Ferroptosis inhibitor improves outcome after early and delayed treatment in mild spinal cord injury.

We show that redox active iron can induce a regulated form of non-apoptotic cell death and tissue damage called ferroptosis that can contribute to secondary damage and functional loss in the acute and chronic periods after spinal cord injury (SCI) in young, adult, female mice. Phagocytosis of red blood cells at sites of hemorrhage is the main source of iron derived from hemoglobin after SCI. Expression of hemeoxygenase-1 that induces release of iron from heme, is increased in spinal cord macrophages 7 days after injury. While iron is stored safely in ferritin in the injured spinal cord, it can, however, be released by NCOA4-mediated shuttling of ferritin to autophagosomes for degradation (ferritinophagy). This leads to the release of redox active iron that can cause free radical damage. Expression of NCOA4 is increased after SCI, mainly in macrophages. Increase in the ratio of redox active ferrous (Fe2+) to ferric iron (Fe3+) is also detected after SCI by capillary electrophoresis inductively coupled mass spectrometry. These changes are accompanied by other hallmarks of ferroptosis, i.e., deficiency in various elements of the antioxidant glutathione (GSH) pathway. We also detect increases in enzymes that repair membrane lipids (ACSL4 and LPCAT3) and thus promote on-going ferroptosis. These changes are associated with increased levels of 4-hydroxynonenal (4-HNE), a toxic lipid peroxidation product. Mice with mild SCI (30 kdyne force) treated with the ferroptosis inhibitor (UAMC-3203-HCL) either early or delayed times after injury showed improvement in locomotor recovery and secondary damage. Cerebrospinal fluid and serum samples from human SCI cases show evidence of increased iron storage (ferritin), and other iron related molecules, and reduction in GSH. Collectively, these data suggest that ferroptosis contributes to secondary damage after SCI and highlights the possible use of ferroptosis inhibitors to treat SCI.

The Whys and Wherefores of Reducing Cannabis Use in Early Psychosis: A Qualitative Study of Service Users' Experiences of Quitting and the Support.

Objectives: Cannabis is the most widely used substance among people with recent onset psychosis, but it can have significant negative consequences for long term wellbeing in this cohort. We explored the perspectives of people with recent onset psychosis who used cannabis on their motivations for quitting, their experiences of trying to do so, and their views of the support they had received and the strategies that they had tried. Methods: Twenty one-to-one qualitative interviews were conducted with Early Intervention in Psychosis service users in England who had participated in the CIRCLE trial. Purposive sampling was used to recruit a mix of demographic, cannabis use status, and other characteristics. Results: Quitting cannabis is often very challenging for people and can require making substantial changes in their lives, including to their social relationships, living arrangements, or pathways through work or education. Participants reported wanting help, but often experienced support from mental health services as insubstantial and poorly tailored. Support from peers with relevant lived-experience, where available, was highly valued. Common reasons for quitting included its impact on key life goals or engaging with hobbies, finances, mental health, incompatibility with self-image, and negative use expectancies of intoxication. Concerns regarding mental health were primarily related to psychotic illness, including fear of exacerbating symptoms or experiencing future hospital admissions. Discussion: It is currently unclear how best to support people in this cohort. Interventions that provide support from people with relevant lived experience may be more valued and more clinically effective than current offerings.

"It's like 'liquid handcuffs": The effects of take-home dosing policies on Methadone Maintenance Treatment (MMT) patients' lives.

BACKGROUND: Methadone Maintenance Treatment (MMT) is widely recognized as one of the most effective ways of reducing risk of overdose, arrest, and transmission of blood-borne viruses like HIV and HCV among people that use opioids. Yet, MMT's use of restrictive take-home dose policies that force most patients to attend their clinic on a daily, or near-daily, basis may be unpopular with many patients and lead to low rates of treatment uptake and retention. In response, this article examines how clinics' take-home dosing policies have affected patients' experiences of treatment and lives in general. METHODS: This article is based on semi-structured, qualitative interviews with a variety of stakeholders in MMT. Interviews explored: reasons for engaging with, or not engaging with MMT; how MMT is conceptualized by patients and treatment providers (e.g., as harm reduction or route to abstinence and/or recovery); experiences with MMT; perception of barriers to MMT (e.g., organizational/regulatory, social) and how MMT might be improved to support peoples' substance use treatment needs and goals. RESULTS: Nearly all of the patients with past or present MMT use were highly critical of the limited access to take-home doses and consequent need for daily or near daily clinic attendance. Participants described how the use of restrictive take-home dose policies negatively impacted their ability to meet day-to-day responsibilities and also cited the need for daily attendance as a reason for quitting or avoiding OAT. Responses also demonstrate how such policies contribute to an environment of cruelty and stigma within many clinics that exposes this already-stigmatized population to additional trauma. CONCLUSIONS: Take-home dose policies in MMT are not working for a substantial number of patients and are reasonably seen by participants as degrading and dehumanizing. Revision of MMT regulations and policies regarding take home doses are essential to improve patient satisfaction and the quality and effectiveness of MMT as a key evidence-based treatment and harm reduction strategy.

Medically high-risk pregnancy: Women's perceptions of their relationships with health care providers.

The purpose of this article is to examine women's perceptions of the patient-provider relationship in the context of medically high-risk pregnancy (MHRP). Sixteen in-depth interviews were conducted with women hospitalized for MHRP on a maternal-fetal medical unit in the US. Tenets of phenomenology guided the data analysis. We found that beyond normative stress related to managing physical aspects of MHRP, women reported added emotional stressors associated with navigating the fragmented health care environment. This study suggests that improved care coordination and systematic integration of psychosocial professionals within the perinatal interdisciplinary health care team are vital to reduce care-related stressors on this vulnerable patient group.

ON BEING MOTHER AND PATIENT: DIALECTICAL STRUGGLES DURING MEDICALLY HIGH-RISK PREGNANCY.

Medically high-risk pregnancy (MHRP) affects 3 to 10% (diagnosis-dependent) of pregnant women in the United States (National Institute of Child Health Development, 2015), threatening maternal and fetal well-being. Although mothers' prenatal distress and mother-infant attachment after birth have been quantitatively researched, little research has examined women's lived experiences of MHRP in the United States. We examined 16 women's experiences of MHRP during hospitalization at an urban, Northeastern U.S. hospital using an interpretive phenomenological approach. Our qualitative findings provide new understanding of how women expend tremendous energy simultaneously navigating new roles of mother and patient. While negotiating these roles, they experienced dialectical struggles and uncertainty relating to emotion management, locus of control, appraisals of self/others, and relational self. Women managed these conflicts within the contexts of their emerging maternal identity, patient-provider relationships, and social relationships. Women struggled as they managed emotion, determined their level of responsibility for fetal outcomes, appraised others and themselves, and worried about how they were perceived. This amplified distress and contributed to women's emotional exhaustion, sense of being overwhelmed, and stress burden. New explication of these energy-depleting dynamic processes underlying women's experiences of MHRP and their impact on the future mother-infant relationship is considered, and strategies for psychosocial support are identified.

Practicing maternal virtues prematurely: The phenomenology of maternal identity in medically high-risk pregnancy.

In this study, we examine the phenomenology of maternal identity development among U.S. women hospitalized with medically high-risk pregnancies (MHRP). We conducted 16 in-depth interviews with women and found that they drew on culturally normative notions of maternal nurture, worry, and sacrifice to construct maternal identity in the context of MHRP. Based on our findings, we suggest that MHRP shape women's sense of connection to and distinctive cognitive representations of their fetus. We conclude that hospitalization simultaneously promotes and challenges women's early maternal identifications.

Factors associated with receipt of medication for opioid use disorder among pregnant individuals entering treatment programs in the U.S.

BACKGROUND: Opioid use disorder (OUD) among pregnant individuals in the U.S. has been on the rise, and carries significant health risks if left untreated. Despite the effectiveness of medication for opioid use disorder (MOUD), rates of treatment utilization remain low, and access varies by state. This study seeks to expand on what is known about the utilization of MOUD by estimating annual percentages of MOUD use among treatment admissions among pregnant individuals across all 50 states and U.S. regions. The study also examines how pregnant people experiencing OUD are referred to substance use treatment programs to better understand which referral sources are most effective at linking them to MOUD. METHODS: This study estimated MOUD utilization among pregnant admissions over a 9-year period, identifying trends in the use of this treatment, using national and state level data from the Treatment Episode Dataset-Admissions (TEDS-A). The sample were pregnant females who admitted to treatment with opioids as a primary substance use problem, in all 50 states, from 2010 to 2018. The study examined the referral pathways through which pregnant individuals enter treatment, identifying variations in how they are linked with MOUD. A binary logistic regression was conducted to estimate significant sociodemographic characteristics and referral sources associated with MOUD receipt in treatment. RESULTS: Among admissions who reported both pregnancy and OUD across nine years (n= 84,492), the average percentage of MOUD use was 50.8%. Average annual MOUD use was highest in the Northeast region (63.42%), and lowest in the South (34.01%). Maine had the highest MOUD use, for an average of 81.99% across all years. Pregnant individuals who were self-referred to treatment comprised the largest percentage of admissions leading to MOUD use (62.1%), and those referred by the criminal justice system or other legal entity resulted in the lowest MOUD use across years (23.6%). Binary logistic regression results found that race, education, employment status, and referral source were significantly associated with MOUD receipt in 2018; specifically, individuals with a higher education, those were unemployed, and those who were referred to treatment by another substance use or healthcare provider or from the criminal or legal system, were significantly less likely to receive MOUD. CONCLUSION: This study estimated that an average of approximately half of admissions who were pregnant with OUD received MOUD as part of their treatment plans, and identified regional and state trends which can be further investigated to understand factors contributing to these geographical variations in MOUD access. Also notable were findings pertaining to low MOUD receipt among those referred from criminal or legal entities, warranting further investigation. These findings can lead to a better understanding of which referral sources to treatment can act as effective pathways to MOUD, and best practices to link pregnant individuals with evidence-based care.

The independent and joint effect of socioeconomic status and Multiracial status on the prevalence and frequency of substance use and depression among U.S. adolescents.

AIM: While the United States is becoming increasingly Multiracial, much is still unknown about the behavioral health of these growing new generations of Multiracial Americans. To narrow this research gap, this study investigated the prevalence/frequency of substance use and major depressive episodes [MDE] among non-Hispanic Multiracial [NHM] adolescents compared to their non-Hispanic White [NHW] counterparts and whether racial differences vary by socioeconomic status. METHODS: We analyzed data from the 2015-2019 National Survey on Drug Use and Health (N = 3,645 NHM and 34,776 NHW adolescents aged 12-17). Average Marginal Effects derived from logistic regression and negative binomial regression were used to examine (1) differences in six outcomes (past-month use of alcohol, cannabis, or drugs other than cannabis [DOTC], past-year MDE, and the frequency of alcohol and cannabis use among past-month users) by Multiracial status; (2) the moderation effect of family income on these associations. RESULTS: Compared to high-income NHW adolescents, high-income NHM adolescents reported significantly higher prevalence of past-month cannabis and DOTC use, and past-year MDE. No racial differences were observed at other income levels. Furthermore, moderation analyses indicated that the effect of Multiracial status on MDE was larger in the highest income group compared to the lowest income group. CONCLUSION: Our findings suggested that NHM adolescents, particularly those from high income families, exhibit increased prevalence of drug use and depression than NHW adolescents. As the US becomes more diverse, there is a need to further examine the social and structural factors driving the identified racial differences.

Implementation and evaluation of pharmacist-led heart failure diagnostic and guideline directed medication therapies clinic.

BACKGROUND: Timely diagnosis of heart failure (HF) and rapid optimisation of guideline-directed medication therapy (GDMT) improves patients qualities of life, reducing mortality and morbidity. Previous papers describe the role of pharmacists in medication optimisation, but not in the diagnosis of HF. AIM: To describe the development, implementation, and evaluation of pharmacist-led heart failure clinics with respect to time from referral to diagnosis, time from diagnosis to first review with a specialist, and the proportion receiving optimal GDMT 180 days after diagnosis. SETTING: Community outpatient clinics in rural west Wales, United Kingdom. DEVELOPMENT: Two experienced non-medical prescribing pharmacists, one of whom had additional diagnostic qualifications in cardiology, delivered the clinic. IMPLEMENTATION: Patients referred with suspected HF were risk-stratified to urgent (within 14 days of referral) or routine (within 42 days) review, based on natriuretic peptide levels. Patients attended the clinic for assessment, including physical examination, electrocardiogram, and echocardiogram. Those with HF with reduced ejection fraction were initiated on drug treatment and referred to the follow-up pharmacist-led GDMT clinic. EVALUATION: A sample of 100 patients was evaluated (50 from pre-existing and 50 from new service). Median time from referral to diagnosis reduced from 61 days (IQR 47-115) to 16 days (IQR 10.5-27.5) for urgent and 19 days (IQR 11.5-33) for routine. Median time to first appointment following diagnosis reduced from 54 days (IQR 36-60.5) to 14 days (IQR 9.75-28.75) (p value < 0.0001), and proportion of patients achieving GDMT at 180 days following diagnosis improved from 24 to 86% (p value < 0.0001). CONCLUSION: This pharmacist HF diagnostic clinic and medication optimisation clinic improved time to diagnosis, time to first specialist review, and proportion of patients' achieving GDMT optimisation in a rural healthcare setting.

Acceptability and feasibility of using contingency management for cannabis reduction in specialist mental health services for psychosis: A qualitative study of staff views.

AIM: There is increasing evidence linking cannabis use to onset, continuation, and relapse of psychosis. Contingency Management (CM) is discussed as a candidate intervention to reduce cannabis use. Our study aimed to explore staff views on the feasibility and acceptability of using CM for cannabis reduction in early intervention services for psychosis (EIS), in order to inform wider learning about implementation of such approaches in mental health services. SETTING: EIS teams in England. METHOD: Semi-structured interviews and focus groups analysed thematically. PARTICIPANTS: Forty managers and staff members working in mental health services where a CM intervention was delivered as part of a trial, four staff who delivered CM in these settings, and three key informants (academic experts in relevant fields). INTERVENTION: A complex intervention comprising CM with incremental financial incentives (vouchers) for reducing or stopping cannabis use, and psychoeducation about the risks of cannabis use. FINDINGS: Acceptability appeared to depend on how well the intervention was seen to fit with the service setting and ethos. Concerns included who should deliver CM; potential impacts on the therapeutic relationship; the ethics of using incentives to reduce socially objectionable behaviours; and how CM fits with the work of mental health practitioners. Feasibility concerns centred on resource limitations including time, cost, training, and national guidance and commissioning. CONCLUSIONS: Staff attitudes are likely to be a crucial influence on successful implementation of contingency management for cannabis reduction in specialist mental health settings. Several contextual barriers would need to be overcome to increase the acceptability of the intervention for use in early intervention services for psychosis.

Social service providers under COVID-19 duress: adaptation, burnout, and resilience.

Summary: This article examines the response of social services organizations and their workers to the COVID-19 pandemic in a northeastern U.S. state. Using an exploratory, cross-sectional survey design with a convenience sample (N = 1472), we ask: (1) how did agencies and social service workers manage service disruptions associated with COVID-19; (2) how did social service workers perceive shifts in clients' needs; (3) how did social service workers experience the transition to remote interactions with clients; and (4) how did social service workers cope with COVID-related transitions and demands. Findings: Our findings tell a story of unprecedented crises alongside powerful attempts at adaptation, innovation, and resilience. Faced with extraordinary need among their clients, fears for their own health, and a breakdown of organizational and community functioning and guidance, social workers were able to learn and implement new technologies, adapt to increasing demands, manage new work-life boundaries, and find ways to address gaps in service while experiencing symptoms of burnout. Application: The impact of supervisory and administrative fragmentation and communication breakdowns in the face of crisis put social workers in an untenable position despite surprising abilities to adapt, innovate, and manage their professional lives while under duress. Assuring better supervisory/administrative infrastructure to support workers as they deliver services during crises will help in future crises.

An LC-MS/MS method for simultaneous analysis of up to six monoamines from brain tissues.

Monoamines are a class of neuromodulators that are crucial for a variety of brain functions, including control of mood, movement, sleep and cognition. From mammals to insects, the nervous system is enriched in monoamines such as dopamine, serotonin and melatonin, analytes which range from being highly polar to non-polar. Here we developed a method using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) to quantify in a single run the amounts of six distinct monoamines in extracts from dissected Drosophila and mouse brain tissues. The measured monoamines were dopamine (DA), serotonin (also known as 5-hydroxytryptamine (5-HT)), octopamine (OA, an insect equivalent of norepinephrine), tyramine (TA), melatonin (MT) and N-acetylserotonin (NAS). The analytical range of these monoamines was between 0.25 and 5.0 ng/mL. This quantitative LC-MS/MS methodology has important use for simultaneous measurement of distinct neuroactive monoamines from precious biological specimens.

Ferroptosis induces detrimental effects in chronic EAE and its implications for progressive MS.

Ferroptosis is a form of lipid peroxidation-mediated cell death and damage triggered by excess iron and insufficiency in the glutathione antioxidant pathway. Oxidative stress is thought to play a crucial role in progressive forms of multiple sclerosis (MS) in which iron deposition occurs. In this study we assessed if ferroptosis plays a role in a chronic form of experimental autoimmune encephalomyelitis (CH-EAE), a mouse model used to study MS. Changes were detected in the mRNA levels of several ferroptosis genes in CH-EAE but not in relapsing-remitting EAE. At the protein level, expression of iron importers is increased in the earlier stages of CH-EAE (onset and peak). While expression of hemoxygenase-1, which mobilizes iron from heme, likely from phagocytosed material, is increased in macrophages at the peak and progressive stages. Excess iron in cells is stored safely in ferritin, which increases with disease progression. Harmful, redox active iron is released from ferritin when shuttled to autophagosomes by 'nuclear receptor coactivator 4' (NCOA4). NCOA4 expression increases at the peak and progressive stages of CH-EAE and accompanied by increase in redox active ferrous iron. These changes occur in parallel with reduction in the antioxidant pathway (system xCT, glutathione peroxidase 4 and glutathione), and accompanied by increased lipid peroxidation. Mice treated with a ferroptosis inhibitor for 2 weeks starting at the peak of CH-EAE paralysis, show significant improvements in function and pathology. Autopsy samples of tissue sections of secondary progressive MS (SPMS) showed NCOA4 expression in macrophages and oligodendrocytes along the rim of mixed active/inactive lesions, where ferritin+ and iron containing cells are located. Cells expressing NCOA4 express less ferritin, suggesting ferritin degradation and release of redox active iron, as indicated by increased lipid peroxidation. These data suggest that ferroptosis is likely to contribute to pathogenesis in CH-EAE and SPMS.

"There is Just a Different Energy": Changes in the Therapeutic Relationship with the Telehealth Transition.

The therapeutic relationship (TR), including its therapeutic frame, is the foundation of the therapeutic endeavor. In response to the COVID-19 pandemic and the rapid transition to videoconferencing for therapeutic encounters, we employed a cross-sectional exploratory survey with 1490 respondents to understand how practitioners adapted to the changes. In this secondary analysis focused on the TR, we analyze the clinicians' (N = 448) spontaneous narratives about facets of the TR. Temporally, we focused on how these adaptations occurred during the initial part of the pandemic before vaccination was available and while the TR was still adapting to teletherapy videoconferencing under the duress of pandemic crises. We find three broad themes: (1) It is a "much more remote relationship"; (2) The "connection…remains surprisingly strong"; and (3) It is "energetically taxing." Each reflects clinicians' views of the TR as altered, but surprisingly resilient. Although grateful for the safety of virtual therapeutic encounters, clinicians mourned the loss of an embodied encounter, experienced depletion of energy beyond Zoom fatigue, and nonetheless recognized their clients' and their own abilities to adapt.

Maternal identity negotiations among low-income women with symptoms of postpartum depression.

In this study, we used a constructivist grounded theory approach to explore maternal identity negotiations among low-income ethnic minority mothers with postpartum depression (PPD) symptoms. Nineteen mothers were recruited from Women, Infant, and Children clinics located in two coastal cities in the United States to participate in in-depth interviews. Constant comparative analysis revealed that mothers experienced their PPD symptoms and poverty as evidence of maternal failure, but also drew on discourses of maternal self-sacrifice, engagement with their children, and pleasure in mothering to construct a positive sense of self. To negotiate these conflicting versions of self, mothers positively appraised their own mothering in relation to stigmatized "others" and framed their depression as a foreign entity, one that stood outside of a core, authentic sense of self. Through our consideration of the intersecting contexts of poverty and postpartum depressive symptoms, this article adds to the literature on PPD and mothering.

Audiometric thresholds measured with single and dual BAHA transducers: The effect of phase inversion.

The bone-anchored-hearing-aid (BAHA) transduces airborne sound into skull vibration. Current bilateral BAHA configurations, for sounds directly facing listeners, will apply forces that are in-phase with each other and directed roughly towards the center of the head. Below approximately 1000 Hz the two cochleae respond in approximately the same direction and with approximately the same phase to each BAHA, thus it may be preferable to drive bilateral BAHAs such that when one pushes, the other pulls. This can be achieved by adjusting the relative phase offset of the BAHAs, and doing so results in greater vibration and improved hearing threshold. In this paper we compare performance of bilateral BAHAs driven in this configuration to the standard configuration. In twelve normal participants we show significant improvements in low-frequency (≤750 Hz) hearing thresholds using out-of-phase BAHAs. The threshold measurements are further supported by velocimetric measurements taken at the cochlear promontory in a cadaveric head. Comparing vibration arising from each configuration confirms that out-of-phase driving results in greater vibration. Neither dataset shows either improved or reduced threshold at high frequencies.

Barriers to service use for postpartum depression symptoms among low-income ethnic minority mothers in the United States.

The risks of untreated postpartum depression (PPD) in the United States are higher among low-income ethnic minority mothers. However, research has not adequately investigated barriers to formal help seeking for PPD symptoms among this vulnerable population. We used convenience and purposive sampling strategies to recruit mothers experiencing past-year (the year prior to interview) PPD symptoms (n=14), community key informants (n=11), and service providers (n=12) to participate in focus groups and individual interviews. A grounded theory analysis of these nested perspectives revealed individual, community, and provider-level barriers operating at various stages of the help-seeking process: thinking about symptoms, seeking advice, and rejecting formal care. Although mothers overwhelmingly recommended "talking it out" for other mothers with PPD, an array of attitudinal and instrumental barriers led mothers to choose self-help practices in lieu of formal mental health care.

Mental Health Trainees' Explicit and Implicit Attitudes Toward Transracial Adoptive Families Headed by Lesbian, Gay, and Heterosexual Couples.

We investigated 109 (79.8% female; 76% White, and 83.5% Heterosexual) mental health trainees' explicit and implicit attitudes toward heterosexual, lesbian, and gay White couples adopting and raising Black children. To determine explicit attitudes, we used a vignette depicting a Black child ready for adoption and three types of equally qualified White families who were headed by a heterosexual couple, gay couple, or lesbian couple. The trainees were asked to indicate which type of family they preferred to adopt the child. To determine implicit attitudes, we used the computer programed latency-based multifactor implicit association test (IAT) protocol. The IAT data were collected from each participant individually. Explicit data showed that over 80% of the participants indicated no strong preference in terms of which type of family should adopted the child. However, IAT data showed that the trainees implicitly preferred lesbian couples. Overall, the degree of congruence between explicit and implicit was very low. Implications for training were discussed.

Saliency interactions between the 'L-M' and 'S' cardinal colour directions.

Two sub-systems characterize the early stages of human colour vision, the 'L-M' system that differences L and M cone signals and the 'S' system that differences S cone signals from the sum of L and M cone signals. How do they interact at suprathreshold contrast levels? To address this question we employed the method used by Kingdom et al. (2010) to study suprathreshold interactions between luminance and colour contrast. The stimulus employed in one condition was similar to that used by Regan and Mollon (1997) for studying the relative 'organizing power' of the two sub-systems, and consisted of obliquely-oriented red-cyan (to isolate the L-M sub-system) and violet-chartreuse (to isolate the S sub-system) stripes within a lattice of circles. In our experiment there were two conditions, (1) the Separated condition, in which the L-M and S modulations were of opposite orientation and presented separately as a forced-choice pair, and (2) the Combined condition, in which the L-M and S modulations were added. In the Separated condition the task was to indicate the stimulus with the more salient orientation structure, whereas in the Combined condition the task was to indicate the orientation that was more salient. Psychometric functions were used to estimate the ratio of L-M to S contrast at the 'balance-point' i.e. point-of-subjective-equality (PSE) in both conditions. We found that across 20 subjects an average of 8% more S than L-M contrast was needed to achieve a PSE in the Combined compared to Separated condition. We consider possible reasons for this PSE difference and conclude that it is either due to an early-stage interaction between the S and L-M sub-systems, or to a later stage in which new colours that arise from their combination are selectively grouped.