate continuity of care across multiple providers as a barrier to timely diagnosis. Patients described locum GPs, rotating medical staff in large primary care practices, specialist appointments, emergency care for pain management and changing GPs as contexts involving multiple providers.Poor information-continuity across medical providers is a well-established diagnostic liability, even when changing doctors within one practice , 46. ManIssues with interpersonal communication and shared decision-making were prominent in the personal accounts of delayed diagnosis across the three countries. In particular, patients’ concerns about symptom seriousness were sources of tension in interactions and relationships with GPs, but also with providers at all levels of care. The refrain, “I wasn’t taken seriously,” which resounds across these stories, is evident also in surveys of EoCRC patient populations , 15.Symptom seriousness has been identified as a crucial point of patient-doctor divergence in medical consultations . Misalig; this may be especially relevant for patients with low risk of CRC and non-specific symptoms.Our data are notable for the absence of documented communication between patients and GPs about diagnostic protocols for CRC detection in people under the age of 50. GPs may pre-empt tensions over symptom seriousness through discussion about the rationale for referral decisions ; this maPrimary care barriers to timely diagnosis are reported by EoCRC patients in three key areas of patient experience: clinical assessment; continuity of care; and patient-centredness of interpersonal interactions. Perceptions of barriers to timely diagnosis across all three areas may stem in part from patients’ limited understanding of the guidelines that steer diagnostic decision-making. Patients perceive their GPs’ low suspicion of cancer given age under 50 as an age bias that contributes to delays. There may be value for GPs in addressing this perception in discussion with patients and providing patients with knowledge about diagnostic protocols.We conclude that with the rising global incidence of CRC in people aged under 50, there is a mounting imperative for GPs to receive information and clinical guidance on EoCRC diagnosis. In the absence of EoCRC-specific diagnostic protocols, some sources of diagnostic delay may be unavoidable, especially for low-risk individuals presenting with broad symptoms. Other sources of GP-led delay described by patients, such as failure to respond to red flags and to take note of repetitive help-seeking, are clearly addressable. The challenges of diagnosing CRC in young people are significant and will become more pressing for GPs, who will usually be the first point of access to a health system for this growing patient population.In providing the demographics represented in the personal accounts, and by presenting the percentages of personal accounts that identify specific barriers in the nominated categories, we have strived for transparency about the limitations of our data. We note, for example, that our data over-represent experiences of younger EoCRC patients and women, and under-represent patients with rectal cancers.Participants self-selected to write their narratives, a known source of bias, and thus our study is not generalisable. Notably, there is an absence of data specific to culturally and linguistically diverse (CALD) EoCRC populations, given the significant Indigenous populations in two of the settings of interest to the study: Australia and NZ. As a consequence, the results do not reflect evidence in the literature that racial and ethnic factors impact timely CRC diagnosis –52. LangAdditional file 1:Appendix. Detailed results of qualitative analysis.


In many animal species, males and females exploit different mating strategies, display sex-typical behaviors, and use distinct systems to recognize ethologically relevant cues. Mate selection thus requires mutual recognition across diverse social interactions based on distinct sensory signals. These sex differences in courtship and mating behaviors correspond to differences in sensory systems and downstream neural substrates engaged to recognize and respond to courtship signals. In many rodents, males tend to rely heavily on volatile olfactory and pheromone cues, while females appear to be guided more by a combination of these chemosensory signals with acoustic cues in the form of ultrasonic vocalizations. The mechanisms by which chemical and acoustic cues are integrated to control behavior are understudied in mating but are known to be important in the control of maternal behaviors. Socially monogamous species constitute a behaviorally distinct group of rodents. In these species, anatomic differences between males and females outside the nervous system are less prominent than in species with non-monogamous mating systems, and both sexes engage in more symmetric social behaviors and form attachments. Nevertheless, despite the apparent similarities in behaviors displayed by monogamous males and females, the circuitry supporting social, mating, and attachment behaviors in these species is increasingly thought to differ between the sexes. Sex differences in sensory modalities most important for mate recognition in across species are of particular interest and present a wealth of questions yet to be answered. Here, we discuss how distinct sensory cues may be integrated to drive social and attachment behaviors in rodents, and the differing roles of specific sensory systems in eliciting displays of behavior by females or males. Had I no eyes but ears, my ears would love. That inward beauty and invisible; Or were I deaf, thy outward parts would move each part in me that were but sensible: Though neither eyes nor ears, to hear nor see, yet should I be in love by touching thee.Say, that the sense of feeling were bereft me, and that I could not see, nor hear, nor touch, and nothing but the very smell were left me, yet would my love to thee be still as much; for from the stillitory of thy face excelling comes breath perfum’d that breedeth love by smelling.Venus and Adonis) in the brain to provide an accurate representation of the identity and state of another individual, be they mate, rival, progeny, or predator. Rodents make use of a range of volatile and non-volatile chemical cues, somatosensation, audition, and vision in their interactions. While the processing of many of these cues has been established in a unisensory context, such stimuli rarely occur in isolation in naturalistic settings, opening many questions about the role these cues play in influencing the perception and downstream consequences of each other to elicit behavioral displays appropriate to distinct ethological contexts.Multisensory integration has been established as a fundamental component of sensory processing, both by rigorous psychophysical and physiological studies that have focused on the initial mechanisms of sensory perception as well as the pathways that convey such information to the neural circuits that drive innate behaviors. The influence distinct sensory modalities exert over one another has been shown to be profound and is reflected in differences in neural activity in response to individual versus multiple cues in many loci throughout the brain. Mating interactions are rife with opportunities for multisensory integration, as conspecifics must detect potential mates, make decisions about whether or not to mate , respond appropriately to ongoing and reciprocal courtship behaviors, mate to successful fertilization, and, in monogamous species, encode the cues that identify a partner in order to form an enduring pair bond. These behaviors are all mediated by passing back and forth sensory cues across diverse modalities during varied social interactions.The importance of combining modalities is becoming increasingly evident in studies of the neural control of mating behavior, but the mechanisms associated with integration are poorly understood. Furthermore, how such representations are encoded to drive attachment related behaviors—i.e., prosocial behaviors toward familiar individuals and rejection of novel potential mates—is even more obscure. Knowledge of the systems that control rodent mating behaviors, beginning with the unimodal sensory processing involved, affords access points to the circuitry of multisensory integration. Here, we review studies of rodent mating neural circuitry with an eye toward the overall role of sensory processing in mating and hypothesizing possible loci of integration in various forms.The transfer of sensory information from one individual to another is the central goal of investigatory behaviors and a key component of the interactions that comprise courtship and mating behaviors. Investigatory behaviors in rodents include approach and tracking, sniffing of volatile and non-volatile (pheromone) odorants, whisking and grooming, audition of ultrasonic vocalizations, and vision of morphological and activity cues. These signals both drive and constitute ongoing, evolving components of sex-specific courtship and mating behaviors.Male rodent courtship and mating behaviors include initial approach, chemosensory investigations, ultrasonic vocalizations, attempts to mount and intromit, and ejaculation. In this section, we consider how sensory stimulation via volatile and non-volatile olfactory, auditory, and somatosensory modalities affects male-specific courtship and mating behaviors.Mus musculus), the VNO and AOB respond to female-specific urinary pheromones (Microtus ochrogaster), surgical ablation of the VNO similarly results in decreased—but not absent—mating behaviors ; this behavior requires intact main olfactory epithelium, but not VNO . SimilarHowever, the roles of these two olfactory systems are more complicated and intertwined than this framing suggests. Early work on the role of the VNO in mate recognition and sexual behavior revealed that the VNO-dependence of many behaviors exists only in sexually naïve animals. Deficits in mounting and production of ultrasonic vocalizations  after surgical VNO ablation are present only in sexually naïve male laboratory mice  and hamsin vivo  is correlated with rejection behaviors . While mWhile volatile and non-volatile olfactory cues are sufficient in isolation for recognition of individuals in males of several rodent species, mating behaviors must be directed to a partner, and the male must orient correctly toward the female methanethiol  and the Scotinomys teguina; Phodopus campbelli; Peromyscus maniculatus bairdi; Meriones unguiculatus; Microtus montanus; Mus musculus females prefer to investigate a speaker playing male USVs instead of a speaker simultaneously playing noise  across a variety of rodent species, including laboratory mice , Alston’ng noise . Reprodung noise , which sng noise , and malng noise . Althougng noise ; USVs maMus musculus may provide a substrate for individual recognition  sensory processing streams converge. Heteromodal inputs can also directly modulate sensory representations, as is frequently the case in cortical sensory areas  and can Many specific mating  behaviors require the presence of another animal to be expressed, suggesting that the indicator of presence or proximity is integrated with other sensory information. For example, male laboratory mice will attack male intruders to their territory. Males recognize other males via olfactory mediated cues; they respond with aggression when another male is present and countermarking when only the pheromone cue is present, indicating a role for presence-detection in pheromone guided aggression . SimilarFollowing mating, female laboratory mice form a memory of the mate; this memory prevents exposure to the mate’s pheromones from inducing the Bruce effect. This memory involves experience-dependent plasticity in the female AOB following mating. Careful circuit dissection has demonstrated that tactile stimulation of the cervix is necessary for such chemosensory memory formation . This taOlfactory and auditory cues co-occur in both mating and parenting contexts; the combination has been shown to have synergistic effects on behavior, which supports the proposal that integration of these cues must be occurring. Female mice demonstrate experience-dependent modulation of auditory cortical responses to pup calls by pup odors , with puMany areas across the rodent brain have been implicated in mating and other social behaviors. The specific neural mechanisms controlling these behaviors are often complex, involving many diverse populations of cells identified by their patterns of gene expression, anatomical location, functional and neuroanatomic connectivity, and patterns of activity across varied social contexts  is a key relay in the processing of information from the VNO. It has been proposed that signals move from the VNO through the brain following a “labeled line” logic, whereby one signal passes with a direct mapping from one relay to another to eventually drive a specific behavioral response . Indeed,in vivo is unknown. The mechanisms mediating the contributions of AOB and MOE information and their regulation of mating have been investigated at a genetic level  has been implicated in rodent sexual behavior in studies of hamsters, gerbils, and laboratory mice. Along with the MeA, the BNST receives significant inputs from the AOB, indicating that it plays a role in processing pheromone cues. Studies using c-fos expression, a molecular proxy of sustained neural activity, identified neural responses in the BNST to opposite-sex odors and sexual experience in male golden hamsters , Syrian le odors . A subsele odors . NotablyThe ventromedial nucleus of the hypothalamus (VMH) has been implicated in mediating aggression and mating behavior in rodents for many decades, but a full picture of the complex genetic and functional divisions of this nucleus is still emerging. Experiments using electrical  and optoIn addition to their role in controlling mating behaviors, VMHvl neurons may play a role in responding to cues from conspecifics . The VMH receives inputs from MeA neurons carrying information about odorants . ProjectThe VMH also plays a role in controlling female receptivity and lordosis behaviors. Activity of VMHvl Esr1+ neurons in female mice increase activity during investigation of a male’s urine and during mating, but increase further during aggressive episodes, indicating that activity in this population does not constitute a simple unimodal representation . ActivitSimilar to the VMHvl, the medial preoptic area of the hypothalamus (MPOA) has a long history of being implicated in controlling mating as well as parenting behaviors , and recThe prefrontal cortex (PFC) is a cortical region implicated in a wide range of behaviors across species. In laboratory mice, the PFC receives inputs from across sensory cortex (as well as a variety of other nuclei) and plays a role in many non-social behaviors  is known to play a key role in integration of affective states and sensory cues relevant to social behavior (reviewed in Much work remains to be done to understand the role and mechanisms of multisensory integration in rodent mating behavior and how these representations and pathways contribute to the social memories that comprise social attachment. The diversity of both mating and social organization systems across rodents and other phyla implies that distinct cues that identify individuals, their reproductive state, and other measures of physiology and health are integrated to build and maintain systems of social structure via enduring relationships between individuals and groups. Monogamous pair bonds in particular require a robust system of recognizing individuals; while this increased need for reliable recognition is perhaps unlikely to drive dramatic differences in sensory processing capacities between monogamous and non-monogamous species, comparative neuroanatomical studies suggest there may be expansions in multisensory processing capacity in monogamous species . FurtherNH and DM contributed to the conception and writing of this manuscript. Both authors contributed to the article and approved the submitted version.


The Henry Ford Health System provides patients with a safe, improved system of continuous kidney replacement therapy using a proprietary, 24-hour sustained low-efficiency dialysis (SLED). The SLED system utilizes regional citrate anticoagulation (RCA) in conventional hemodialysis machines that have been configured to provide slow dialytic therapy. Within our hospital complex, SLED-RCA systems are deployed in intensive care units distributed over 4 floors in 2 buildings. This widespread footprint represents a spatial challenge for hemodialysis technicians. Fifteen SLED-RCA machines may be running at one time, and each deployed unit may signal an alarm for multiple reasons. Previously, audible alarms prompted intensive care unit nurses to identify the alarming machine and manually notify technicians by telephone. Technicians would then travel to resolve the alarm. To improve the process of addressing SLED-RCA machine alarms, we developed a remote alert alarm system that wirelessly notifies hemodialysis technicians of specific machine alarms. A quality improvement analysis of nearly 1,000 SLED-RCA alarms over a 1-week period revealed that the average time for alarm correction with a remote alert alarm system was approximately 5 minutes. Reducing alarm resolution time may free technicians and nurses for other critical duties. In particular, the COVID-19 pandemic caused an increased demand for SLED-RCA units, which put pressure on the overworked, struggling staff in an overcrowded ICU. In the absence of a centralized alarm system, correcting dialysis machine alarms is often delayed. The amount of time for dialysis machine alarm resolution in the ICU has been inconsistent and attributable to unfavorable onsite staff-to-machine ratios. Also, ICU nurses are not universally trained in hemodialysis technology and generally are not expected to resolve hemodialysis machine alarms; therefore, “simple fixes” that need minimal technical input still require the appearance of a hemodialysis technician to resolve the problem.Our continuous kidney replacement therapy treatment protocol requires dialysis personnel to go on rounds to chart the SLED-RCA machines at 2-hour intervals, and personnel who conduct SLED-RCA therapies are not continually present in patient rooms to monitor treatments. When a SLED-RCA machine alarms due to changes in machine parameters, adverse consequences for the patient could occur; therefore, systems that shorten the time for responding to alarms are needed. To prevent iatrogenic adverse events in patients receiving dialysis, we developed and implemented a real-time sentinel remote alert alarm system to address SLED-RCA machine alarms with the aims of responding quicker to alarms and enhancing protection of critically ill patients undergoing SLED-RCA. We implemented the remote alert alarm system at our institution in 2015 and have consistently optimized the system to a point where we believe it is functioning sustainably. Thus, we performed a quality improvement analysis to characterize the remote alert alarm system. We assessed the number and types of alarms as well as the mean alarm response time and queried dialysis machine technicians about their perceptions of the system. Here, we describe our remote alert alarm system: how it is set up, how it works, and the benefits that we believe it has provided to clinical care at our institution. We hope that this quality improvement narrative will inspire other institutions to implement similar systems to optimize care of patients who require hemodialysis.Our proprietary protocol for SLED-RCA requires 2 intravenous infusion pumps. Citrate is infused into the arterial blood line of the extracorporeal circuit just after the connection to the central venous hemodialysis catheter. Before blood is returned to the patient’s circulation, a second intravenous pump normalizes the ionized calcium via an infusion of a calcium- and magnesium-containing solution into the venous return line of the circuit. Box 1If blood flow through the extracorporeal circuit is stopped, the blood pump (B) rollers will automatically occlude the arterial blood line. However, the first infusion pump will continue to deliver citrate (C) that directly enters the patient’s systemic circulation via the arterial branch of the hemodialysis catheter, which can be life-threatening if it leads to depressed plasma ionized calcium levels. If the SLED-RCA machine alarm system detects an error, which could include issues involving temperature, composition of the dialysate, conductivity, blood leak, and others, the machine will alarm and enter a “bypass” mode, where dialysate does not enter the dialyzer and the dialytic process is suspended until the alarm is cleared. A list of dialysis machine alarm triggers is listed in Blood from the patient (P) flows into the arterial blood line (A) where citrate (C) is infused. Plasma containing citrate-calcium complexes passes through the blood pump (B) for clearance by the dialyzer (D) as spent dialysate (S). The blood exits the dialyzer and enters the venous line (V) where calcium and magnesium (E) are infused and blood enters the systemic circulation (P). An alarm condition that stops the blood pump (B) is unsafe because the arterial line is occluded at point (O) where the pump roller contacts the arterial blood line. Under this condition, citrate is infused into the systemic circulation of the patient (P) via the arterial blood line (A). A bypass mode alarm condition that stops the flow of dialysate is unsafe because dialysis is suspended and citrate is not removed. The blood pump (B) will continue to operate as citrate is infused into the arterial blood line (A). The blood will pass through the dialyzer (D) without citrate removal, into the venous line (V), and then into the patient (P). The complexity of this system and the dire consequences of malfunction underscore the need for rapid response time.The SLED-RCA machines at our institution are now monitored remotely with the remote alert alarm system, which uses a secure internal WIFI and telephone system (ASCOM). We developed the remote alert alarm system alarm telemetry software system to provide critical, timely surveillance of SLED-RCA systems. The remote alert alarm system has been in use at our institution since June of 2015, and To facilitate the notification of our dialysis nurses and technicians via the remote alert alarm system, we created a software instrument panel , that displays machine and patient data from multiple hemodialysis machine/patient parameters and alerts technical staff for immediate resolution of problems by sending notifications to ASCOM phones. The ASCOM software module, MailGate, provides text alerts in specific intervals to proprietary phones until the alarm is resolved. Building on this infrastructure, we developed a system to leverage the hospital’s secure, encrypted WIFI system to deliver hemodialysis machine alarm text-alert notifications to hemodialysis technicians and nurses with ASCOM phones . In shorFor connecting the remote alert alarm system to the dialysis machines, first-generation model Fresenius hemodialysis machines without built-in computer screens were furnished with all-in-one medical grade computers with touchscreens A. The exBefore we had implemented the remote alert alarm system, if ICU nursing staff observed or heard a hemodialysis machine alarm, the nurse would first press the reset button on the machine to clear the alarm. If that did not clear the alarm, the nurse would then call for assistance from a hemodialysis technician. With the remote alert alarm system, the hemodialysis technician first receives an alert on an ASCOM phone and then calls the ICU nurse, providing guidance on how to operate the hemodialysis machine and clear the alarm. Alert messages transmitted to ASCOM phones include alarm type, patient name, room number, hemodialysis machine number, alarm description, specific machine alarm, date, and time of alarm. The specific machine alarm information facilitates the technician’s diagnosis of the alarm. For example, the alarm for the server data shown for patient 1 in To ensure that alarms are not missed by hemodialysis technicians, the remote alert alarm system transmits the same alert to the ASCOM phone every 1 minute for 5 minutes and then every 5 minutes until the alarm is cleared on the hemodialysis machine. All alarms generated for SLED-RCA machines are critical and cannot be suppressed by the remote alert alarm system. Remote alert alarm system alarms are time-stamped and saved. This storage feature permits review of the hemodialysis technician alarm response for calculating response times. The remote alert alarm system also sends messages to technicians 10 minutes before the 10-hour hemodialysis treatments are set to terminate so that supplies can be promptly brought to the machine to start the next 10-hour round of treatment time.As further backup, our remote alert alarm system has an alarm display screen on the dialysis machine for daily checks on remote alert alarm system functionality. Because our IT infrastructure footprint is large, upgrades, server migration, and server retirement can result in interruptions of service. If our IT service provides notice of upcoming changes, we can test preemptively to avoid disruption. If the remote alert alarm system needs to be interrupted for system upgrades, dialysis personnel increase the frequency of rounding to monitor all machines.ASCOM provides communication with an IP-messaging tool, MailGate, that interfaces to our email system. This tool delivers notification alerts directly to an ASCOM telephone or pager as soon as an email arrives. MailGate is interfaced to all email servers and clients supporting simple mail transfer protocol. Functionality, such as filtering and forwarding conditions, varies depending on available features in the existing mail server. Each telephone or pager in the ASCOM system has a unique email address and phone number. Portions of an incoming email are automatically forwarded and displayed as notifications on the unit. The staff are immediately alerted that the received notification requires attention. Overall, we deployed Microsoft Exchange for its simple mail transfer protocol and distribution group feature to email the notification alert to carriers in our group.Patient data can be sent over the remote alert alarm system because the network is secure within the hospital. ASCOM phones can also be tied to EPIC, the hospital’s electronic medical record, so EPIC alerts can be selectively texted to the user of the phone . The EPIC alerts are especially useful for medical staff who are rounding in the hospital and distant from the medical device. These alerts refer to hemodialysis machines that are not functioning properly and that could possibly cause patient harm unless corrected. For example, on a typical day, up to 40 alarms on 6 hemodialysis machines might occur. As the machine population doubles or triples, the number of potential alarms escalates. Our system, which includes a medical grade computer software  and email alerts sent via the ASCOM telephone service, eliminates patient machine errors, and reduces possible harm resulting from medical and technical errors. Another advantage of our WIFI-enabled computers running the dedicated software module is that data are transmitted to the central exchange email server at 5-minute intervals. This dedicated server creates a list of active machines and locations . ConsequDeveloping the remote alert alarm system incurred several costs. Our main investment for developing the system was in software engineering by 2 nephrology software engineers and 1 IT specialist who configured the ASCOM communication module. Overall, the entire project took 2 months of part-time effort with 2 months of testing before full implementation. The entire electronic remote alert alarm system runs unattended and requires very little maintenance. Our IT department maintains the ASCOM and Outlook architecture 24/7, while nephrology staff update and support the remote alert alarm system software.Because the remote alert alarm system has been used and optimized since 2015, we performed a descriptive, quality improvement assessment of the system to better characterize our novel approach. We analyzed the number of alarms, the types of alarms, and the average weekly number of alarms that occurred through the remote alert alarm system in 15 SLED-RCA units between December 26, 2020 and May 12, 2021. We also calculated the mean alarm resolution time during a 1-week period when the system logged over 1,000 alarms per week (higher than the average).The WIFI remote alert alarm system has been in use at our institution since June 2015. Infrequent failure is a hallmark of the system; however, when a communication failure in the system does occur, ICU nurses manually call technicians to resolve SLED-RCA alarms. Alert logs from 15 SLED-RCA machines during the study period included 11,896 alerts. Alerts indicated alarm situations where dialysis was suspended. The most frequent alarm involved approximately 6,000 blood pump alerts from arterial or venous pressure alarms that caused the pump to stop. The second most frequent alarm was the dialysate flow alert alarm triggered by improper conductivity or temperature, totaling 2,754 alerts. The average weekly alarm rate during the analysis period was close to 600 alerts per week.We chose a 1-week timeframe within the study period that included nearly 1,000 SLED-RCA alarms to assess alarm resolution time and observed an average correction time of approximately 5 minutes. The baseline alarm resolution time for the previous manual phone alert system could not be calculated because technicians had not historically recorded this parameter, and the time it had taken for ICU nurses to call technicians under the previous system was unknown. However, eliminating the need for a phone call by the ICU nurse most likely saved precious time, the goal of the remote alert alarm system initiative.In 2020, after the remote alert alarm system had been in use for over 5 years, we sent an anonymous, paper survey with 7 multiple choice questions to dialysis technicians to query their perceptions about the functioning of the remote alert alarm system. These questions were developed by management and nursing leaders for quality improvement purposes and were not developed to gather generalizable information.Of the 11 technicians who were sent informal surveys regarding the remote alert alarm system, 10 responded . All theHere, we described a quality improvement initiative that included creating and implementing a remote alarm alert system monitoring dialysis machines to optimize the clinical response time for alarm resolution in the ICU and to maintain the highest possible level of patient safety. Remote alert alarm system wireless telemetry for dialysis machine alerts has the potential to improve patient safety, reduce technical errors, and improve the ability to correct problems rapidly. Improvement of SLED-RCA can be achieved by incorporating the essential feature of alarms, but this endeavor requires human and organizational network infrastructure to create a distributed alarm system for remote caregivers. Future improvements to be addressed include incorporating machine learning to enable intelligent decision-making around resolving alarms for transient issues.We believe that the remote alert alarm system has optimized dialysis machine alarm response in several ways. First, nurses conducting hemodialysis in ICUs no longer need to contact a technician for each SLED-RCA alarm, saving time. Also, hemodialysis staff are directly notified by the system as to when treatments are nearing completion and when machines must be reset to continue for the next 10-hour treatment period, which may reduce treatment interruptions. Long alarm intervals can occur when a machine runs out of dialysate concentrate because resupplying the concentrate can take as long as 30 minutes. With the remote alert alarm system, the low conductivity alarm is transmitted directly to the technician, so concentrate can promptly be brought to the machine. Thus, health care providers, even when they are not in the vicinity of the units, can readily determine which patients are actively undergoing SLED-RCA and plan accordingly for maintenance and care. Also, because of the tracking and archival features of the remote alert alarm system, critical incidents and errors can be interrogated retroactively. These improvements may be real timesavers for ICU medical staff since the system encourages prompt resolution of dialysis machine alarms. Lastly, alarms, on average, are now resolved within 5 minutes, although we were not able to determine how this compares to the previous system since that system had not been tracked. Quicker alarm resolution time also reduces noise, which is beneficial for both patients and health care providers.The initial costs of remote alert alarm system implementation were high since we had to equip each dialysis machine with a medical grade touch screen computer. Each computer cost $2,000 US, and we acquired 15 of them. However, newer dialysis machine models come equipped with on-board computers and WIFI for screen sharing with the dialysis machine, eliminating the need to purchase all-in-one medical grade computers. It took us only 3 months to develop software and to coordinate with Henry Ford Health System IT to integrate our development with the hospital phone system, and the remote alert alarm system is portable, since the dialysis machine interface with the computer is already functional. For hospitals that may want to create a similar system, interfacing with a hospital’s WIFI should be relatively simple, but phone system integration may be a challenge, albeit an achievable one. Thus, patient safety may be enhanced by leveraging existing technologies at nominal institutional expense.The remote alert alarm system, by ideally reducing alarm resolution time, may ultimately liberate technicians and nursing staff for attending to other critical duties. The system can also be leveraged for increasing clinical communication. Adjunct to an alarm tote board, we created a web portal to display a running list of patients currently undergoing critical care hemodialysis. The list is refreshed every 5 minutes through remote alert alarm system monitoring of the dialysis machines that are actively treating patients, allowing the attending staff to easily determine the location of individuals undergoing critical care dialysis throughout the hospital.Adding beneficial features to existing equipment by marrying technologies gives end users greater rewards and has the potential to increase patient safety. Melding current technology to create a new paradigm in dialysis machine alarm response by integrating WIFI with phone communication is a novel solution for enhancing patient safety. Unresolved dialysis alarms can lead to dire consequences for patients, and approaches to minimize risk are desired. Using SLED-RCA for continuous kidney replacement therapy combined with the remote alert alarm system alert approach has produced very few problems in the last 6 years, and our institution will continue to dynamically monitor and optimize these systems for delivering excellent care for patients who need dialysis.Our quality improvement assessment of the remote alert alarm system dialysis machine alert approach has several limitations. First, the remote alert alarm system is a convenience feature that we implemented to allow technicians to track alarms and direct them to the location and type of alarm, and we did not plan a formal research study to assess generalizable results. We were not able to measure improvement compared to the previous system since that system had not been monitored previously, and data are routinely removed from the database for technical reasons. Therefore, our results regarding perceived improvements after system implementation are qualitative. Overall, this project was a technological enhancement of a communication system, and our findings are mainly anecdotal.Implementation of the remote alert alarm system as a remote alert system for monitoring dialysis machine alarms may increase technician efficiency and may be a way to reduce the time for responding to machine alarms. The remote alert alarm system may also save nursing time and prevent potentially dangerous situations from evolving, since it eliminates several tasks that nurses previously had to perform when responding to dialysis machine alarms. A remote real-time system for alerting hemodialysis technicians about machine issues may allow health care providers to be more responsive to alarm situations and expedite resolutions, reducing noise in the ICU and reducing patient risk while improving clinical care.


Race, as a social construct without a clear genetic underpinning, is frequently referenced in medicine as predictor of multiple diseases including that of infertility. The authors will discuss how systematic racism can have downstream consequences ranging from overt physician bias to use of medical algorithms that may potentiate the same disparities they attempt to narrow. Then, the authors explore the utility and pragmatic use of genetic ancestry to estimate disease prevalence, instead of racial categories. Finally, the authors explore how health inequities, rooted in systematic racism, can influence disease heritability effectively advocating for research to disentangle the contributions of racism to genetic susceptibility in infertility. As recently as 2020, the American Medical Association (AMA) voted to adopt policies underscoring race as a socially constructed category . This acWhen providers use race or ethnicity to withhold or alter treatment, whether consciously or not, they become conduits of the racism that perpetuates disparities in medicine. Overt racism is less accepted in modern medicine; however, false beliefs of biological differences based on race often conceal unconscious bias and perpetuate the influence of racism in medicine. Hoffman et al. found at least 50% of residents and medical students held at least one false belief regarding biologic differences between White and Black Americans. Medical trainees with a greater number of false beliefs were less likely to recommend the appropriate treatment for Black patients in this fictional case study . Direct In an era of increased algorithms, tools to quickly identify patients who may be at risk for an adverse outcome have emerged. Several of these tools utilize race and ethnicity to determine risk stratification, which has in many cases resulted in an inadvertent disparity of healthcare delivery. The most notable in the field of women’s health is the vaginal birth after cesarean (VBAC) risk calculator. When used, self- or provider-reported Black race or Hispanic ethnicity decreased one’s probability of a successful live birth. Thus, these women would be less likely offered the opportunity for VBAC. This decrement was comparable to the net benefit one could gain with a history of a prior vaginal delivery or VBAC . SimilarAccepting these limitations yet understanding the desire for evidence-based treatment algorithms, is there ever a time where race/ethnicity should be considered? The answer to this is — well — yes. However, instead of highlighting racial and ethnic differences, the focus should be shifted towards identifying ancestral markers that influence disease prevalence. The limiting factor in the use of race as a surrogate marker for genetic ancestry is that in most studies, including those reflected in reproductive medicine, race is self-reported. Kaseniit et al. found self-reported race was an imperfect proxy for genetic ancestry as roughly (only) 9% of patients who underwent genetic testing were found to have concordance between their genetic ancestry and self-reported race. Concordance was lowest among those who self-reported Middle Eastern, Ashkenazi Jewish, and Southern European descent . FurtherCertain diseases like endometriosis and PCOS have increased heritability within families but how it applies to self-reported racial groups may need to be reexamined. Other reproductive health diagnoses, such as uterine fibroids, have stronger ties along self-reported racial groups, but this is more likely a consequence of genetic ancestry than physical attributes of race. Keaton et al. investigated genetic ancestry proportions for populations clustered into six geographic groups and found northern European ancestry to be protective against fibroids while west African ancestry typically conferred increased risk of fibroid prevalence among Black and White women . SimilarFinally, we are only just beginning to understand the degree to which environmental exposures influence transgenerational health. Diethylstilbestrol (DES) is an endocrine disruptor that is a well-known transplacental pathogen. Exposure in utero leads to increased risks for reproductive tract anomalies, infertility, and clear cell adenocarcinoma. However, third-generation women exposed have been shown to have an increased risk of preterm birth and menstrual irregularities as compared to their counterparts, suggesting long-term effects that permeate multiple generations . ThroughHealth inequities exist in a complex, multi-factorial environment and are related to differences in access to care, differences in resources that promote health, and yes, due to the impact of systematic racism that is pervasive in the USA. Simply reporting health disparities is not enough anymore—arguably, it was never enough. Research needs to focus on how genetic ancestry may affect a population’s disease susceptibility and can be effectively and equitably used to identify prevention and treatment strategies. Tools to validate one’s risk using ancestral markers must originate from unique populations to increase their generalizability and subsequent clinical utility. Meanwhile, all fields of medicine must take a stark look at systematic inequities and work to dismantle them. Now is the time to move beyond our traditional categorizations of humans, steeped in division and hierarchy, and to some extent rooted in white supremacy and patriarchy, to discover new paradigms for improving health and medical care for all.


To date, projections of human migration induced by sea-level change (SLC) largely suggest large-scale displacement away from vulnerable coastlines. However, results from our model of Bangladesh suggest counterintuitively that people will continue to migrate toward the vulnerable coastline irrespective of the flooding amplified by future SLC under all emissions scenarios until the end of this century. We developed an empirically calibrated agent-based model of household migration decision-making that captures the multi-faceted push, pull and mooring influences on migration at a household scale. We then exposed ~4800 000 simulated migrants to 871 scenarios of projected 21st-century coastal flooding under future emissions pathways. Our model does not predict flooding impacts great enough to drive populations away from coastlines in any of the scenarios. One reason is that while flooding does accelerate a transition from agricultural to non-agricultural income opportunities, livelihood alternatives are most abundant in coastal cities. At the same time, some coastal populations are unable to migrate, as flood losses accumulate and reduce the set of livelihood alternatives . However, even when we increased access to credit, a commonly-proposed policy lever for incentivizing migration in the face of climate risk, we found that the number of immobile agents actually rose. These findings imply that instead of a straightforward relationship between displacement and migration, projections need to consider the multiple constraints on, and preferences for, mobility. Our model demonstrates that decision-makers seeking to affect migration outcomes around SLC would do well to consider individual-level adaptive behaviors and motivations that evolve through time, as well as the potential for unintended behavioral responses. Sea-level change (SLC)—including sea-level rise (SLR) and associated extreme sea levels—will drive human migration from vulnerable coastlines to the safer interior  by threaCurrent estimates of coastal migrants fail to capture the dynamic, complex relationships between migration and the gradual changes in the landscape caused by SLC , 4 creatFuture projections of SLC driven migration must contend with a stalemate between a seemingly endless set of behavioral responses to SLC impacts and a lack of data on potential responses. Most estimates navigate this challenge by assuming a straightforward relationship between populations exposed to SLC and migration . With feimmobility of coastal populations. First of all, as SLC risk intensifies, a greater abundance of coastal livelihood opportunities in rural agricultural and urban labor markets may nevertheless attract migrants toward high-risk coastal areas, compared to safer, inland areas  . VulneraOur results identify two important groups of agents: (a) those inclined to move to the coastal districts ; and (b) people who are unable to find an affordable, improved alternative livelihood portfolio elsewhere, who we might describe as ‘immobilized.’ We employ a random-forest algorithm to identify the parameters that best explain differences in the size of these groups across our experiment , with SLAccess to credit is the greatest impediment for those who find it difficult to leave coastal districts, supporting the growing evidence that liquidity constraints inhibit mobility , 15. incTo gauge understanding of the drivers of this phenomenon, we explore what are the characteristics of these ‘immobilized’ agents in the context of rising access to credit. While they do not differ behaviorally by their risk preferences  or discoThe mechanisms we identify are spatially overlapping. Districts with the greatest net in-migration coincide with districts having the greatest percentage of ‘moored’ populations, with this relationship significantly stronger (more highly correlated) in coastal districts than in interior districts . Livelih3.Our principal finding that flood impacts on income are not sufficient to drive out-migration from coastal districts by 2100 runs counter to common narratives about SLC and migration, and to some existing findings on distress migration from the coast , 41. It In a context where agricultural activities can be easily adapted but there are significant land market frictions (i.e. access to land is not so open), our model provides a plausible counter-narrative to the strong literature expectation for livelihood transitions under projected SLR scenarios, and identifying the specific mechanisms that drive these model outcomes, namely access to credit and experience of flooding. Access to credit reinforces the role of credit in poverty reduction and speaks to the impact that policy responses to hazards can have on mobility and vulnerability. Future migration modeling exercises could thus be improved by including assumptions on potential policy responses, including the provision of grants to buffer enterprises against natural disasters , 43 or pceteris paribus examination of the effects of flooding on individuals via damages to income streams, holding the broader macro-economy constant. Should coastal risk in a future Bangladesh lead the economic sectors that are driving current coastal opportunities to relocate elsewhere, our findings would likely differ  to make realistic estimates about the future. Second, we have highlighted the need for better quantitative data on how people adapt to shocks, and how quickly the unexpected can become the norm. Finally, since we cannot experiment on vulnerable populations, we need models that provide realistic expectations about policy responses and how they might influence access to credit and livelihood opportunities, both now and dynamically in the future. While we can speak qualitatively of plausible future pathways, our capacity for prediction is limited without better efforts at assembling relevant data particularly on thresholds of exposure, and interpretations of risk , as wellThe dominant narrative is that inundation from SLC will lead to large-scale displacement and migration from coastal areas. However, our results show that the opposite is as well plausible for Bangladesh: the economic amenities of coastal areas could lead to continued in-migration despite SLC flooding. Further, our results show that while the accumulated damage of SLC to livelihoods may eventually undermine people’s ability to move away, immobilizing many coastal in-migrants in increasingly hazardous coastal areas, there are other factors behind staying in place that need to be disentangled. Migration, when it takes place, is associated with experience of flooding, showing that people have their own thresholds to risk and damage that are eventually exceeded. Thus, simple inundation-migration models, by failing to incorporate the livelihood context and behavioral responses, miss these important dynamics. Rather than SLC creating out-migration, our results show how livelihood diversification and access to credit could plausibly help a growing coastal population continue to adapt against its negative impacts on agricultural productivity.Supp Materials


Dear Editor, The authors have used novel statistical methods to demonstrate geometric changes in the mediastinum following coronary artery bypass grafting (CABG) surgery.We have read with interest the article “Retrosternal Deformations after Coronary Artery Bypass Surgery Using Statistical Shape Analysis” by Bademci et al.. Another technique that produces less inflammation is the mini-extracorporeal circulation (MECC) during CABG. Therefore, postoperative adhesions and scar tissue formation could be attenuated in patients who are revascularized with off-pump CABG or using MECC.The authors conclude that, following CABG, “the main pulmonary artery approximates to the sternum” with “narrowing of the retrosternal area”. They attribute this finding to the formation of scar tissue and adhesions which are the result of inflammation associated with cardiac surgery. We would like to inquire if the authors believe operative techniques affect the geometric changes in the mediastinum. Surgeons vary greatly in their CABG techniques, choice of grafts, pericardial closure, and use of cardiopulmonary bypass (CPB). On-pump CABG may precipitate inflammatory processes more potently compared to off-pump CABGIt is also possible that CPB times, blood transfusions, perioperative medications, and patient factors affect the amount of inflammatory response in the postoperative period. Data related to CPB and other factors that induce inflammation in the patient group in the study may be relevant. The cannulation strategy is also important, as central arterial cannulation may result in more retrosternal adhesions than femoral cannulation. The placement of a pulmonary vent catheter and the extent of tissue dissection around the pulmonary artery may influence the adhesions present in the postoperative period.. If the authors can identify a cohort of patients who had chest computed tomography before and after surgery, their methods can be applied to distinctly assess the effect of CABG surgery on retrosternal adhesions. This would also allow controlling or comparing other important factors in inflammation.For their statistical shape analysis, the authors have compared patients with previous CABG with a control group without a history of cardiac surgery. In our opinion, this overlooks interpersonal geometric differences in mediastinal anatomy. The size of the great vessels can be different in the population of patients who require cardiothoracic surgery than individuals who did not require an operation. Comorbidities accompanying heart diseases, including, but not limited to, aortic enlargement or elevated pulmonary pressure increasing great vessel diameters, may complicate the comparison of retrosternal distanceWe congratulate the authors for their study in the underexplored field of retrosternal adhesions in cardiac surgery. The findings from this study can guide cardiac surgeons who face the perils of retrosternal adhesions in redo operations.


Prostate cancer is a heterogeneous disease with variable clinical outcomes. Despite numerous recent approvals of novel therapies, castration-resistant prostate cancer remains lethal. A “real-world” clinical-genomic database is urgently needed to enhance our characterization of advanced prostate cancer and further enable precision oncology.The Prostate Cancer Precision Medicine Multi-Institutional Collaborative Effort (PROMISE) is a consortium whose aims are to establish a repository of de-identified clinical and genomic patient data that are linked to patient outcomes. The consortium structure includes a (1) bio-informatics committee to standardize genomic data and provide quality control, (2) biostatistics committee to independently perform statistical analyses, (3) executive committee to review and select proposals of relevant questions for the consortium to address, (4) diversity/inclusion committee to address important clinical questions pertaining to racial disparities, and (5) patient advocacy committee to understand patient perspectives to improve patients’ quality of care.The PROMISE consortium was formed by 16 academic institutions in early 2020 and a secure RedCap database was created. The first patient record was entered into the database in April 2020 and over 1000 records have been entered as of early 2021. Data entry is proceeding as planned with the goal to have over 2500 patient records by the end of 2021.The PROMISE consortium provides a powerful clinical-genomic platform to interrogate and address data gaps that have arisen with increased genomic testing in the clinical management of prostate cancer. The dataset incorporates data from patient populations that are often underrepresented in clinical trials, generates new hypotheses to direct further research, and addresses important clinical questions that are otherwise difficult to investigate in prospective studies. Despite advances in treatment, the median overall survival from onset of metastatic castrate-resistant prostate cancer (mCRPC) remains dismal . In thisThe approvals of PARP inhibitors make it imperative to obtain somatic sequencing for all men with advanced prostate cancer. In addition, germline testing is also recommended for all men with metastatic prostate cancer per National Comprehensive Cancer Network guidelines, and in selected men with localized disease based on clinical risk and histologic subtypes as well as family history . In factThe Prostate Cancer Precision Medicine Multi-Institutional Collaborative Effort (PROMISE) is a consortium of academic cancer centers with the goal of better defining the clinical-genomic features across the entire prostate cancer disease spectrum. Herein, we outline the rationale, design, and objectives of our multi-institutional, retrospective clinical-genomic database of advanced prostate cancer patients that addresses this important need.SPOP mutations and ETS family gene fusions . S–9. S6–9] fusions . The mosectively . Additioes (~5%) , 9. Thessistance . StructuSPOP gene and WNT pathway are associated with lower rate and longer time to castration resistance [In metastatic hormone-sensitive prostate cancer (mHSPC), treatment options have rapidly expanded, yet decision-making is based mainly on clinical factors without integration of genomic biomarkers. A recent study describes potential biomarkers of disease aggressiveness . Specifisistance . FurtherOur understanding of the molecular landscape of advanced prostate cancer provides a platform for the development of targeted therapies, and for optimizing therapeutic combination strategies and sequencing. Excitingly, intense investigation is already taking place to leverage this knowledge and expand therapeutic options for men with advanced prostate cancer. Increasingly, genomic sequencing is also becoming a pre-requisite for clinical trials, thus availability of routine genetic testing becomes imperative to ensure patients have access to biomarker-driven therapies and clinical trials.BRCA1/2 and ATM, which may predict for sensitivity to PARP inhibitors and platinum agents [BRCA1/2. Despite these approvals, many questions remain about the relevance of PARP inhibitors in patients harboring non-BRCA HRR genes. Many of these questions can be answered with a real-world database such as PROMISE. In addition to PARP inhibitors, exceptional responses to platinum-based chemotherapy have also been observed in BRCA2-mutant CRPC cases [CDK12 loss, which has shown to correspond with high focal tandem duplications and high neoantigen burden, potentially sensitizing CDK12-altered tumors to immune checkpoint blockade [ATM mutations or less common HRR gene alterations is needed.Approximately 20–25% of men with mCRPC have germline or somatic alterations involving HRR genes, such as m agents . Large cm agents . In May PC cases , 14. Howblockade –17. ThusPTEN gene (~40%), which has previously proven to be a difficult target with single agents and is associated with poor prognosis [PTEN-deficient mCRPC [PTEN loss, compared to AR blockade alone [AKT1 gene, which occurs in about 1% of mCRPC patients. AKT inhibitors exhibit clinical activity in AKT-mutated breast cancer and other solid tumors [PIK3CA, PIK3C2B, BRAF, MAP2K1, and KRAS genes. Recently the first PI3KCA inhibitor, alpelisib, was approved for PIK3CA-mutated breast cancer [About 45% men with mCRPC harbor pathogenic genomic alterations within the PI3K pathway. The majority of alterations involving this pathway occur in the rognosis . Preclinrognosis . A phasent mCRPC . In the de alone . Anotherd tumors  and are t cancer , a develAbout 3–5% of patients with CRPC also have evidence of DNA mismatch repair deficiency (dMMR) and/or microsatellite instability (MSH)-high that are found through immunohistochemistry to evaluate for loss of MMR protein and/or DNA sequencing . These pIn addition to potential actionable alterations discussed, multi-institution clinical trials such as Targeted Agent and Profiling Utilization Registry  by American Society of Clinical Oncology highlight the aims of understanding the safety and efficacy of novel targeted agents in advanced prostate cancer and other malignancies. In addition, large registries of real-world data are being built to identify novel targets. The American Association of Cancer Research (AACR) has implemented Project GENIE (Genomics Evidence Neoplasia Information Exchange), which consist of real-world data among 19 leading cancer centers in the world. Despite the robustness of these pan-cancer platforms, the nuances of different clinical states of prostate cancer will not be captured. To complement these efforts, our consortium was developed to leverage the wealth of existing clinical-genomic data to expand our understanding of prostate cancer biology and to improve current therapeutic approaches. In the remaining sections, we highlight some key clinical questions that are present in routine practice to provide context into the design, structure, and objectives of PROMISE.The last two decades have seen significant new advancements in the treatment of metastatic prostate cancer. Much wider availability of next-generation sequencing (NGS) panels has made it possible to individualize treatment options for a subset of prostate cancer patients with specific tumor markers or alterations. These developments have created a plethora of new questions, many of which may be answered though accumulation of clinical and genomic data in a “real-world” dataset. The following examples highlight current challenges in the treatment of advanced prostate cancer as well as potential solutions and strategies to overcome barriers to the realization of the true promise of precision medicine in prostate cancer.With the evolution of multiple novel treatment options in mCRPC, including novel hormonal agents and PARP inhibitors, as well as the emergence of novel therapeutic classes such as PSMA-targeted radioligand therapies, there is increasingly a wealth of options to offer patients in a disease space where only a couple of decades ago there were relatively few , 33. In As novel treatment options are also introduced earlier in the disease course of prostate cancer, such as novel androgen receptor signaling inhibitors (ARSIs) –37, the As treatment for prostate cancer is increasingly individualized and new biological subsets are identified through increased use of NGS, it is also important to better define the natural history of these patient populations. The molecular characterization of exceptional responders and non-responders to standard of care therapies will help better define molecular predictive biomarkers. In addition, as of 2020 there are now two agents, olaparib and rucaparib, specifically approved for the treatment of mCRPC with HRR alterations  as well Many studies focusing on characterizing the molecular alterations in prostate cancer have included a very limited number of ethnically diverse subsets of patients. Understanding how race/ethnicity impacts genomic profile and response to therapy is critical to bridging the disparities gap in men with prostate cancer. Real-world data from this platform can fill this gap. Black men remain underrepresented in phase 3 trials in prostate cancer despite being disproportionately impacted by lethal prostate cancer  and despAll of the above clinical questions and scenarios in advanced prostate cancer illustrate the importance and potential utility of a large and well-maintained real-world database that serves as a repository for clinical and genomic data of prostate cancer patients. There are several pertinent reasons necessitating such a database as an important clinical research tool in advanced prostate cancer.Prospective randomized clinical trials remain the gold standard in clinical cancer research and shape the current standard of care. While prospective clinical trials capture data on efficacy, observational studies can help to better understand effectiveness of the treatments in the real-world setting. Importantly, most prostate cancer patients do not get their cancer treatment as part of a clinical trial. A recent study estimated that only about 8% of oncology patients enroll in a clinical trial . ConsequThe inclusion of underrepresented minorities in this dataset is one of the important missions of this consortium. Data from retrospective series can more extensively capture clinical outcomes and other information of more diverse populations, including minority populations underrepresented in clinical trials. The low participation rates of patients who identify as underrepresented minorities in clinical trials of prostate cancer have been well documented and remain a significant challenge in clinical research and the conduct of trials . The reaIt is also important to keep in mind that although randomized clinical trials remain the gold standard for generating clinical data, many relevant clinical questions are initially asked in hypothesis-generating retrospective studies. Important descriptive data of the natural history of disease in these specific subgroups can be obtained through retrospective chart review. Many important prognostic and predictive markers and biomarkers of interest can initially be identified through analyses of real-world data and are subsequently validated prospectively. Furthermore, in contrast to prospective clinical trials where treatment options are prespecified, retrospective observational studies can also attempt to capture clinical decision-making, such as decisions made based on the results of genomic testing. In databases with large numbers of patients and well-annotated clinical and genomic data, important insights can be gleaned from this approach.As treatments are increasingly individualized for molecularly selected subsets of patients with mCRPC, the careful collection of genomic data in large real-world cohorts can also help shed light on tumor biology and help advance questions that produce important validation studies. The availability of multiple tissue or blood samples from the same patient can also be particularly instructive. This information can help better define the evolution of molecular alterations or other biomarkers in the tumor throughout the course of disease progression. The understanding of such changes obtained from serial sampling of either repeat solid biopsies or of repeated cfDNA sampling can also help define the changes in the tumor that happen during progression on specific treatments. Further important comparisons can be drawn in the molecular alterations and other biomarkers detected in solid biopsies and cfDNA in the same patient.Overall, our long-term goal is to develop a large real-world dataset collected from institutions including both academic and large community-based hospital systems, which by definition will be both heterogeneous and also more representative of real-world trends. Clinical and genomic information from many patients who are unable or unwilling to be treated on a clinical trial due to clinical, logistical or other reasons will also be included. This will make potential findings more generalizable relative to the data obtained from carefully selected clinical trial populations. The patient population included in a real-world dataset will also reflect the diversity of treatment options and strategies employed, diagnostic and genomic testing used, and the diverse patient populations across the different geographic regions.The PROMISE consortium was formed with the recognition of the significant clinical and research needs of linking clinical and genomic data to outcomes, in order to better inform treatment decisions and outcomes for patients with advanced prostate cancer. Data collected in this consortium will address significant knowledge gaps that come about as the underlying biology of prostate cancer becomes better understood and multiple novel agents and classes of drugs emerge as treatment options. The structure of the PROMISE consortium including all of the committees and the flow chart of data analysis are shown in Fig. PROMISE is currently a consortium of 16 academic institutions with the common goal of understanding the real-world data in patients with advanced prostate cancer. The goal is to expand the reach of this database to include academic institutions and community practices. The consortium has two main aims:(1) To establish a large, diverse, inclusive, and well-annotated repository of completely de-identified clinical and genomic patient data that is linked to clinical characteristics and disease-related outcomes.(2) To investigate prognostic and potentially predictive biomarkers in patients with advanced prostate cancer treated with approved therapies including genomic, transcriptomic, and proteomic biomarkers.Inclusion criteria for patients in this dataset consist of having advanced prostate cancer with either mHSPC or castrate-resistant prostate cancer (CRPC). In addition, patients should have undergone prior germline and/or somatic tumor molecular profiling studies including, but not limited to, one or more of the following blood or tissue-based assays: tumor DNA sequencing , germline DNA sequencing and transcript profiling studies . In total, consecutive patients with available clinical and genomic data at each site will be included to limit selection bias. Clinical and treatment data is collected from the time of initial prostate cancer diagnosis Table . All datThe PROMISE consortium participating institutions are listed in Table The mission of the PROMISE consortium is to investigate the outcomes of patients with advanced prostate cancer who have genomic and molecular profiling information and therefore to bridge the knowledge gap between real-world genomic data and clinical outcomes in patients with advanced prostate cancer. Consortium structure will also provide significant opportunities for mentorship of junior investigators and trainees. The consortium will plan to pursue multiple projects addressing specific questions which are proposed by the participating site investigators and selected through scientific review by the executive committee with priority given to projects proposed by junior investigators and trainees. Given the important potential contribution of evaluating outcomes in a more diverse population than that represented in clinical trials, a subcommittee for diversity and inclusion has been created with a plan to implement strategies to increase diversity if the database fails to maintain a balanced population.In a short period of time, we have gathered vast amounts of clinico-genomic information to answer important clinical questions. We are looking forward to expand our database to include many more academic institutions and community practices to make our patient population more representative of the real-world setting. In addition, once the database becomes robust for large-scale analyses, these data may be made publicly available for future research, following efforts such as cBioportal. Lastly, there is a long-term plan to develop infrastructure for blood- and tissue biorepository to perform molecular analyses.Precision medicine holds significant promise for helping to individualize treatment approaches for patients with advanced prostate cancer and to help understand the underlying mechanisms of this heterogeneous disease. The PROMISE consortium is an important new collaboration among leading academic centers in the United States that aims to bridge the gap between clinical and genomic information for patients with metastatic prostate cancer and available genomic data from commercial and institutional assays. The well-annotated, de-identified patient data collected for this consortium will be leveraged to help answer specific questions and guide projects proposed by the consortium members. Genomic data entered into the database will be vetted by a bioinformatician and individual projects approved by the executive committee as part of the consortium structure. This organized approach will help to address important questions at the intersection of clinical and genomic data that are most optimally addressed using a real-world dataset. It is our hope that this approach will eventually help to improve outcomes for patients with advanced prostate cancer.


The Ras-Raf-MEK-ERK signaling pathway is responsible for regulating cell proliferation, differentiation and survival. Overexpression and overactivation of members within the signaling cascade have been observed in many solid cancers and especially in thyroid cancers. These members are therefore the target of inhibitory therapies, for example tyrosine kinase inhibitors or monoclonal antibodies. These drugs are already used in clinical practice, but their efficacy is not always satisfactory, and they could be subject to escape phenomenon. This is the reason why research is focusing on developing new molecules. We aimed to provide an overview of the MAPK pathway’s physiologic regulation. Furthermore, we summarized the preclinical and clinical studies including redifferentiation studies that used MAPK pathway inhibitors in thyroid cancers.BRAFV600E hotspot mutation occurring in about 60% of papillary cancers and 45% of anaplastic cancers. Therapies targeting the different protagonists of this signaling pathway have been tested in preclinical and clinical models: first and second generation RAF inhibitors and MEK inhibitors. In clinical practice, dual therapies with a BRAF inhibitor and a MEK inhibitor are being recommended in anaplastic cancers with the BRAFV600E mutation. Concerning RAIR-TC, these inhibitors can be used as anti-proliferative drugs, but their efficacy is inconsistent due to primary or secondary resistance. A specific therapeutic approach in thyroid cancers consists of performing a short-term treatment with these MAPK pathway inhibitors to evaluate their capacity to redifferentiate a refractory tumor, with the aim of retreating the patients by radioactive iodine therapy in case of re-expression of the sodium–iodide symporter (NIS). In this work, we report data from recent preclinical and clinical studies on the efficacy of MAPK pathway inhibitors and their resistance mechanisms. We will also report the different preclinical and clinical studies that have investigated the redifferentiation with these therapies.Thyroid cancer is the most common endocrine cancer, with a good prognosis in most cases. However, some cancers of follicular origin are metastatic or recurrent and eventually become radioiodine refractory thyroid cancers (RAIR-TC). These more aggressive cancers are a clinical concern for which the therapeutic arsenal remains limited. Molecular biology of these tumors has highlighted a hyper-activation of the Mitogen-Activated Protein Kinases (MAPK) pathway (RAS-RAF-MEK-ERK), mostly secondary to the  Thyroid cancer (TC) is the most frequent endocrine cancer with 586,202 new cases worldwide in 2020 , with inBetween 90 and 95% of TC derives from thyroid follicular epithelial cells, whereas the remaining develops from C cells resulting in medullary thyroid cancers. Therefore, TCs of follicular origin can be histologically classified into four main groups according to the recent 2022 WHO classification of thyroid neoplasms . Both arBRAF, of which the most frequently found genetic event is the BRAFV600E hotspot mutation. This mutation is present in 60% of PTCs ) who were randomly assigned 2:1 to selumetinib or placebo for approximately 5 weeks followed by 3.7 GBq RAI-therapy. The effectiveness of this approach was not demonstrated as no statistically significant difference in complete response rate 18 months after RAI was found  . HoweverV600EBRAF is the most common molecular alteration in thyroid cancers and is associated with tumor aggressiveness and poor prognosis because of the continuous activation of the MAPK pathway leading to cell proliferation and survival.Therapies targeting key players of the MAPK pathway such as RAF and MEK have shown encouraging results in thyroid cancers, but less impressive than in melanoma where the MAPK pathway is also at the basis of oncogenesis. It is therefore necessary to understand differences in efficacy observed between thyroid cancers and other cancers with activation of the MAPK pathway, as well as mechanisms of resistance to MAPKi.Drug resistance can occur due to genomic instability with the proliferation of pre-existing resistant clones harboring intrinsic mutations or the occurrence of new genetic and epigenetic alterations, which often activate molecules up/downstream from the MAPK pathway. Several other resistance mechanisms have been identified and induce a MAPK pathway paradoxical activation or the recruitment of another proliferation signaling pathway.There is therefore a growing need to develop and test in preclinical studies new molecules targeting the MAPK pathway, such as pan RAF inhibitors, RAS or ERK inhibitors. There is also a necessity to explore drug combinations as novel strategies to overcome single-agent-induced resistance. These combinations could include multiple MAPKi or one MAPKi with a promising drug targeting another proliferation pathway or counteracting a specific mechanism of secondary resistance.Clinical studies must test molecules which show promising results in preclinical studies, with a rigorous methodology and try to include a large number of patients.The redifferentiation strategies are very original and could be useful in thyroid cancers, particularly in refractory metastatic diseases or as adjuvant therapy in diseases at high risk of recurrence. These strategies provide a combined and perhaps synergic antitumor effect of the targeted therapy and the RAI-therapy. One of the major challenges is to first identify cancers accessible to these strategies and then to choose the most effective inhibitor or combination of drugs that will be used. Thyroid cancers not accessible to redifferentiation strategies must be studied as a separate entity and be better characterized at the molecular level.


Swimming and other recreational water activities at public beaches are popular outdoor leisure activities among Canadians. However, these activities can lead to increased risks of acquiring acute gastrointestinal illness and other illnesses among beachgoers. Young children have much higher rates of exposure and illness than other age groups. These illnesses have a significant health and economic burden on society. Climate change is expected to influence both the risk of exposure and illness. A warming climate in Canada, including more severe summer heatwave events, will likely lead to increased recreational water use. Warmer temperatures will also contribute to the growth and increased range of harmful algal blooms and other climate-sensitive pathogens. Increased precipitation and heavy rainfall events will contribute to fecal and nutrient contamination of beach waters, increasing risks of gastrointestinal illness and harmful algal bloom events. There is a need to enhance recreational water research and surveillance in Canada to prepare for and adapt to these changing risks. Key research and policy needs are suggested and discussed, including evaluating and monitoring risks of recreational water illness in Canadian contexts, improving timely reporting of recreational water quality conditions, and enhancing approaches for routine beach water surveillance. Swimming and other recreational water activities  at public beaches are increasingly popular summertime activities in Canada. For example, a national survey in 2015 found that nearly 30% of Canadians reported engaging in any recreational water activities in the prior 7-day period in the summer  are associated with an elevated risk of various illnesses, particularly acute gastrointestinal illness (AGI), among beachgoers  is under-reported and under-diagnosed in Canada, as those with self-limiting illness may not seek medical attention or submit samples for diagnosis, and illnesses may be misattributed to food-borne exposures. These illnesses have a significant burden and cost to society. Although we lack RWI burden data in Canada, approximately 90 million cases are estimated to occur in the US each year, costing US$2.2–3.7 billion annually  are frequently associated with human sewage contamination and are the most common infectious agents responsible for RWI  in recreational freshwater bodies are commonly reported in Canada due to the growth of photosynthetic cyanobacteria. HABs due to cyanobacteria are a public health concern because they can produce various cyanotoxins and contain cell-surface endotoxins that can lead to human exposure through water ingestion, inhalation of aerosols, or skin contact . PAM is a rare but usually fatal brain infection that results from recreational water exposure to the amoeba. An analysis of cases in the US from 1978 to 2018 found a northward expansion of PAM cases and an association with higher ambient air temperatures  and HABs  for enterococci in beach water . This information can be used to target pollution prevention efforts (Edge et al.,


Body dysmorphic disorder (BDD) is a highly complex mental disorder, which is characterized by preoccupation with one more perceived flaw in the individual’s appearance. It often results in repetitive behavior strategies to hide, check, or alter these flaws causing massive distress and impairment as well as low quality of life . Recent There is sound evidence that cognitive behavioral therapy (CBT), besides pharmacological therapy with high-dose selective serotonin reuptake inhibitors (SSRIs), is the first line of treatment showing good effects in symptom reduction . BesidesThe following model  incorporBesides relying solely on symptom severity it might be helpful to take a closer look at aspects that facilitate or hinder therapy processes. Massive social avoidance and isolation may be a factor that enormously obstructs outpatient treatment, leading to a situation where core treatment elements such as behavioral experiments and exposure as well as mirror confrontations, etc., may not be possible. Furthermore, complex symptomatology and complex comorbidities  that require specific differential diagnosis or a multi-professional treatment approach  suggest an inpatient setting. In cases of frequent self-harm or suicidal ideation, a more secure and stabilizing therapy setting seems appropriate. Finally, living conditions that help to maintain BDD symptoms such as high family accommodation or ongoing bullying or criticism urge the removal of the patient from these surroundings and place them in a more constructive environment.We highly recommend taking the inpatient setting into consideration, as it provides the chance for an intensive and multi-professional treatment approach and offers patients the chance to encounter other BDD patients which have proven to be very useful in our clinical experience. Specific and intensive therapy might help to save resources and lower treatment costs in the long run and prevent patients and healthcare professionals from recurring unsuccessful outpatient therapies.Overall, this requires more specialized treatment settings with specialized centers, both out- and inpatient, which focus on body dysmorphic disorders, incorporating psychological, psychiatric, and psychodermatological competencies, as well as close cooperation between dermatologists, psychologists, and psychiatrists and a thorough screening and assessment process.CS conceptualized and wrote the manuscript and developed the suggestions for differential criteria on in- and outpatient treatment. K-MT substantially contributed ideas and reflection on the manuscript and added ideas on clinical implications. Both authors contributed to the article and approved the submitted version.