The HPA connections and brain areas implicated in ELS and psychopathology are also explored. In a targeted review of HPA activation in mood and psychotic disorders, cortisol is generally elevated across mood and psychotic disorders. However, in bipolar disorder and psychosis patients with previous early life stress, blunted cortisol responses are found to awakening, psychological stressors and physiological manipulation compared to patients without previous early life stress. These attenuated responses occur in bipolar and psychosis patients on a background of increased cortisol turnover. Although cortisol measures are generally raised in depression, the evidence for a different HPA activation profile in those with early life stress is inconclusive. Further research is needed to explore the stress responses commonalities between bipolar disorder and psychosis in those patients with early life stress.Studies of early life stress (ELS) demonstrate the long-lasting effects of acute and chronic stress on developmental trajectories. Such experiences can become biologically consolidated, creating individual vulnerability to psychological and psychiatric issues later in life. The hippocampus, amygdala, and the medial prefrontal cortex are all important limbic structures involved in the processes that undermine mental health. Hyperarousal of the sympathetic nervous system with sustained allostatic load along the Hypothalamic Pituitary Adrenal (HPA) axis and its connections has been theorized as the basis for adult psychopathology following early childhood trauma. In this review we synthesize current understandings and hypotheses concerning the neurobiological link between childhood trauma, the HPA axis, and adult psychiatric illness. We examine the mechanisms at play in the brain of the developing child and discuss how adverse environmental stimuli may become biologically incorporated into the structure and function of the adult brain  Alterations of the hypothalamic–pituitary–adrenal (HPA) axis is one of the most notable neurobiological findings in psychiatry , 2. HoweIn this review, we explore the developmental trajectory of the child and the psychopathological consequences of early childhood trauma. We also discuss the normal HPA-axis stress response and a targeted review of HPA-related findings in mood disorders and psychosis.Stress may be classified into three distinct categories . “PositiVarious tools designed to assess adverse childhood experiences of stress and trauma exist . Using tEpidemiological studies have shown a moderate to high prevalence of childhood trauma across populations. In the United Kingdom, 16% of children report having experienced trauma , but figAccording to the neurosequential model , the devImplications of the neurosequential model indicate that throughout human development, there are periods when certain biological systems are more malleable in response to environmental stimuli. These sensitive periods can be defined as time frames (or windows) during which developmental systems are vulnerable to certain stimuli , 19.To demonstrate the importance of sensitive periods it is important to first understand how they operate. A sensitive period is triggered by intense neural activity initiated by an experience . This phAccording to the first view, maturational and/or environmental factors cause neurochemical changes in certain brain areas which increase the rate of pruning leaving strong existing patterns in full functional capacity. Areas with strong synaptic connectivity become permanently linked, and therefore indicate the end of a sensitive period. Several sensitive periods appear to end as an animal (or human) approaches sexual maturity . For insThe second view proposes that the process of learning may produce changes in the brain that reduce the system's overall plasticity . StudiesThe third view suggests that plasticity does not reduce but rather the constraints of plasticity become stable. For example, Thomas and Johnson  describeA further conceptual model known as the “stress acceleration model” argues that experiences of toxic stress or trauma may lead to faster (or accelerated) maturation of the neural circuits responsible for emotional processing and is therefore evidence of early system adaptation . The modRecent work has also explored the possibility of “reopening” sensitive periods. For example, MDMA has been found to reopen a striatal-sensitive period involved in social reward learning in rodents . FluoxetThe human response to a threat results in hyperarousal; facilitated by the sympathetic nervous system. This hyperarousal can be viewed on a continuum, including states of calmness to arousal to alarm, fear, and terror – this final stage commonly referred to as the “fight, flight or freeze” response . HyperarThe HPA axis represents the major neuroendocrine stress response system that serves to adapt an organism to demanding change. The release of Corticotropin Releasing Hormone (CRH) by the hypothalamus induces alertness and increased attentional capacity. CRH prompts the release of adrenocorticotropic hormone (ACTH) from the pituitary, which subsequently induces the secretion of adrenal cortisol and cortisone. Under normal conditions, cortisol is released with a distinct diurnal rhythm, characterized by levels increasing during the night just prior to waking, a transient acute spike in release following awakening (the cortisol awakening response), followed by a steady decline throughout the day until sleep. Physical or psychological stressor also induces a temporary spike of cortisol . In contA potential mechanism underlying the mediating effects of adverse experiences during childhood on adult psychopathology has been seminally modeled in McEwen's  theory oPituitary volume changes have been reported in MDD with both increased , 47, redAlthough the HPA axis is regulated internally through negative feedback loops withing the axis itself, it is also recieves dense connections from brain regions involved in the processing of stress. This regions in include the limbic system and medial prefrontal cortex (mPFC) .The Limbic System is a group of interconnected brain regions involved in emotion, memory.and behavior . The amyThe amygdala lies anterior to the hippocampus in the medial temporal lobe and consists of three functional nuclear divisions: the central, basolateral, and corticomedial groups. The HPA axis is largely influenced by the central and corticomedial groups which project in abundance to the hypothalamus. Lesions to these groups have been shown to reduce ACTH and corticosterone secretion following stress , 67. StiInduced early life stress has been associated with amygdalar hypertrophy in primates , with inThe hippocampus inhibits the HPA axis through its fornix outputs to the hypothalamus , 63, 64.Reduced hippocampal volumes is the most reported finding in MDD –103 inclIn contrast, reduced hippocampal volume is an established finding in schizophrenia , 112–117The medial prefrontal cortex (mPFC) regulates the response of the amygdala by processing additional sensory information experienced during a traumatic event . StructuChildren diagnosed with preschool onset MDD have reduced right ventromedial PFC volume compared to controls . Many stThe process of HPA axis sensitization to stress as a result of childhood trauma may occur long before adulthood. Dysregulated cortisol responses are detectable in adolescents with a history of child abuse  and expoA wide disparity exists across studies investigating HPA axis reactivity in adolescents who have experienced childhood trauma. While some studies report hyperactivation of the HPA axis in response to stress  others rAn important question remains, will these findings generalize to adult sensitization and will such sensitization result in psychopathology? A retrospective review of current rodent models shows promising results in favor of this relationship. Recreations of early life neglect  in rodent offspring have allowed for insight into the potential long-term biological and behavioral effects of trauma. Neglected rodent offspring have shown increased susceptibility to anxiety and depressive-like behaviors when exposed to stress in both adolescence and adulthood , 146. SiEarly life stress (ELS) due to childhood abuse and/or neglect has been linked to increased risk of psychiatric illness onset and recurrence, increased disease severity and poor treatment response (pharmacotherapy and psychotherapy) , 149. ThMDD and BD are the most common mood disorders and are both associated with poor life quality, increased disability, and mortality . In the A case-control study found that childhood trauma severity was not associated with high diurnal salivary cortisol  in currently depressed MDD patients with although this association was present in patients with glucocorticoid resistance . AnotherA meta-analysis of 651 depressed children and adolescents found greater basal cortisol levels in MDD children and adolescents compared to controls . Higher An increase in CAR in those with childhood neglect has been found irrespective of a diagnosis of MDD , 165. NoLower cortisol and ACTH responses were shown following the TSST in children with comorbid MDD and PTSD; however, adults with PTSD commencing in adulthood and those with social anxiety disorder (SAD) showed no differences. When HPA axis feedback was measured through metyrapone challenge, no differences in cortisol levels were found . In contN = 388) revealed higher cortisol post DST in a metaanalysis. Conversely, cortisol and ACTH levels post-CRH infusion were non-significant between groups  found a small to medium increase in morning cortisol concentration in patients compared to controls  found that the response was lessened in patients with psychosis compared to healthy controls (n = 180), patients demonstrated a blunted response compared to controls, with males in particular revealing lower cortisol AUCi and AUCg following stressors  who had a history of childhood maltreatment (n = 63) with childhood trauma compared to those without trauma , cortisol was elevated in a study of patients with schizophrenia (reatment . Similart trauma .n = 33), a family history of psychosis (n = 22), or typically developing children (n = 40), no association was found between the CAR and the numbers of negative life events in any group (n = 25) demonstrated a blunted response to a psychosocial stressor  compared to controls (n = 25) (n = 40) and controls (n = 34) found that cortisol concentrations reduced in patients and increased in controls following the task   with patthe task . In thosThe relationship between early life stress (ELS), Hypothalamic Pituitary Adrenal (HPA) axis activity and psychiatric illnesses is complex. The development of the brain during childhood involves sequential and heirarchical development of brain regions and is susceptible to biological and psychological insults, particularly during developmentally sensitive periods. Toxic stress from childhood adversity may result in sympathetic hyperarousal through sustained allostatic load along the hodological associations of the HPA axis. Such connections include limbic structures involved in memory, behavior and emotion such as the hippocampus, amygdala and the medial prefrontal cortex. Inconsistencies exist in the literature regarding the hyperactivation of the HPA axis in adolescents who experienced childhood trauma. As such, it is thought that HPA axis changes may specific to the trauma subtype being studied, with further research needed in the domain.Our targeted review of the literature surrounding mood disorders and psychosis suggests that cortisol concentration is raised across psychiatric disorders. However, both bipolar disorder (BD) and psychosis is associated with more attenuated HPA responses to awakening (the cortisol awakening response), psychologicial stressors  and physiological manipulation  in those patients who have experienced early life stress compared to those who have not. These reduced cortisol responses in BD and psychotic patients exist on a common background of increased long term cortisol and cortisol turnover. This suggests a hyperfunctioning HPA axis with little reserve remaining for a robust cortisol response to extra stress. The evidence from our targeted review for a similar effect in depression (MDD) is equivocal, despite the signficantly larger number of studies examining early life stress and HPA changes in MDD.Psychosis and BD share a number of commonalities in their biological basis. Psychosis is often a feature of mania in Type 1 BD  . Common Structural abnormalities common to both BD and schizophrenia have also been observed on neuroimaging. Diffusion studies of the uncinate fasciculus  connect have shoIn conclusion, the effect of the early life stress on the developing brain is highly complex and dependent on unique characteristics such as individual vulnerability, developmental sensitivity window, stressor type and duration. The suggestion of a common HPA profile in both BD and psychosis but not depression from our targeted review needs verification with large carefully conducted robust metaanalyses of daily cortisol concentrations and cortisol responses across these disorders.AN, FM, DC, KR, AG, and ER: writing, editing, and formatting manuscript. VS, LK, AO, and MH: proofreading and editing. DR and MC: leading the group, writing, editing, and formatting manuscript. All authors contributed to the article and approved the submitted version.The work was funded by iHEAR study - MC.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. 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Overdose-associated deaths and morbidity related to substance use is a global public health emergency with devastating social and economic costs. Complications of substance use are most pronounced among people who inject drugs (PWID), particularly infections, resulting in increased risk of hospitalization. PWID often require intravenous access for medical treatments such as antibiotics; however, vascular access may be limited due to the impacts of long-term self-venipuncture. While vascular access devices including peripherally inserted central catheters (PICCs) allow reliable and sustained routes of administration for indicated therapies, the use of PICCs among PWID presents unique challenges. The incidence and risks associated with self-injecting non-prescribed substances into vascular access devices (SIVAD) is one such concern for which there is limited evidence and absence of formal practice guidance.We report the experience of a multidisciplinary team at a health organization in Vancouver, Canada, working to characterize the incidence, patient and healthcare provider perspectives, and overall impact of SIVAD. The case study of SIVAD begins with a patient’s perspective, including patient rationale for SIVAD, understanding of risks and the varying responses given by healthcare providers following disclosure of SIVAD. Using the limited literature available on the subject, we summarize the intersection of SIVAD and substance use and outline known and anticipated health risks. The case study is further contextualized by experience from a Vancouver in-hospital Overdose Prevention Site (OPS), where 37% of all individual visits involve SIVAD. The case study concludes by describing the systematic process by which local clinical guidance for SIVAD harm reduction was developed with stakeholder engagement, medical ethics consultation, expert consensus guideline development and implementation with staff education and planned research evaluation.SIVAD is encountered with enough frequency in an urban healthcare setting in Vancouver, Canada, to warrant an organizational approach. This case study aims to enhance appreciation of SIVAD as a common and complex clinical issue with anticipated health risks. The authors conclude that using a harm reduction lens for SIVAD policy and research can provide benefit to clinicians and patients by offering a clear and a consistent healthcare response to this common issue. Vancouver, British Columbia, Canada, with a metropolitan population of 2.5 million in a province of 4.7 million people, is facing a public health emergency of drug overdose and associated death . In 2021Many of these bacterial infections require ongoing intravenous (IV) medications and vascular access devices (VADs). Peripheral intravenous catheters and peripherally inserted central catheters (PICCs) are clinically indicated in these circumstances. A PICC is often used when vascular access is limited or IV medications such as antibiotics are required for several weeks. Traditional peripheral VAD options may be limited in some PWID as a result of chronic venous disease induced by years of self-venipuncture, making PICCs an important (and sometimes necessary) consideration when protracted IV therapy is required .Clinicians caring for patients who use substances in hospital and community settings, including Overdose Prevention Sites (OPS) and Supervised Consumption Sites (SCS) , may encThis paper describes a case study at Providence Health Care (PHC), an organization in Vancouver, British Columbia, where SIVAD is encountered with relative frequency. It begins with an exploration of SIVAD from the perspective of an individual patient, followed by data collected from a local Vancouver OPS and a review of the available literature in an attempt to characterize the clinical context, incidence and anticipated risks of SIVAD. The case study concludes by describing the systematic efforts of a multidisciplinary team in Vancouver to create and implement a local nursing clinical practice guideline and associated education and research plan around harm reduction approaches to SIVAD.The authors also discuss current knowledge gaps and controversies around the medical, ethical and legal legitimacy of harm reduction for SIVAD and applicability of the Vancouver approach to other national and international contexts. This paper’s aim is to enhance the clinical understanding of SIVAD and through transparent shared experience, encourage other healthcare teams to develop and research SIVAD-related practices that are appropriate for their local context.This descriptive case study is comprised of multiple related research efforts sharing a common research objective: understanding SIVAD practice and impact at our health organization to inform development and implementation of related policy and practice. Rather than having a prespecified overarching research plan and methodology, this case study integrates mixed methods of multiple related projects identified and purposefully brought together through organization-wide efforts—risk management and ethics consultations—triggered in part by incident cases of SIVAD. The methodology of individual projects is further outlined in relevant sections.Patient-centered care begins with exploring patient perspectives. As outlined in “Robin’s” case  and others unique to SIVAD . Harms may be more likely if patients are unaware of best practices around VAD care including the need for sterile technique and proper routine flushing following injection of substances , 23. TheIn the absence of formal practice guidelines, Overdose Prevention Sites (OPS) and Safe Consumption Sites (SCS) in Vancouver have developed informal harm reduction approaches to SIVAD. OPSs, like SCSs, are spaces where people can inject their own non-prescribed substances using single-use, sterile equipment. While SCSs are federally funded and have nursing staff on site, OPSs are typically staffed by peers (people with lived/living experience of substance use) and are provincially sanctioned as a temporary response to British Columbia’s drug overdose and death public health emergency , 24.At Insite, an SCS in Vancouver’s Downtown Eastside neighborhood, staff report engaging in harm reduction activities around SIVAD since 2006 and have developed an internal nursing resource covering risk education  and sterile self-injection procedures , 26. StaIn 2018, the St. Paul’s Hospital Overdose Prevention Site (SPH OPS) was opened , 28. ThiWhen the OPS initially opened, peers reported witnessing a variety of approaches to SIVAD including, but not limited to, using water from a water bottle to flush VADs, not cleaning the PICC hub prior to injection and inserting needles into the IV tubing itself as opposed to the access port . At the Due to these observed safety concerns, quality improvement measures were instituted at the SPH hospital-adjacent OPS and other Vancouver OPSs. Since 2019, peers receive standardized education on how to provide harm reduction interventions for SIVAD through a “street degree” program and OPSs stock supplies specific to SIVAD  . HospitaIn response to observed SIVAD in Vancouver acute and community care settings, as well as growing SCS/OPS experience offering SIVAD harm reduction education and supplies, a multidisciplinary healthcare team at Providence Health Care (PHC) took steps in 2018 to examine SIVAD more formally. PHC is a health organization in Vancouver that administers care to approximately 600,000 patients annually via two acute care hospitals with approximately 500 acute beds in total. The goal of this work was to develop consistency in the response to SIVAD through a practice guideline based on available evidence and expert consensus, as well as to identify SIVAD as an issue worthy of formal clinical response, education and research.Instigated by a series of distressing SIVAD incidents noted by healthcare providers , the organization’s Risk Management and Patient Safety program commissioned a SIVAD risk analysis review. A group of Infectious Diseases, Urban Health and Addiction Medicine specialist physicians, nurses, clinical ethicists and the organization’s lawyer, was assembled to discuss potential patient, healthcare provider, institutional and wider community implications of SIVAD and potential harm reduction policy interventions . A failuThe FMEA ranked priorities to be anticipated and addressed when considering policy development and monitoring. The most concerning risk anticipated to arise following harm reduction implementation was increased SIVAD rates amongst the larger community of PWID  should it be misperceived that “clinicians now condone the use of VADs for self-injection”. VAD access dysfunction was the next most concerning risk. Somewhat surprisingly, participants articulated less concerns about risk of infectious complications and overdose. This may reflect acknowledgement of baseline risks associated with IDU independent of SIVAD and an understanding that a SIVAD policy or guideline would intentionally aim to mitigate such harms.Will the organization support the development of a policy/guideline that permits clinicians’ discretion to deliver SIVAD harm reduction education and supplies to patients with substance use disorders upon request, while also allowing for conscientious objection should clinicians wish to opt out of the practice?What ethical, medical and organizational considerations ought to be considered with this approach?Building from the FMEA, a more in-depth investigation was required to explore the implications of possible practice changes around SIVAD. In November 2019, the organization’s Ethics Services program was consulted by the Urban Health program to review the following questions:Following approval from the Senior Leadership Team in February 2020, Ethics Services conducted an organizational ethics consultation that took 6 months to complete. Organizational ethics is the discipline concerned with the principles and standards by which an organization operates. It focuses on finding the “right” way to respond to complex challenges and opportunities within the communities that the organization serves . BecauseA total of 50 stakeholders were interviewed, including patients with lived/living experience of drug use/SIVAD, program leaders, physicians and nurses working in acute care or community in Vancouver, as well as clinicians at other Canadian sites. An interview question guide was developed by Ethics Services in consultation with a Clinical Nurse Educator in Substance Use. Interviews were one hour long, semi-structured, non-remunerated and occurred in person or over videoconferencing, either individually, or in small groups of up to 4 participants per participants preference. Several individuals provided information only over email. We identified stakeholders by contacting program leaders in Infectious Disease, Internal Medicine, Urban Health, Addiction Medicine, Psychiatry, IV Therapy, Risk Management, and Nursing Professional Practice. Additional stakeholders were identified during the interviews themselves (i.e. “who else should we speak to about this question?”). Stakeholder responses were organized into themes , existing organizational guidelines related to general VAD care and maintenance and information regarding strategies employed by other sites  , 35.A common concern raised by frontline nurses was potential legal liability if a nurse inadvertently flushed an IV line containing substances previously injected by a patient, resulting in patient overdose. Risk Management indicated that nurses are not liable for autonomous decisions made by capable patients, including use of substances and/or if patients experience an adverse event attributed to SIVAD. The importance of documenting an informed discussion with patients regarding risks of SIVAD was emphasized. As the organization takes a more formal harm reduction approach to SIVAD, liability coverage is in place provided nurses are practicing at the expected standard and this has been indicated within the guideline itself.The group also consulted PHC’s Nursing Professional Practice consultants and the British Columbia College of Nurses and Midwives about nursing scope of practice pertaining to harm reduction and SIVAD specifically. These bodies endorsed that harm reduction practices, including providing education and sterile supplies, are within the scope of nursing practice . ImportaThe guideline also emphasizes that nurses have the ability to exercise discretion as to whether they will provide SIVAD education and sterile supplies to patients. If nurses choose to opt-out of this practice , they are advised to transfer patient care to another clinician who can assess the patient. Nurses can also consult addiction medicine or more experienced colleagues and/or direct patients to the in-hospital OPS where this care is routinely offered.informally provided to patients by nurses on a case-by-case basis in hospital as well as at community SCS/OPSs over the last several years.The revised version of the guideline was approved and posted within the organization. The guideline is clear that providing supplies and education does not equate to condoning SIVAD or substance use in hospital and patients are directed to the in-hospital OPS. The guideline also formalizes clinical practices around SIVAD that were already being At the end of 2020, the hospital-adjacent OPS moved to a new location which created a gap in service for hospital inpatients. In response, SPH opened an in-hospital OPS in February 2021 . It is sBetween its opening on February 1st to October 23, 2021, the site has had 1,655 visits, 611 (37%) of which involved SIVAD, which is recorded whenever a nurse notes a patient accessing their VAD to inject substances. Staff anecdotally report that SIVAD harm reduction education is the most common education requested by patients, many of whom already express existing knowledge about harm reduction practices for self-venipuncture .Nurse educators specialized in the care of patients with substance use disorders presented the new guideline at in-service sessions across acute care settings. The sessions equip nurses with skills to engage in harm reduction counselling with patients  and to ensure that nurses understand the purpose and limitations of harm reduction. The guideline was also presented to nursing leadership at frontline nursing meetings across the organization so that nurses could bring this information back to their colleagues.To enhance the reach of SIVAD-specific guidance, presentations at departmental rounds have been an important avenue for ongoing discussion and education. The British Columbia Centre on Substance Use hosts a monthly “What’s New in Addiction Medicine?” lecture series that is attended by a diverse range of healthcare professionals provincially. A rounds presentation reviewing SIVAD literature and approaches to VADs in PWID was delivered in May of 2021. This presentation had 65 live attendees and 102 registrants with access to online material .In line with the organizational ethics consult recommendations, research has been prioritized. Ethics approval has been obtained for a mixed-methods study of the attitudes, beliefs and practices of patients who engage in SIVAD and is currently in recruitment and data collection phases. Investigators are exploring patients’ understanding of SIVAD-associated risks , personal beliefs (e.g. why patients are using VADs to inject) and influencing factors (e.g. how the practice is being learned). Investigators will also conduct chart reviews to evaluate patient outcomes, including incidence of blood stream infections, thrombosis, occlusion, VAD malposition or accidental removal. Research to determine prevalence of SIVAD in an existing community study cohort of PWID is also underway.There is evidence that a patient-centered, harm reduction approach to care helps PWID engage in healthcare and reduces overall harms of IDU , 40–42. For patients who are informed of the anticipated risks associated with SIVAD but continue to endorse a plan to use their VAD, harm reduction interventions, including counselling about sterile technique and flushing and provision of sterile supplies is philosophically, ethically and medically analogous to sterile needle exchange/availability programs. If patients fear judgement from healthcare providers about SIVAD, they may engage in SIVAD covertly to avoid consequences such as VAD removal and premature discharge from hospital. Loss of patient engagement and concerns about overdose and adverse events up to and including death must be acknowledged. Harm reduction interventions, including safer injection techniques for non-prescribed substances helps support safer drug use patterns, access to primary care and reduced overdose frequency . It is tThere may be concern among healthcare providers that inserting PICCs or providing education on SIVAD to PWID may lead to increased IV drug use or SIVAD. Data is currently being collected and analyzed with respect to the incidence of SIVAD at the in-hospital SPH OPS following the introduction of the nursing guideline, to ascertain trends in SIVAD over time. It should be noted that the percentage of visits involving SIVAD rose from 27% in the hospital-adjacent OPS (May 2018–January 2021) to 37% at the in-hospital SPH OPS (February–October 2021). The significance of this observation requires more detailed analysis accounting for confounders and clinical outcomes. Populations accessing community and hospital-adjacent OPSs and those visiting in-hospital OPS are dissimilar and difficult to compare.In order to mitigate the risk of increased SIVAD among populations of PWID following the introduction of harm reduction measures, it is important that any policies or guidelines developed are clear that the main goal of SIVAD harm reduction counselling is to provide education regarding potential risks and to discourage the patient from using their VAD to inject substances. Guidelines should be clear that providing supplies and education does not mean substance use or SIVAD is condoned.Ongoing data collection to establish baseline incidence of SIVAD among PWID in inpatient and outpatient settings and documenting the type and rate of complications are needed to understand incidence and impact of SIVAD. Furthermore, qualitative assessment of patient experiences and perspectives regarding SIVAD are needed to contextualize this data and understand how it intersects with overall health and substance use. While a study in Vancouver is underway to begin to delineate these aspects of SIVAD, larger more inclusive multicenter collaborative research evaluating SIVAD is needed to appropriately account for heterogeneity of substance use behaviors, health system resources, policies and practices. Studies relating to PICC use and complications in PWID should include consideration of SIVAD, including creating standard means of identifying and documenting SIVAD in research protocols.Assessment of the impacts of possible SIVAD harm reduction interventions  are also needed. Such harm reduction-oriented studies should include evaluation of the rates and types of complications, while also exploring impact on patient quality of life, engagement in healthcare and substance use trajectories. Concurrent guidance and research, rather than a typical sequential approach of research followed by policy development should be considered, reflecting urgency arising from the ongoing overdose crisis in BC and elsewhere , 51.Vancouver represents a unique intersection of patient population and practice landscape, where addiction medicine services and harm reduction interventions are widely accepted and available, including SCS/OPSs. The generalizability of the work described herein may be limited or of low priority in settings without such resources and research opportunities may be scarce in settings where SIVAD incidence is believed to be low.SIVAD poses complex clinical and ethical challenges that require efforts to close knowledge gaps towards the creation of guidelines and policies that support patients, clinicians and organizations in reducing harms and improving health outcomes for PWID. Although healthcare providers and organizations may prefer that patients avoid SIVAD, clinicians must be willing to engage with patients within the reality that currently exists. Much work remains ahead to establish a foundation of evidence and organizations should actively seek opportunities within their own institutions and multidisciplinary teams to study and formalize guidelines and policies around this important area of practice, reviewing and amending them as new evidence becomes available. As organizations gain experience, the publication of guidelines and collaborative efforts between institutions will be essential.


Between September 2020 and March 2021, Mercy Corps piloted hybrid digital (CAPI) and paper-based (PAPI) data collection as part of its tuberculosis (TB) active case finding strategy. Data were collected using CAPI and PAPI at 140 TB chest camps in low Internet access areas of Punjab and Khyber Pakhtunkhwa provinces in Pakistan. PAPI data collection was performed primarily during the camp and entered using a tailor-performed CAPI tool after camps. To assess the feasibility of this hybrid approach, quality of digital records were measured against the paper “gold standard”, and user acceptance was evaluated through focus group discussions. Completeness of digital data varied by indicator, van screening team, and month of implementation: chest camp attendees and pulmonary TB cases showed the highest CAPI/PAPI completeness ratios (1.01 and 0.96 respectively), and among them, all forms of TB diagnosis and treatment initiation were lowest (0.63 and 0.64 respectively). Vans entering CAPI data with high levels of completeness generally did so for all indicators, and significant differences in mean indicator completeness rates between PAPI and CAPI were observed between vans. User feedback suggested that although the CAPI tool required practice to gain proficiency, the technology was appreciated and will be better perceived once double entry in CAPI and PAPI can transition to CAPI only. CAPI data collection enables data to be entered in a more timely fashion in low-Internet-access settings, which will enable more rapid, evidence-based program steering. The current system in which double data entry is conducted to ensure data quality is an added burden for staff with many activities. Transitioning to a fully digital data collection system for TB case finding in low-Internet-access settings requires substantial investments in M&E support, shifts in data reporting accountability, and technology to link records of patients who pass through separate data collection stages during chest camp events. As handheld digital devices and data collection tools become more accessible in areas with low Internet access, health outreach initiatives are weighing the advantages and challenges to transitioning from paper and pencil interviewing (PAPI) to computer-aided personal interviewing using digital tools including phones and tablets (CAPI) . CAPI daRecording data on paper forms is still a common practice among health outreach implementers in low-resource settings due to its familiarity and ease of use, cultural acceptance, and the negative suspicions of the security of digital data ,21. The Using paper to collect data in the field is especially common in TB ACF settings due to the unique workflow of TB chest camps, which requires attendees to move through multiple locations where data collection, and hence form linkage, occurs. This process reflects the TB diagnostic cascade and involves the verbal screening stage, sputum collection stage, X-ray examination stage, and hours or days later, the laboratory procedures. Data collected at each stage must be linked to the correct individual’s record. This can be accomplished digitally if individual records are immediately uploaded to a server and chest camp attendees carry with them a unique ID, barcode, or QR code which can be scanned at each stage. This unique identifier is used to later link data entered at various stages of the cascade in the server database. While this method of digital data collection and linkage has been successfully implemented in a variety of settings, it requires substantial reallocations in technical, logistical, financial, and human resources which many implementers may not be fully equipped or ready to invest in when there is a desire to make the digital shift. Many CAPI tools have been developed to function fully offline, such as the OpenDataKit suite of tools and REDCap, but these do not entirely meet the needs of TB chest camp implementers in remote areas. The various stages of data collection, in which data on individual camp attendees must be entered at different times and locations, and the requirement for a unique ID to link these data throughout different stages, require a sophisticated data management process and tools to facilitate this process .For the above reasons, some TB ACF implementers have started to transition all or elements of data collection from PAPI to CAPI. Hybrid approaches have been effective in largescale maternal and child health surveys, household health surveys, and facility-based data collection pilots, enabling some data elements to be digitized, while keeping other data elements paper-based for a variety of reasons ,29. As cMercy Corps’s shift toward ACF digitization is also reflective of the paradigm shift adopted by Pakistan’s National TB Program (NTP) to analyze and understand TB burden at the subnational level. TB decision-makers globally are increasingly recognizing the value of having more local, context specific TB burden and epidemiology profiles to prioritize case detection. In Pakistan as in many other LMICs, the wealth of data resulting from active case-finding often goes under-utilized and perhaps “over-aggregated” to high administrative levels, creating challenges in understanding which localities to target for case-finding .With these advances in mind, Mercy Corps piloted a hybrid PAPI/CAPI approach to chest camp data collection between August 2020 and March 2021. Our primary research objective was to compare the quality of data entered in the respective (matching) CAPI and PAPI patient-based records by evaluating completeness, accuracy, and consistency of both datasets. Our secondary objective was to evaluate users’ perceptions on feasibility and sustainability of the hybrid PAPI/CAPI approach and full CAPI approach in low Internet chest camp settings.TB ACF was conducted through mobile chest camps in Punjab and Khyber Pakhtunkhwa provinces of Pakistan between August 2020 and March 2021. A map of all tehsils in which chest camps were conducted is shown in To implement a hybrid PAPI/CAPI data collection approach, technical assistance providers to Mercy Corps developed a customized offline-functional Android compatible CAPI tool to capture the essential individual level indicators also captured in the PAPI forms already in use by Mercy Corps, and exact locations of the chest camp which could be optionally captured. An overview and descriptions of the various data collected for these indicators are presented in To assess user acceptance and perceptions on feasibility of using the CAPI tool as part of a hybrid PAPI/CAPI approach, we developed a topic guide for focus group discussions in English comparing perceptions on user-friendliness, efficiency, and safety of both CAPI and PAPI tools. The topic guide was translated into Urdu for the focus group discussions by a local consultant.Teams operating chest camps entered all individual-level data using both CAPI and PAPI tools . One DFSAfter obtaining informed consent, the local consultant conducted three 90 min long focus group discussions (FGDs) using the Urdu topic guide with six DFSs each, all of whom had conducted chest camps using the hybrid CAPI/PAPI approach. Each of the five vans (teams) was represented in at least one of the FGDs. FGDs were recorded and transcribed first into Urdu and then into English by the local consultant. Each DFS entered data using CAPI and PAPI tools, either at the verbal screening station or following the chest camp event to retrospectively fill in data.We assessed feasibility of the hybrid PAPI/CAPI approach using a mixed methods approach. We assessed CAPI data quality quantitatively by comparing CAPI and PAPI aggregate chest camp data; assessed user acceptance as measured through FGD responses; and triangulated quantitative and qualitative results.While our study utilized chest camp data, we referred to the conceptual framework to evaluate digital technology uptake in survey settings to address our research aim, as the framework’s indicators on data completeness, accuracy, and consistency translated well to our study design . We extrCAPI and PAPI records also contained van team, geographic location, and date variables, which were used for stratified analysis. The numbers of chest camp events and event indicators shown in completeness by calculating ratios and 95% confidence intervals of all CAPI individual records per chest camp indicator amongst total PAPI individual records.We assessed Accuracy was assessed by identifying the number of CAPI chest camps with the exact same  number of data points as those appearing in the respective PAPI chest camp, also per chest camp indicator. For example, a chest camp event X was assessed as accurately entered in the CAPI tool for each indicator if, e.g., 100 individuals were indicated as presumptive in the PAPI tool and 100 individuals were marked as presumptive in the CAPI tool. If the CAPI tool showed 99 presumptive individuals for chest camp X and the PAPI tool showed 100 presumptive individuals for chest camp X, the CAPI records were considered inaccurate.Consistency was assessed by calculating means and 95% confidence intervals of observed differences for each chest camp indicator (subtracting CAPI from PAPI) per van.To accommodate for data dependencies which could be expected from van teams screening in specific geographic clusters, all confidence intervals were calculated using STATA’s surveyset command identifying the van as the clustering factor.To assess user acceptance of the CAPI tool, we used a thematic coding framework following the principles of user-friendliness, efficiency, and safety. The local consultant used the English translation of the Urdu transcriptions for analysis, and coded topic-specific responses into positive, negative, and neutral views.Ethical approval was provided for quantitative and qualitative data collection and analysis by Pakistan National Tuberculosis Program’s Institutional Review Board on 20th January 2020 with approval code F number IRB-CMU-2020-10. Consent to participate in focus group discussions was sought and provided by all DFS participants prior to data collection. Patient-level data were anonymized before analysis in both CAPI and PAPI datasets by discarding personal identifiers from the study database.Of 142 chest camp events in the PAPI database and 147 in the CAPI database, a total of 140 events were found in both and therefore used for quantitative analysis. These 140 chest camp events were conducted in a total of 121 union councils located in 36 tehsils of Punjab and Khyber Pakhtunkhwa provinces . Exact lIn the PAPI dataset, 6876 individuals were registered as attendees across the 140 chest camp events, and the CAPI tool registered 6922 individual patient records . For onlThe CAPI/PAPI completeness ratios for all remaining indicators were less than 1.0, meaning that fewer records were entered digitally (via CAPI) than on paper . People We also explored van-level mean PAPI-CAPI differences in consistency of all chest camp indicators. For indicators in which the overall agreement between PAPI and CAPI varied largely across chest camp events , the primary users of the tool. These aspects are the tool’s ease of use and usefulness, the tool’s effects on workload and efficiency, and safety concerns regarding using CAPI tools.The vast majority of the DFS found the CAPI tool to be generally easy to use after an initial acclimation period. While there were DFS who immediately found the tool to be user friendly, some others took a few months to become comfortable making entries at the speed required in chest camps. It was acknowledged in the focus groups that the digital literacy of the group varied considerably prior to use of the tool, and those who had little experience using digital devices seemed to struggle the most when training on and acclimating to the tool in the field. Even users with limited previous digital experience, however, were ultimately able to manage using the tool adeptly. All DFS in the focus group discussions claimed that it was quite user friendly.Many DFS identified useful components of the CAPI tool. On top of being able to improve efficiency of data entry, the DFS claim that in the event of loss or damage to paper based records, it is valuable to have the data backed up digitally. DFSs also found it practical to have access to all their digital data entry records on the web-based platform when they were asked to recall or share data from previous chest camps, which the CAPI tool allows them to do. Several of the DFS also shared that the tool helped to improve their digital literacy.Data collection and patient registration in the Mercy Corps chest camps are currently completed through a hybrid process using PAPI and CAPI tools. As the CAPI tool has been added, instead of replacing PAPI, it created more work for the DFS during the data entry process. Many DFS vocalized that the increased workload from this hybrid model was at times burdensome and reduced their efficiency during camps, or that they were less able to give chest camp participants the same amount of attention before CAPI. Some DFSs appreciated how the CAPI tool’s automated functions can improve the workflow and organization of other components of chest camp. This includes the tool’s function of flagging presumptive patients based on symptom screening. DFS discussed that less time is now needed to analyze PAPI forms to identify patients for clinical follow up, as all presumptives are flagged in the CAPI tool. Although many DFS mentioned that the CAPI tool added time to their work process, they pointed out efficiency gains in producing monthly reports, which could eventually be dropped if CAPI technology is fully adopted.The DFSs largely found that the use of digital tools in the field has not posed any physical safety issues to them, nor increased their risk of being targeted for robbery. They do, however, voice concerns about the comfort level of some community chest camp participants with the CAPI tool, who have on occasion seemed anxious about logging their personal data in a digital database following recent reports about local COVID-19 patients being traced and isolated.One DFS in the focus group discussion did present some concern about data safety, claiming that in any sector, digital data can be hacked and misused. Most, however, did not share his concern and felt that having a digital repository backing up the paper documents has only served to create a safety net for the possibility of paper files getting lost or damaged.Digital data collection tools are increasingly used to monitor and evaluate the effectiveness and success of TB interventions. Although transitioning from paper to digital data collection can improve data quality and timeliness, there is limited documentation on how this can be operationalized in resource-limited settings. This paper has identified operational barriers which could hamper the uptake of digital tools and has quantified differences in completeness and accuracy between PAPI and CAPI data. Data quality of the CAPI tool was assessed from the perspectives of completeness, accuracy, and consistency with respect to PAPI records. CAPI completeness varied by month, increasing slightly over the first three months and tapering off through the next four months. DFSs reported an increase in the acceptance of CAPI after training and practice, consistent with other CAPI evaluations ,14,18,22The relatively high degree of completeness of data reported through CAPI demonstrates that users were capable of utilizing the tool as intended (number of chest camp attendees (101%), people with abnormal chest X-ray (92%), people presumptive for TB 235%), and people diagnosed with B+ TB (95%)). The reason for apparent over-reporting of presumptives in CAPI was due the CAPI tool’s programmed logic: when any symptom was indicated, an individual was identified as presumptive as specified by Mercy Corps operational protocol. In practice, however, DFSs used a more specific definition to mark someone as presumptive based on the verbal screen, which was captured in PAPI chest camp records. In this case, CAPI data more completely represent the number of presumptives based on the definition set according to Mercy Corps policy, adding evidence to other studies reporting improved data completeness due to programmable logic in CAPI 5%, and p,17. HoweIndicators showing lower completeness such as chest X-rays (83%), lab tests (72%), and AFTB patients initiated on treatment (63%) may have reflected field staff data priorities. These fields were not mandatory in the CAPI tool, and were often skipped when the data input would have been equivalent to a zero , or for perceived lower priority TB results . DFSs were pressed for time during chest camps, and most data entry for stages beyond verbal screening was performed after chest camp hours. In light of the fact that DFSs were held accountable for complete PAPI records but not CAPI, the observed volume of incomplete CAPI data seems a logical outcome of balancing time available, and the double burden of PAPI and CAPI data entry during busy periods. This prioritization of PAPI when accountability of CAPI data entry was no longer enforced also helps to explain the decreasing accuracy of chest camp level indicator totals over time.Significant differences in consistency between van teams suggest that team practices are directly associated with data quality. Other studies have shown that CAPI users typically received at least one to two weeks of training on the CAPI tool, either in one stretch or through a series of trainings and periodic supportive supervision ,28,31. ADFSs with a variety of digital literacy backgrounds described CAPI as practical, user-friendly, and enjoyable. These attitudes and their ability to use CAPI support other studies’ conclusions that users do not need to be familiar with digital technology to use CAPI effectively and that trainings should accommodate users with varying degrees of digital literacy ,32. HoweMercy Corps stated that once users show overall proficiency with CAPI, it can then replace the PAPI tool, which in similar studies has led to improved efficiency, replacing the arduous backend process of aggregating all paper data forms into a single excel file on a monthly basis and filling in both CAPI and PAPI forms during chest camps . UnfortuThere are considerable analytical benefits to collecting TB chest camp data using CAPI. Exact locations for all chest camp event data entered through CAPI were captured and available in near real-time. Having the data and locations digitally available as soon as the CAPI data were uploaded to the server allows implementers to understand where demand for TB services is located, and how TB burden is distributed geographically  . This enThere were several limitations in implementing the hybrid PAPI/CAPI data collection model effectively. The double workload of PAPI and CAPI data entry reduced the motivation to complete CAPI data entry, which was compounded by limited on the ground training M&E support, and a contractual issue caused CAPI data entry to taper out at the end of 2020. With more physical involvement, it may have been easier to address users’ concerns about the CAPI tool, and to improve the fit of the CAPI tool design to accommodate chest camp workflow, by introducing a scannable unique individual identifier. Furthermore, the hybrid approach necessitated identifying PAPI as the gold standard against which to compare CAPI data, but due to the limited M&E resources, we were unable to assure the quality of the PAPI data aggregated at the chest camp level.Implementation of CAPI in low Internet access TB ACF settings is feasible, as demonstrated by high data completion during the first two months, high completeness by individual vans, and positive overall user feedback. The observed gaps in data quality and user dissatisfaction about the workload highlight two key takeaways. First, introducing digital technology is ideally accompanied by several key resources: record linking technology, clear protocols, supportive supervision, and data mentoring. Secondly, CAPI/PAPI hybrid models should be temporary until a full CAPI model is possible, even if rolled out for individual screening teams one by one. However, to make this transition, accountability for users must be placed on completion of digital, rather than paper tools.Using devices with offline, location capturing, and record matching functionalities should greatly increase the scope of geographic areas in which CAPI can be used for TB ACF data collection, which is particularly relevant for low-Internet-access settings found throughout Pakistan and many other countries. Expanded use of CAPI in TB ACF settings and data sharing with NTPs will enable NTPs to consolidate ACF results into a single central geospatial repository, thereby collecting local estimates of TB prevalence measured at the community level. This will help TB programs to identify areas where under-detection or reporting is likely by comparing facility-based and ACF positivity rates and numbers needed to screen, and to help steer ACF activities in a more timely and evidence-based manner.


Post-hoc pairwise testing identified four attentional strengths with significantly higher rates in ASD than in ADHD. Attentional strength scores were not associated with impairment or poor cognitive flexibility, but predicted levels of perseveration/perfectionism. The effect of attentional strengths on impairment and cognitive flexibility did not differ between autistic and Control children, but the higher perseveration/perfectionism scores seen in ASD were not found in Control children. ASD is associated with a pattern of attentional strengths that is not found in ADHD Characterizing the full range of attentional abilities in autistic children may explain variability in outcomes such as quality-of-life indicators and identify protective factors, providing targets for strength-based behavioral interventions. The clinical and etiological implications of the subgroup of autistic children with attentional strengths require further investigation.The comorbidity of autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) diagnoses is well established. An ASD diagnosis is associated with elevated ADHD traits and symptoms, as well as strengths in attention. In the ASD literature, attentional strengths have been described as maladaptive , in contrast with positive portrayals in the typically developing population . The objective of this study was to (1) compare profiles of attentional strengths and weaknesses in ASD and ADHD and (2) determine whether attentional strengths in ASD are associated with impairment, poorer cognitive flexibility, and perseveration/perfectionism. In a community sample of 5,744 children and youth, 131 children were reported as having a diagnosis of ASD (mean age 10.3 years) and 346 children were reported as having a diagnosis of ADHD (mean age 10.7 years). We used the Strengths and Weaknesses of Attention-Deficit/Hyperactivity-symptoms and Normal-behaviors (SWAN) rating scale to calculate attentional and hyperactive/impulse control strength and weakness counts and scores. The Autism-Spectrum Quotient Switching factor served as a measure of cognitive flexibility. Impairment was assessed with the Columbia Impairment Scale. We used the symmetry/ordering factor on the Toronto Obsessive-Compulsive Scale as a measure of perseveration/perfectionism. No differences were found between the ADHD and ASD groups in SWAN weakness scores, symptoms, or hyperactive/impulse control strengths; however, autistic children had higher rates of attentional strengths [odds ratio: 5.7, 95% CI ,  Autism spectrum disorderIn contrast to this negative perspective on over-focused attention in ASD and ADHD, the state of “flow” described in typically developing people is described similarly as intense absorption to the point of losing track of time and perception of the outside world but without the negative connotation associated with hyperfocus. The term “flow” was coined by Csikszentmihalyi  in referAshinoff and Abu-Akel  proposedopposite extreme of the high, symptomatic end of continuous ADHD traits . Typical ADHD rating scales cannot identify strengths because they are limited to questions about the presence or absence of individual symptoms or deficits. Informants can rate a person as “not having a symptom” but cannot rate them as having an apparent strength in that trait . The development of the Strengths and Weaknesses of Attention-Deficit/Hyperactivity-symptoms and Normal-behaviors  and reduced impairment as measured using the Columbia Impairment Scale  in univariable models , e models . Howeverp = 0.0003] but not attentional strengths ] corresponding to a response of “very little problem” and, in the Control group, was −2.41 [95% CI: ], just above a response of “no problem” providing little room for improvement with increasing attentional strength scores .There was no evidence that higher scores on the TOCS symmetry/ordering factor in ASD was driven by individuals with a comorbid diagnosis of OCD. Only two autistic children reported a comorbid OCD diagnosis: one child had an attentional strength score of 0.8 and the second child had an attentional strength score of 0, and neither reported OCD symptoms in the symmetry/ordering domain. Although TOCS symmetry/ordering scores increased significantly with higher attentional strength scores, the average TOCS symmetry/ordering item predicted from the multivariable linear regression model across the range of observed attentional strength scores all fell below the cut-off for an OCD symptom.p = 0.0007, p = 0.002, p = 0.005, In a univariable model, higher levels of attentional strengths were significantly associated with higher average AQ-short-C numbers and patterns scores [β = 0.90, 95% CI: , In a sensitivity analysis, we repeated all the multivariable models in the ASD–ADHD sample only and in the parent respondent sample . ResultsThe goal of this study was to characterize attentional strengths in ASD. We took advantage of the unique structure of the SWAN ADHD questionnaire to create measures of ADHD weaknesses, ADHD strengths, ADHD symptoms and overall total ADHD scores. The ASD group had comparable levels of ADHD symptoms and ADHD weaknesses as the ADHD group consistent with the literature showing high rates of comorbid ADHD and high subthreshold ADHD traits among ASD individuals. However, when we expanded the focus to the full range of ADHD trait scores measuring both strengths and weaknesses, we discovered that children on the autism spectrum had significantly lower total scores than those with ADHD. These differences in trait profiles were driven by an increase in apparent attentional strengths in autistic children. Four attentional strengths were significantly more common in ASD than in ADHD: “sustain attention on tasks or play activity,” “engage in tasks that require sustained mental effort,” “remember daily activities,” and “give close attention to detail/avoid careless mistakes.” ADHD and ASD did not differ in the proportion of hyperactive/impulsive control strengths. These results were replicated in an independent sample, revealing a consistent profile of apparent attentional strengths in ASD across different samples.The four apparent attentional strengths identified as being more common in ASD than in ADHD are well established ASD traits. Both the Weak Central Theory of autism  and the In much the same way that hyperfocus describes attentional strengths through a negative lens and flow through a positive lens, the Weak Central Theory of autism describes a preference for local processing (attention to detail) stemming from difficulties understanding the big picture, in contrast with the hyper-systemizing theory where strengths in attention to detail are an asset used in support of recognizing patterns and rules that govern systems . Given tWhile there is no doubt that attentional strengths can be seen as beneficial in ASD, as one autistic adult explains, “I believe the unwavering focus to a subject has aided me academically” , autistiThe attentional strengths identified as more common in ASD than ADHD are well established ASD behaviors, yet research on comorbid ASD and ADHD has focused on weaknesses that are common to both disorders and not on the apparent attentional strengths that may serve to discriminate between them. More research is needed to characterize the co-occurrence of apparent strengths and weaknesses to inform ADHD diagnostic decisions in individuals on the autism spectrum. The ability to enter a state of intense focus depends on task engagement and does not preclude the presence of difficulties with focus in other contexts. That is, the same individual may sometimes exhibit attentional strengths and at other times attentional weaknesses on the same SWAN item, depending on their interest in and enjoyment of their current activity. This apparent contradiction may underlie some cases of poor respondent agreement on ADHD questionnaires. In their expert consensus guidelines, Young et al.  warn thaOur findings highlight the importance of designing questionnaires that measure both extremes of a behavioral trait. Such questionnaires can improve the homogeneity of empirically defined phenotypic subgroups, increasing our power to identify susceptibility genes in linkage studies  as well Hyperfocus or flow? Our failure to find a significant association between attentional strength scores with impairment and cognitive flexibility in either Control or autistic children belies the conventional belief that high levels of focused attention in Control children is a strength, as represented by flow, but invariably maladaptive in autistic children. Whether this is because some children on the autism spectrum experience high levels of strengths without the challenges associated with hyperfocus while others exclusively experience hyperfocus, or whether both positive and negative levels of attention can be seen within the same child remains to be determined. Compared to flow research, the research in hyperfocus is in its infancy. With more study, a consensus on the distinguishing features, overlap, and boundaries between flow and hyperfocus can be established, facilitating research into the conditions that lead to more positive flow experiences rather than negative hyperfocus ones.We characterized a broad range of attentional strengths in autistic children as described by parents using a single score to describe the prevailing trend across each item in the previous 6-month period. As such, we were unable to determine if individuals can present with both strengths and weaknesses for the same item across different contexts. Individuals with high strength scores may present with different profiles of strengths, not all of which are characteristic of hyperfocus . Participants visiting a science center may not be representative of or generalizable to the general population. Notably, there were fewer individuals from the lowest SES quintile and more high SES individuals participating in the 2009–2010 study than across the surrounding area , Susan Bradley Health Clinician Scientist Endowment (JC) and the Alberta Innovates Translational Health Chair in Child and Youth Mental Health (PA).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Tritrophic interactions among plants, herbivorous insects and their parasitoids have been well studied in the past four decades. Recently, a new angle has been uncovered: koinobiont parasitoids, that allow their host to keep feeding on the plant for a certain amount of time after parasitism, indirectly alter plant responses against herbivory via the many physiological changes induced in their herbivorous hosts. By affecting plant responses, parasitoids may indirectly affect the whole community of insects interacting with plants induced by parasitized herbivores and have extended effects on plant fitness. These important findings have renewed research interests on parasitoid manipulation of their host development. Parasitoids typically arrest their host development before the last instar, resulting in a lower final weight compared to unparasitized hosts. Yet, some parasitoids prolong their host development, leading to larger herbivores that consume more plant material than unparasitized ones. Furthermore, parasitoid host regulation is plastic and one parasitoid species may arrest or promote its host growth depending on the number of eggs laid, host developmental stage and species as well as environmental conditions. The consequences of plasticity in parasitoid host regulation for plant–insect interactions have received very little attention over the last two decades, particularly concerning parasitoids that promote their host growth. In this review, we first synthesize the mechanisms used by parasitoids to regulate host growth and food consumption. Then, we identify the evolutionary and environmental factors that influence the direction of parasitoid host regulation in terms of arrestment or promotion of host growth. In addition, we discuss the implication of different host regulation types for the parasitoid’s role as agent of plant indirect defence. Finally, we argue that the recent research interests about parasitoid plant-mediated interactions would strongly benefit from revival of research on the mechanisms, ecology and evolution of host regulation in parasitoids. Parasitoids are typically small wasps that lay their eggs inside (endoparasitoids) or outside (ectoparasitoids) a host that serves as food source for the entire larval stage of the parasitoids offspring. They are important model organisms in the study of behavioural and evolutionary ecology that are ubiquitous in many natural and agricultural ecosystems: virtually all immature insect can be parasitized by at least one parasitoid species Godfray .Recently, studies have shed light on a novel ecological phenomenon in tritrophic interactions: koinobiont parasitoids indirectly affect plant responses to herbivory, which, in turn, alter the attraction Many parasitoids harbour endogenous viruses from the family of the Polydnaviridae that reproduce in the calyx of adult wasps and are injected inside the host during oviposition Rotheram . The assManduca sexta larvae injected with calyx fluid derived from parasitoids had a longer developmental time and a higher weight than hosts injected with parasitoid eggs that were parted of the calyx fluid  or neuropeptides that are controlling metamorphosis, pupation or feeding behaviour  (Beckage and Gelman (b)VenomWhile parasitizing their host, koinobiont parasitoids also inject non-paralysing venom, a complex mixture mainly composed of enzymes with diverse functions (Asgari and Rivers (c)TeratocytesSome parasitoid species from two families (Braconidae and Platygastroidea) inject eggs that have a specialized membrane that differentiates into autonomous cells  that ar(d)Parasitoid larvaeCotesia congregata, when only the parasitoid larvae are injected in an unparasitized Manduca sexta (without venom or PDVs), the host may stop feeding after the larvae emerged, similar to naturally parasitized hosts, suggesting that the larvae are responsible for this arrestment of feeding behaviour  Fritz . TherefoThe evolution of parasitoid host regulation is also constrained by the feeding ecology of parasitoid larvae. Koinobiont endoparasitoids can be categorized in two larval host-utilization strategies: tissue and haemolymph feeders Environmental factorsFinally, the evolution of parasitoid host regulation type is affected by their life-history strategies (i.e. solitary and gregarious Godfray ) and theParasitoid host regulation can be plastic: the intensity in decreasing or increasing their host weight can greatly vary according to environmental factors linked with parasitoid resource needs. Furthermore, in different ecological contexts, parasitoids from the same species can exert either a decrease or an increase of their hosts weight.Venturia canescens has a stronger effect on the arrestment of its host development when developing in a large host species  compared to a smaller one (Anagasta kuehniella) , the reduction in host weight due to parasitism will be stronger. This is particularly the case for tissue-feeder parasitoids that entirely consume their host in order to pupate, as having too much resources can be particularly detrimental Harvey , 2005. T) Harvey .The increase of parasitized host weight tends to be stronger when the amount of resources available in the host is not sufficient for an optimal development of the parasitoid larva(e). This is particularly the case for gregarious parasitoids, as several larvae are developing in the same host and therefore the amount of resources needed is higher compared to their solitary counterparts Table . ImportaMeteorus pulchricornis, a solitary parasitoid that feeds on its host haemolymph, strongly reduces its host development compared to unparasitized hosts when developing in a large host species (Mythimma separata) , with likely not enough resources for an optimal parasitoid larval development, host maximum weight was increased by 30% compared to an unparasitized host. Similarly, the gregarious endoparasitoids Cotesia glomerata either reduce or increase their host final weight when developing in a big (Pieris brassicae) or small (P. rapae) host, respectively . For example, y Harvey .Depending on the direction of host regulation, parasitoids can have either a beneficial, neutral or negative effect on plant performance. This may have important consequences for the role of parasitoids as part of plant indirect defence.In many cases, koinobiont parasitoid host regulation leads to a reduction of the host final weight compared to unparasitized hosts, especially when parasitoids are tissue-feeders and solitary Table . In thisSome koinobiont parasitoids regulate their host in a way that they increase their final weight as well as the amount of plant tissue consumed, compared to unparasitized herbivores Ode , Table 2For a plant trait to be positively selected via natural selection, the main factor to consider is the final overall fitness gain. Therefore, if on average a plant has a net fitness gain when attracting koinobiont parasitoids with HIPVs, this trait will be positively selected via natural selection, even if the plant also interacts with parasitoids that have a negative effect. This raises the following questions: 1) what is the ratio of parasitoids that reduce their host plant consumption versus parasitoids that increase it in natural environments?, 2) do they have the same effect size on plant damage? and (3) does variation in plant damage always translate into an effect on plant fitness? First, it seems that solitary and tissue-feeder parasitoids are more prevalent than gregarious and haemolymph-feeders, probably because haemolymph feeding and gregariousness are relatively recent adaptations  effects of herbivore population reduction by parasitoids on plant fitness Ode . Indeed,Pieris genera, parasitism may be predominantly by gregarious parasitoids. In such specific cases, there are higher chances that the overall consequences of parasitoid attraction could be negative for plant fitness. This may result in a local selection against plant volatile production followed by a local reduction in plant volatile emission (Kergunteuil et al. Furthermore, for some herbivorous hosts such as caterpillars from the Over the last two decades, the significance of parasitoid host manipulation has been extended to indirect plant-mediated species interactions that are initiated by parasitized herbivores. We argue that the identification of an extended phenotype of parasitoid host manipulation to plant–insect interactions requires deep understanding of the changes in parasitized herbivores.First, we should explore whether parasitoids that arrest host growth differ in their impact on plant responses to parasitized herbivores compared to parasitoids that prolong host development. Although some studies compared plant induced responses to hosts parasitized by a solitary parasitoid that arrest growth with a gregarious parasitoid that promotes development (Poelman et al. Second, parasitoid host manipulation affects plant-mediated species interactions through quantitative aspects such as amount of food consumed by parasitized hosts as well as qualitative aspects such as composition of herbivore oral secretions (Poelman et al.


Acute lung injury (ALI) is a heterogeneous inflammatory condition associated with high morbidity and mortality. Neutrophils play a key role in the development of different forms of ALI, and the release of neutrophil extracellular traps (NETs) is emerging as a common pathogenic mechanism. NETs are essential in controlling pathogens, and their defective release or increased degradation leads to a higher risk of infection. However, NETs also contain several pro-inflammatory and cytotoxic molecules than can exacerbate thromboinflammation and lung tissue injury. To reduce NET-mediated lung damage and inflammation, DNase is frequently used in preclinical models of ALI due to its capability of digesting NET DNA scaffold. Moreover, recent advances in neutrophil biology led to the development of selective NET inhibitors, which also appear to reduce ALI in experimental models. Here we provide an overview of the role of NETs in different forms of ALI discussing existing gaps in our knowledge and novel therapeutic approaches to modulate their impact on lung injury. ALI is an inflammatory condition characterized by the acute onset of lung tissue damage and pulmonary dysfunction originating from infectious or sterile insults . TypicalAirway neutrophilia has been historically considered a hallmark of ARDS . HoweverIn this review, we will discuss general mechanisms of NETosis and NET-mediated tissue damage Figure 1NETosis was first described in 2004 when Brinkman and coworkers observed that activated neutrophils could kill bacteria by releasing nuclear chromatin decorated with proteins usually confined to their granules . Followivia several and frequently interconnected activation pathways , cathepsin G (CatG), proteinase 3 (PR3), and neutrophil serine protease 4 (NSP4). Due to their antimicrobial and immunomodulatory function, these pre-stored catalytically active mediators play a major contribution in the physiological response to infection . HoweverOther proteases such as PR3 and Cat G are known to enhance inflammatory reactions by modulating the balance between pro and anti-inflammatory proteins . HoweverIn summary, besides the explicit role of NE in NET-mediated lung microvascular damage, the overall contribution of neutrophil serine proteases to NET-dependent inflammation in ALI is still undefined.Candida albicans, Klebsiella pneumoniae or cholesterol crystals , expresses endonucleases that degrade the NET DNA scaffold allowing for bacterial escape  which inhibits the release of NETs by increasing cAMP levels and reducing intracellular ROS production  infection, which in its most severe clinical presentation, is associated with ALI/ARDS and multiple organ failure –101. COVvia Thromboxane A2  . The phyA recent study by Sayah and colleagues demonstrated a pathogenic role for NETs in primary graft dysfunction (PGD), a common form of LTx-related LIRI occurring within 72 hours. after surgery. Using a mouse model of syngeneic orthotopic left lung transplant (OLT), this group detected the presence of intra-graft NETs in association with platelet activation. Pretreatment with aspirin or intrabronchial administration of DNase were both able to attenuate signs of PGD in the OLT model . A laterAltogether, the observations from the LIRI models and human LTx recipients with PGD support the notion that DAMPs released from the ischemic tissues induce innate immune responses resulting in NETosis and tissue injury. Interfering with the mechanisms that activate NETosis rather than enhancing the degradation of NETs appears a more desirable option for attenuating LTx-related ALI without increasing the risk of allograft rejection.VILI is a form of ALI triggered by mechanical ventilation . NeutropIn summary, the current evidence shows that NETs are released during VILI and that targeting NETs may be beneficial in preventing injury in this setting. The differing effects observed with DNase treatment may be related to the use of alternative experimental models suggesting further pre-clinical evaluation is likely necessary to better characterize the effects of NETosis on VILI.Trauma is defined as an injury caused by an external physical force, as it may result in the consequence of blunt force impact, penetrating injuries, or extensive thermal and chemical burns. Although advancements in surgery and resuscitation have substantially increased the chance of surviving a major trauma, some patients still develop systemic inflammatory response syndrome (SIRS) and infections . ARDS isIn summary, ALI associated with trauma appears to display peculiar immunological features, possibly related to the sudden and massive release of DAMPs and the alteration of regulatory mechanisms that promote DAMP clearance. How different DAMPs control neutrophil metabolism, differentiation and NETosis as well as shape host responses to trauma remains to be determined.Increasing evidence suggests that NETs play an essential role in infectious and sterile ALI and that circulating NET markers can predict worst clinical outcomes in ARDS subjects . Most ofIn conclusion, future studies that better define the mechanisms involved in the formation, release, and degradation of NETs could form the basis of therapeutic strategies that target ALI without disabling pathogen surveillance.DS, FL, AK, DK, and AG contributed to conception and design of the study. DS wrote the first draft of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.This study was funded by the NIH .The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Two fundamental questions for evolutionary studies are the speed at which evolution occurs, and the way that this evolution may present itself within an organism’s genome. Evolutionary studies on invasive populations are poised to tackle some of these pressing questions, including understanding the mechanisms behind rapid adaptation, and how it facilitates population persistence within a novel environment. Investigation of these questions are assisted through recent developments in experimental, sequencing, and analytical protocols; in particular, the growing accessibility of next generation sequencing has enabled a broader range of taxa to be characterised. In this perspective, we discuss recent genetic findings within the invasive European starlings in Australia, and outline some critical next steps within this research system. Further, we use discoveries within this study system to guide discussion of pressing future research directions more generally within the fields of population and evolutionary genetics, including the use of historic specimens, phenotypic data, non-SNP genetic variants , and pan-genomes. In particular, we emphasise the need for exploratory genomics studies across a range of invasive taxa so we can begin understanding broad mechanisms that underpin rapid adaptation in these systems. Understanding how genetic diversity arises and is maintained in a population, and how this contributes to adaptability, requires a deep understanding of how evolution functions at the molecular level, and is of fundamental importance for the future studies and preservation of biodiversity across the globe. Evolutionary theory states that the immense diversity existing on this planet does so through a complex combination of factors. These factors include genetics, epigenetics, and plasticity, and it is the interplay of these processes that allow species to evolve within our increasingly changing world . We are Population and evolutionary genomics play pivotal roles in answering these questions. Technical advances have given rise to cheap “reduced representation” data (subsampling genomic variation) and the growing feasibility of whole genome resequencing (WGS) for non-model organisms. Population genetics can now move beyond the characterisation of broad genetic patterns to uncover evolutionary important genetic variants at a resolution previously inaccessible to non-model organism studies , 2021. EStudies in invasive species genomics are fundamental to these efforts. By examining how invasive populations’ genetic diversity is shaped by novel selection regimes, we obtain insight into the molecular patterns underpinning evolution. Invasive species, by nature, are successful following genetic bottlenecks , and provide an avenue for understanding what aspects of genetic diversity    is a staulgaris) , the staulgaris) , has colThe Australian starling invasion has a well-documented, but complex, introduction history, with multiple geographically dispersed introduction points that are separated in some instances by thousands of kilometres . StarlinExploration of starling populations identified several broad trends that characterize patterns of genetic change in this species. First, comparing invasive populations on separate continents , or distSecond, selection  within starling populations often occurs at sites with moderate allele frequencies , and levThird, examining the location of putative sites under selection across the starling’s genome reveals a larger number of genomic sites than expected under selection in the major sex (Z) chromosome . These rLastly, assessing genetic alongside environmental and morphological data indicates that genetic variation is positively correlated with phenotypic variation, and this relationship becomes more pronounced under a temporally variable environment  contributions to adaptation. However, phenotypic plasticity itself can have different underlying causes and mechanisms. Deeper understanding the role of plasticity in shaping a populations’ adaptive potential requires expanding omics data collection beyond just the genome. Co-analysing genetic and phenotypic data will be greatly aided by the inclusion of, for example, transcriptome, proteome, or epigenome data . These cEvolutionary genomic studies often produce a list of genetic sites flagged as under putative selection or associated with phenotypic or environmental data. While generating a shortlist of biologically interesting variants is the first of many steps towards biologically validating these results, knowing whether a variant has an adaptive advantage (or disadvantage) may require additional data , or even “evolve and resequence” studies under one or more standard environmental conditions . It is vAcridotheres tristis) to yield insights into the repeatability of adaptive change in invasive taxa. While the lack of comparative studies is simply because the field is in its relative infancy, we are quickly moving into an age where enough studies have now been published for us to begin employing meta-analytical approaches to conduct formal inter -population or -specific comparisons. This will allow us to begin confirming whether results from a singular study are an isolated phenomenon within a particular system, or are broadly applicable over many. Comparing patterns of genomic change across a broad range of invasive species is of vital importance to invasion population genomics to answer questions about the importance of different genomic variants and the role they play in rapid adaptation and species persistence. Further, comparisons between invasion genomics and the fields of conservation and agricultural genomics also promise to yield interesting answers (As we acknowledge the utility in cross-study comparisons of variants of interest, so too must we acknowledge the lack of these within the field of evolutionary and population genomics. Such approaches can start more modestly, with comparisons across similar species (for example, comparison between the invasive sturnids, the starling and the common myna  answers .Technology continues to shape the nature of the questions that can be asked and reveals the importance of previously understudied types of variation. WGS captures genome-wide genetic information that improves on reduced representation sequencing approaches, as it does not rely on subsampling species-specific genomic loci. This provides a more uniform starting point for further analysis and more long-term utility, provided careful scientific reporting and best practices are followed . FurtherThe incorporation of published data into cross study comparisons is greatly aided by a high-quality species genome. While putative chromosomes may assembled using syntenic approaches e.g., , completThe study of invasive systems have and will continue to yield many important discoveries within the fields of population and evolutionary genomics. Characterising rapid adaptation from the molecular to the macro level within invasive populations enables scientists to appreciate how genetic variation interacts with a variety of selection processes to allow species to evolve. Within these studies, starlings present a valuable system for understanding evolution, providing opportunity to investigate everything from subtle morphological shifts within a region, to observing broad patterns of parallel change across the globe. The research conducted on this system demonstrates the complex nature of standing genetic diversity and the means through which it facilitates adaptation. From these results we also see some promising directions of future study within the field of evolutionary and population genomics. Collectively pursuing these directions using this system and that of other invaders will facilitate a deeper appreciation of how evolution functions at the molecular level. Ultimately, through deep studies across a broad range of taxa, we may learn to precisely explain and predict patterns of evolution, to protect precious biodiversity.


Frontiers in Host-Parasite-Vector Interactions: Invasion and Persistence, received six articles, including four original research studies and two reviews. All four original articles and one review paper relate to the intracellular protozoan parasite Leishmania, its interaction with the host, and resulting pathogenesis. The other review article updates our understanding of the biochemical and physiological mechanism of gametogenesis in Plasmodium, which could be targeted to control parasite and malaria transmission, and highlights gaps that still exist within our understanding of the process of gametogenesis. Together, these articles are related to protozoan parasites causing human diseases. This is not surprising as parasitic infections are responsible for severe mortality and morbidity worldwide, particularly in developing countries. In fact, millions of lives are lost due to parasitic infections each year, and most mortality and morbidity are due to protozoan infections. Most protozoan infections are caused by Leishmania spp., Plasmodium spp., and Trypanosoma spp. These pathogens can establish persistent and sometimes long-term infections. Several of these intracellular pathogens have developed diverse immune escape strategies and can overcome immune responses by residing and replicating inside host immune cells, primarily mononuclear phagocytic macrophages.This Research Topic, Leishmania spp. and Trypanosoma spp., that are capable of actively infecting these hostile cells. To establish infection, these intracellular parasites must first find ways to enter their host cells. For example, some pathogens  exploit phagocytic pathways by engaging specific phagocytic receptors. Once inside, these pathogens must employ clever strategies to survive, grow, and replicate in a hostile intracellular environment. Such strategies include deactivating the host cells by modulating host response by subverting intracellular signal transduction pathways of activation. A deeper understanding of the immune evasion mechanisms used by these devastating protozoan parasites can pave the way to develop targeted therapies to treat diseases caused by these parasites. Studies presented in this special issue of “Frontiers in Cellular and Infection Microbiology” serve as a significant step in the right direction by revealing the complex interface between parasites and their hosts.Although macrophages are armed with potent anti-infection properties, there are certain microbial pathogens, including several parasites like Singh et al. showed that upregulation of the expression of CD300a, an immune inhibitory receptor, on antigen-presenting phagocytic cells resulted in the inhibition of their anti-microbial effector functions. Abrogation of CD300a signals in Leishmania-infected mice helped in the early clearance of parasites from their visceral organs and implicated CD300a as an important determinant of phagocytic host-cell function and T cell differentiation against Leishmania antigens.Leishmania secretory exosomes/extracellular vesicles on leishmaniasis unlocked a new area of potential and intricacy regarding our understanding of the disease. In this regard, Shokouhy et al. isolated extracellular vesicles (EVs) from non-pathogenic L. tarentolae and functionally tested these vesicles in mice infected with L. major for the production of cytokines and pathogen survival. Upon prior treatment with L. tarentolae EVs (tEVs) in L. major-infected human monocytic cells (THP-1), there was a significant increase in the production of proinflammatory cytokines like IFN-γ, TNF-α, and IL-1β, but not anti-inflammatory cytokines like IL-6 when compared to cells treated with L. major EVs prior to the infection. Excitingly, they also observed a significant decrease in parasite survival in tEV-treated Leishmania-infected macrophages and advocated tEVs as a potential drug delivery platform for parasitic infections.Recent understanding of the role of Doehl et al. showed that initial inoculation of Leishmania donovani parasites in the skin led to the clustering of myeloid cells resembling the shape of innate granulomas, followed by further infection in the newly recruited cells, eventually translating to self-propagating networks of patch clusters. This presents a novel perspective on the behaviour of phagocytic cells and the skin-parasite landscape following infection. Lastly, Sghaier et al. examined the healed lesions caused by Leishmania major infection in humans for the persistence of parasites. This study involved biopsies of cutaneous scars from 53 volunteers cured of cutaneous leishmaniasis. These tissue samples were investigated for the presence of residual parasites using multiple methods. Unexpectedly, their investigation did not find evidence of residual pathogens. This situation contrasts with other Leishmania species causing chronic, diffuse forms of leishmaniasis where parasites persist in healed lesions. It will be of interest to extend this observation to other anatomic sites like lymph nodes. Such findings could be valuable in guiding the design of effective vaccines against cutaneous leishmaniasis in the near future.In order to understand the skin-parasite landscape, Al-Khalaifah focuses on major molecular factors related to Leishmania pathogenicity. Most of these molecular factors are also known as “virulence factors” and are considered ideal targets for designing small molecule inhibitors to attenuate the survival of Leishmania spp. He also touches on metabolic changes of host macrophages in relation to Leishmania infection and survival. It was interesting to note that some infections dampen the immune response of their mammalian hosts by the depletion of amino acids that are essential to immunological processes. Thus, it is becoming increasingly clear that Leishmania manipulates host metabolic fluxes to evade host immunity, resulting in prolonged Leishmania survival and pathogenicity. This paper also highlights the importance of further research into leishmanial virulence factors, and how this could aid in the development of novel therapeutics to treat disease by providing better knowledge of disease pathogenesis and etiology.The review article by Dash et al. entitled “Gametogenesis in Plasmodium: Delving Deeper to Connect the Dots” summarizes potential strategies to control the transmission of malaria. One such strategy is blocking the gametocyte-gamete transition, thus potentially restricting the successful transmission and progression of the disease. This can then be exploited for designing transmission-interfering strategies. As a result, Dash et al.’s review mainly focuses on summarizing the current understanding of the biochemical and physiological mechanisms involved in gametogenesis in the malaria parasite Plasmodium, which could be targeted to control parasite and malaria transmission. Interesting questions were raised regarding gametogenesis biology in Plasmodium, and are worth investigating for a better understanding of the process of gametogenesis.A review article by Leishmania. We hope these contributions will help investigators in the field of host-pathogen interactions and intracellular pathogenesis in their continuous scientific pursuit to understand the molecular mechanism of the pathogenesis of intracellular protozoan pathogens. This could pave the way to develop effective clinical therapeutics to treat human diseases caused by these protozoan pathogens.Taken together, the six papers of our Research Topic provide a valuable addition to the field of host-pathogen interactions. This includes a number of exciting new scientific findings regarding emerging evasion strategies used by intracellular pathogens like The author confirms being the sole contributor of this work and has approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.