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Abstract Promiscuous females reduce male reproductive control. Males can attempt to monopolise access to these females, but distractions and sneaky rivals mean extra copulations cannot always be blocked. By mating first, males can obtain a headstart in sperm competition, but this may be negated by sperm storage and cryptic female choice mechanisms. We carry out an indirect rare test of an early mating advantage in a population of free-living wild animals. Using Bayesian GLMM analysis of a long-term life history database spanning 17 years, we show that banded mongoose males who interacted with females in earlier days of oestrus had a higher chance of siring their offspring compared with later rivals. An early mating advantage would intensify initial male-male competition and hence selection for male choice, as any initial mistake identifying preferred mating partners could see paternity lost to rivals.

Abstract Background The healthcare workforce is one of the six core components of a well-functioning and sufficient health system. The WHO highlights that improving education and training of the health workforce is critical to improving health systems. Medical education is a pillar of the healthcare workforce. The educational environment - the physical circumstances or conditions under which learning takes place - is an important factor determining medical education’s effectiveness. Its academic and clinical effects significantly determine medical students’ attitudes, knowledge, skills, progression, and behaviors. To ensure strong health systems, there is a need for improvement in medical education. Improvement must be contextual and informed by locally relevant data. This study, which assessed Ugandan medical students’ perception of their learning environment, provides crucial context-specific data highly relevant to the current state of medical education in Uganda. Methods This quantitative cross-sectional study was conducted among medical students across five medical schools in Uganda between December 2021 and February 2022. Participants completed an online questionnaire with a demographics section and the Dundee Ready Education Environment Measure (DREEM) tool. The data was analyzed using R in R Studio version 2021.09.0 + 351. The average score for each DREEM sub-scale and the total DREEM score were calculated, and their relationship with demographic characteristics was examined. Results The average total DREEM score of the 335 participants was 112.27/200 (56.12%). We found that 69% (231/335) of the students had a positive perception. The sub-scale mean scores were as follows: Perception of Atmosphere – 25.14/48, Social Self-perception − 14.94/28, Perception of Teachers − 24.86/44, Perception of Learning − 28.8/48, and Academic Self-perceptions – 19.04/32. “ There is a good support system for students who get stressed” was the item with the lowest mean score (1.41/5). Conclusions The study’s findings indicate that medical students’ perceptions of their learning environment are just above average. This suggests a need for improvement, particularly in the atmosphere and social support, to ensure the training of a robust health workforce. The results of this study should motivate stakeholders to initiate changes that will enhance the quality of medical education in Uganda.

Background: African people demand the reformation of current development evaluation practices because they are less democratic and marginalise their ways of knowing and valuing. Objectives: This article examined wisdom in Swahili proverbs that could inspire and guide efforts to reform development evaluation practices to make them more democratic and transformative. Method: A total of 45 Swahili proverbs were analysed to uncover their wisdom and guidance on framing meanings and purposes of evaluation and the rights and duties of participants in the evaluation process. The appropriateness and feasibility of the framed meanings, purposes, rights and duties were tested in a survey involving 61 Swahili-speaking evaluators. Results: Based on the uncovered wisdom, development evaluations are social activities initiated by and involving people to systematically inquire and assess aspects of ongoing or completed development projects and programmes to: (1) determine performances in keeping promises made, (2) determine preventive and corrective measures for possible and actual implementation challenges and (3) co-learn and co-produce histories of the completed development projects and programmes. Insights in these three development evaluation practices adequately guide respecting people’s rights and freedoms to initiate and lead the evaluations of their development projects and programmes and integrate their ways of knowing and valuing. Conclusion: Swahili wisdom provides solid theoretical bases and numerous methodological strategies for supporting people in initiating, conducting and using evaluations. Contribution: This research contributes to the proverb-based approach to developing African-rooted evaluation theories and methodologies by offering lessons on generating and applying proverbial wisdom to improve development evaluation practices.

Reproductive activity is costly in terms of future reproduction and survival. Oxidative stress has been identified as a likely mechanism underlying this cost of reproduction. However, empirical studies have yielded the paradoxical observation that breeders often sustain lower levels of oxidative damage than non-breeders. The oxidative shielding hypothesis attempts to explain such data, and posits that breeders pre-emptively reduce levels of oxidative damage in order to protect their germ cells, and any resultant offspring, from harm caused by exposure to oxidative damage. While there is some empirical evidence of oxidative shielding in females, there have been no explicit tests of this hypothesis in males, despite evidence of the oxidative costs to the male reproductive effort and the vulnerability of sperm cells to oxidative damage. In this study, we assess lipid oxidative damage (malondialdehyde, MDA) in the ejaculates of reproducing and non-reproducing wild banded mongooses. We found that, among breeding males, ejaculate MDA levels were lower during mate competition compared to 2 months later, when individuals were not mating, which is consistent with the oxidative shielding hypothesis, and similar to findings in females. However, ejaculate MDA levels did not differ significantly between breeding and non-breeding individuals at the time of mating, contrary to expectation. The finding that ejaculate MDA was not higher in non-breeders may reflect individual differences in quality and hence oxidative stress. In particular, breeders were significantly older than non-breeders, which may obscure differences in oxidative damage due to reproductive investment. Further research is needed to establish the causal relationship between reproductive investment and oxidative damage in ejaculates, and the consequences for offspring development in banded mongooses and other species.

Transport-energy transitions pose complex challenges that have been extensively studied in high-income countries in response to national mandates for climate action. Low- and middle-income countries, however, have low but rapidly growing motorisation rates and face very different challenges in adopting new technologies to foster economic development and ensure equitable access to clean transportation. Here, we present a set of narrative scenarios for the future of the Kenyan transport-energy system co-developed through engagement with 41 local experts and decision-makers. Through the co-development of a Kenyan transport-energy system model, we present a decision-support tool, populated with those scenarios, to assist policymakers at regional, national and international levels in building policy and investment pipelines to support low-carbon economic growth. We find that Kenya’s transport-energy system can meet both development and climate goals, but this demands strong policy support for efficient public transport and targeted support for road vehicle electrification. Increased support for non-motorised transport is essential to provide equitable access to services and economic opportunities. Favourable pathways result in significant e-mobility uptake, which is anticipated to increase electricity demand by 5%–56% from 2023 to 2040, relative to the IEA Kenya Energy Outlook’s Stated Policies scenario, representing a 2.7–3.9x increase in Kenya’s total electricity demand over the same period. From a macro-fiscal perspective, results show that e-mobility has two important consequences for Kenya. Firstly, under high e-mobility scenarios, there is a negative fiscal impact that taxation revenues from the sale of transport fuels reduce by up to 41% relative to the low e-mobility scenario (though, notably, they still increase marginally from the 2023 level because of increasing transport demand). Secondly, high e-mobility scenarios have a positive impact on balance of payments by reducing the fuel import bill by up to 69% relative to the low e-mobility baseline. This corresponds to a reduction in foreign exchange requirement of up to $4.2bn annually by 2050.

This study aims to identify and map out circular economy in scientific literature in the global and Africa context. The circular economy has been adopted mostly in industrial production systems in the developed economies, its application in Africa is limited mostly to environment sector. A paucity of scholarly research and scientific publications on CE instigated the need to map out circular economy for sustainable development Africa. This article provides an overview of scientific publications on circular economy built in Africa through the Scopus database. The study used bibliometric analysis based on data obtained from Scopus database highlighting scientific literature. The analysis obtained 414 publications from 2005 to 2024. It provides descriptive and analytical graphs and bibliographic maps generated in R-Studio software. Findings shows main scientific and scholars are in European and Chinese universities with scanty publications in Africa. These findings signal the inadequacy of scientific research to inform policies on circular economy in Africa. It calls for future demand for more research and scientific publication on circular economy linked to sustainability in Africa.

Introduction: While older adults generally mount weaker antibody responses to a primary COVID-19 vaccine series, T-cell responses remain less well characterized in this population. We compared SARS-CoV-2 spike-specific T-cell responses after 2- and 3-dose COVID-19 mRNA vaccination and subsequent breakthrough infection in older and younger adults. Methods: We quantified CD4+ and CD8+ T-cells reactive to overlapping peptides spanning the ancestral SARS-CoV-2 spike protein in 40 older adults (median age 79) and 50 younger health care workers (median age 39), all COVID-19 naive, using an activation-induced marker assay. T-cell responses were further assessed in 24 participants, including 8 older adults, who subsequently experienced their first SARS-CoV-2 breakthrough infection. Results: A third COVID-19 mRNA vaccine dose significantly boosted spike-specific CD4+ and CD8+ T-cell frequencies to above 2-dose levels in older and younger adults. T-cell frequencies did not significantly differ between older and younger adults after either dose. Multivariable analyses adjusting for sociodemographic, health, and vaccine-related variables confirmed that older age was not associated with impaired cellular responses. Instead, the strongest predictors of CD4+ and CD8+ T-cell frequencies post-third-dose were their corresponding post-second-dose frequencies. Breakthrough infection significantly increased both CD4+ and CD8+ T-cell frequencies, to comparable levels in older and younger adults. Exploratory analyses revealed an association between HLA-A*02:03 and higher post-vaccination CD8+ T-cell frequencies, which may be attributable to numerous strong-binding HLA-A*02:03-specific CD8+ T-cell epitopes in the spike protein. Conclusion: Older adults mount robust T-cell responses to 2- and 3-dose COVID-19 mRNA vaccination, which are further boosted following breakthrough infection.

Abstract Humoral responses to COVID-19 vaccines in people living with HIV (PLWH) remain incompletely characterized. We measured circulating antibodies against the SARS-CoV-2 spike protein receptor-binding domain (RBD), ACE2 displacement and viral neutralization activities one month following the first and second COVID-19 vaccine doses, and again 3 months following the second dose, in 100 adult PLWH and 152 controls. All PLWH were receiving suppressive antiretroviral therapy, with median CD4+ T-cell counts of 710 (IQR 525–935) cells/mm3, though nadir CD4+ T-cell counts ranged as low as

IntroductionThe continuous flow of ecosystem services (ESs) within coastal and marine ecosystems supports communities' well-being and security by harnessing required resources such as seafood that address food security. The overexploitation of these coastal resources places communities at risk of losing ES. This study assesses how preference for the ES flow from these ecosystem types (i.e., mangrove forests, coastal lagoons, seagrass beds, coral reefs, and the deep sea) vary by gender in Diani Chale and Kisite-Mpunguti Marine Protected Areas in Kwale County, Kenya. Specifically, the objective of this article was to assess the pattern and variation in mean scores of ES flow across coastal and marine ecosystem types by gender.MethodsA total of 148 respondents (87 men and 61 women) aged 20-72 years participated in describing ES through focus group discussions and the Delphi technique. Respondents were engaged in a participatory activity that involved filling of perceived ES flow scores using a 6-point Likert-type scale in the lookup tables (also known as matrix). Data were analyzed using descriptive statistics for mean scores of ES flow across coastal and marine ecosystem types as perceived by men and women. One-way MANOVA was used to test for the significant differences between mean scores of men and women in ES flow across ecosystem types.ResultsThe aggregate scores for non-use values, regulating services, and cultural services, were scored higher than provisioning services by ecosystem service flow. The overall ES flow scores were higher in the mangrove forests 52/90 and least in the coastal lagoon 39/90. There was a significant variation (p < 0.05) of ES flow by gender: the mean score of men was significantly higher than women for most ES flow in cultural, regulating, and provisioning services across some coastal and marine ecosystem types. However, there was no significant variation (p > 0.05) in the flow of non-use values by gender across ET.ConclusionThe findings of this study highlight the importance of understanding gender views in ES access and use at local levels to support food security. Including gender perspectives in coastal and marine ecosystem governance is critical, especially toward achieving sustainable development goals.

KCERT 2050 is a modelling tool designed to assist in the identification and evaluation of synergies and trade-offs within sectoral decarbonization pathways for Kenya. KCERT 2050 is positioned as a user-friendly and dynamic tool that bridges complex energy systems and emissions models with integrated impact assessment tools, aimed at aiding decision making towards carbon neutrality in both public and private sectors. The tool considers greenhouse gas emissions from various economic sectors and is validated through a collaborative process involving experts from diverse backgrounds. This study uses KCERT 2050 to examine the prospects of achieving a net−zero emissions pathway by 2050. In the baseline scenario, a significant emission trajectory is observed, with the transport sector emerging as the largest contributor. Transitioning to the net−zero pathway reveals substantial reductions across key sectors, such as transport, industry, and land use, driven by strategies including electrification, waste reduction, and afforestation. The sensitivity analysis underscores the potential for emission mitigation through various levers, including land use optimization and the adoption of cleaner transportation modes. In conclusion, our findings emphasize the potential and feasibility of Kenya’s ambitious net−zero emissions target. To attain this goal, it is imperative to prioritize sustainable land use and innovative waste management strategies.

SARS-CoV-2 Omicron infections are common among individuals who are vaccinated or have recovered from prior variant infection, but few reports have immunologically assessed serial Omicron infections. We characterized SARS-CoV-2 humoral responses in an individual who acquired laboratory-confirmed Omicron BA.1.15 ten weeks after a third dose of BNT162b2, and BA.2 thirteen weeks later. Responses were compared to 124 COVID-19-naive vaccinees. One month post-second and -third vaccine doses, the participant’s wild-type and BA.1-specific IgG, ACE2-displacement and virus neutralization activities were average for a COVID-19-naive triple-vaccinated individual. BA.1 infection boosted the participant’s responses to the cohort ≥95th percentile, but even this strong “hybrid” immunity failed to protect against BA.2. Reinfection increased BA.1 and BA.2-specific responses only modestly. Though vaccines clearly protect against severe disease, results highlight the continued importance of maintaining additional protective measures to counteract the immune-evasive Omicron variant, particularly as vaccine-induced immune responses naturally decline over time.

Introduction: Uganda is one of the largest refugee-hosting nations in the world, with the majority of the refugees having fled South Sudan. In the early 2000's the local government and refugee health systems were merged to create a more equal and integrated system for refugees and the host population. Our aim is to investigate whether mothers from the two groups experience the same access to and quality of maternal health services, and whether refugee- and host-community mothers perceive the maternal health services differently.Methods: In November–December 2019, we conducted a household survey of 1,004 Ugandan nationals and South Sudanese refugee mothers aged 15–49 in the West Nile region covering the districts of Arua, Yumbe, and Adjumani, and elicited information on access to maternal health care services, perceptions of the quality of services, and feelings of discrimination. The data was then analyzed using Ordinary Least Squares and logistic regression.Results: Our analyses do not reveal large differences between refugees and the host community in terms of access to and the quality of maternal health services. Results from bivariate models indicate that refugee mothers are 6% points less likely to receive antenatal care (p-value < 0.05) but are 8% points more likely to give birth at a health facility (p-value < 0.05). Refugee mothers are generally less satisfied with how they were treated during antenatal care (0.132 lower average value on a Likert scale, p-value < 0.01). Refugee mothers are also 4% points more likely to feel discriminated against during ANC compared to their counterparts in the host community (p-value < 0.05).Discussion: The way women feel treated at the health facility during maternal health care is an important aspect of quality care. While there seems to be equal access to resources between refugees and host community mothers in Northern Uganda in terms of access to and quality of care, there is still a discrepancy between the two groups in terms of how the women feel treated. Policymakers and practitioners in the health sector should pay attention to these perceived inequalities between refugees and women from the host communities to ensure equally inclusive treatment across groups.

Escherichia coli such as E. coli O157:H7, a non-sorbitol-fermenting (NSF) E. coli, is an essential human pathogen among other common zoonotic pathogens carried by animals especially cattle. They are discharged through cattle faeces into the environment. With the increasing practice of urban farming, livestock manure is used as organic fertiliser in either fish ponds or vegetable gardens. This practice increases the risk of transmission of such pathogens to humans. This study aimed at determining the occurrence, antimicrobial resistance profiles, and genetic relatedness of E. coli isolates from manure, vegetables, and fish. Microbiological standard methods were used to isolate and identify E. coli isolates from manure, vegetable, and fish samples. Confirmed isolates on biochemical tests were tested for resistance against six antibiotics using the disc diffusion method. Enterobacterial repetitive intergenic consensus polymerase chain reaction (ERIC-PCR) typing method was used to generate fingerprints and determine the genetic relatedness of the E. coli isolates. Of 156 samples including 89 manure, 53 vegetables, and 16 fish, 36 (23.1%) samples were positive for E. coli from where a total of 48 E. coli different isolates were recovered that were subjected to antimicrobial susceptibility testing and genetic relatedness. Of these isolates, 25 (52.1%) were resistant to at least one antimicrobial agent and 12 (48.0%) showed multidrug resistance. ERIC-PCR profiles of E. coli isolates from manure, vegetables, and fish showed genetic diversity with genetic relatedness ranging from 74.5% to 100%. Nine phylogenetic clusters (I–IX) determined at 90% threshold level of genetic relatedness were identified among the isolates. This study determined the occurrence, antimicrobial resistant patterns, and genetic diversity of antimicrobial-resistant E. coli isolates from different sources. This study showed the potential of microbial health risk to humans through contamination, and hence, it is necessary to monitor and improve husbandry practices in urban farming.

Studying ecological and evolutionary processes in the natural world often requires research projects to follow multiple individuals in the wild over many years. These projects have provided significant advances but may also be hampered by needing to accurately and efficiently collect and store multiple streams of the data from multiple individuals concurrently. The increase in the availability and sophistication of portable computers (smartphones and tablets) and the applications that run on them has the potential to address many of these data collection and storage issues. In this paper we describe the challenges faced by one such long-term, individual-based research project: the Banded Mongoose Research Project in Uganda. We describe a system we have developed called Mongoose 2000 that utilises the potential of apps and portable computers to meet these challenges. We discuss the benefits and limitations of employing such a system in a long-term research project. The app and source code for the Mongoose 2000 system are freely available and we detail how it might be used to aid data collection and storage in other long-term individual-based projects.

ABSTRACT HIV-1 Nef binds to the cytoplasmic region of HLA-A and HLA-B and downregulates these molecules from the surface of virus-infected cells, thus evading immune detection by CD8+ T cells. Polymorphic residues within the HLA cytoplasmic region may affect Nef’s downregulation activity. However, the effects of HLA polymorphisms on recognition by primary Nef isolates remain elusive, as do the specific Nef regions responsible for downregulation of HLA-A versus HLA-B. Here, we examined 46 Nef clones isolated from chronically HIV-1 subtype B-infected subjects for their ability to downregulate various HLA-A, HLA-B, and HLA-C molecules on the surface of virus-infected cells. Overall, HLA-B exhibited greater resistance to Nef-mediated downregulation than HLA-A, regardless of the cell type examined. As expected, no Nef clone downregulated HLA-C. Importantly, the differential abilities of patient-derived Nef clones to downregulate HLA-A and HLA-B correlated inversely with the sensitivities of HIV-infected target cells to recognition by effector cells expressing an HIV-1 Gag-specific T cell receptor. Nef codon function analysis implicated amino acid variation at position 202 (Nef-202) in differentially affecting the ability to downregulate HLA-A and HLA-B, an observation that was subsequently confirmed by experiments using Nef mutants constructed by site-directed mutagenesis. The in silico and mutagenesis analyses further suggested that Nef-202 may interact with the C-terminal Cys-Lys-Val residues of HLA-A, which are absent in HLA-B. Taken together, the results show that natural polymorphisms within Nef modulate its interaction with natural polymorphisms in the HLA cytoplasmic tails, thereby affecting the efficiency of HLA downregulation and consequent recognition by HIV-specific T cells. These results thus extend our understanding of this complex pathway of retroviral immune evasion. IMPORTANCE Recognition of genetically diverse pathogens by the adaptive immune system represents a primary strategy for host defense; however, pathogens such as HIV-1 can evade these responses to achieve persistent infection. The HIV-1 nef gene and the HLA class I locus rank among the most diverse genes of virus and host, respectively. The HIV-1 Nef protein interacts with the cytoplasmic region of HLA-A and HLA-B and downregulates these molecules to evade cellular immunity. By combining molecular, genetic, and in silico analyses, we demonstrate that patient-derived Nef clones downregulate HLA-A more effectively than HLA-B molecules. This in turn modulates the ability of HIV-specific T cells to recognize HIV-infected cells. We also identify a naturally polymorphic site at Nef codon 202 and HLA cytoplasmic motifs (GG314,315 and CKV339–341) that contribute to differential HLA downregulation by Nef. Our results highlight new interactions between HIV-1 and the human immune system that may contribute to pathogenesis.

Objective: We investigate offspring alcohol use outcomes as a function of unremitted and remitted parental alcohol use disorder (AUD)., Methods: Self-report data of participants in the Collaborative Study on the Genetics of Alcoholism (COGA) were used. Offspring (n=2244, mean age 16.3 at baseline, 26.9 years at follow-up, 50.8% female) were linked to parent data. Time-varying associations of parental AUD and remission with offspring age at first drink, years from first drink to AUD onset, and years from AUD onset to first remission were tested in Cox models adjusted for polygenic risk for problematic alcohol use (PGSPAU). Analyses were stratified by genetically inferred continental groups of European (EA, 65.9%) and African (AA, 34.1%) Americans due to sociocultural factors that can contribute to differences in alcohol use and problems., Results: In EA, maternal remission was associated with increased risk for offspring AUD; neither maternal nor paternal remission was associated with other outcomes. In AA, maternal and paternal remission were associated with increased likelihood of early drinking; the association with maternal drinking varied as a function of whom offspring lived with during adolescence. Paternal, but not maternal, remission was associated with heightened risk for AUD onset. Parental status had no association with offspring remission in EA or AA., Conclusions: Evidence that parental remission can help mitigate the risk associated with parental AUD and increase likelihood of remission in affected offspring was limited and mixed based on continental group and sex. These nuanced outcomes highlight the complex interplay of parental AUD status and offspring's alcohol-related behaviors.

Background: In the United States, ~50% of individuals who meet criteria for alcohol use disorder (AUD) during their lifetimes do not remit. We previously reported that a polygenic score for AUD (PGS AUD ) was positively associated with AUD severity as measured by DSM-5 lifetime criterion count, and AUD severity was negatively associated with remission. Thus, we hypothesized that PGS AUD would be negatively associated with remission., Methods: Individuals of European (EA) and African ancestry (AA) from the Collaborative Study on the Genetics of Alcoholism (COGA) who met lifetime criteria for AUD, and two EA cohorts ascertained for studies of liver diseases and substance use disorders from the Indiana Biobank were included. In COGA, 12-month remission was defined as any period of ≥12 consecutive months without meeting AUD criteria except craving and was further categorized as abstinent and non-abstinent. In the Indiana Biobank, remission was defined based on ICD codes and could not be further distinguished as abstinent or non-abstinent. Sex and age were included as covariates. COGA analyses included additional adjustment for AUD severity, family history of remission, and AUD treatment history., Results: In COGA EA, PGS AUD was negatively associated with 12-month and non-abstinent remission (p ≤ 0.013, βs between -0.15 and -0.10) after adjusting for all covariates. In contrast to the COGA findings, PGS AUD was positively associated with remission (p = 0.004, β = 0.28) in the Indiana Biobank liver diseases cohort but not in the Indiana Biobank substance use disorder cohort (p = 0.17, β = 0.15)., Conclusions: PGS AUD was negatively associated with 12-month and non-abstinent remission in COGA EA, independent of behavioral measures of AUD severity and family history of remission. The discrepant results in COGA and the Indiana Biobank could reflect different ascertainment strategies: the Indiana Biobank participants were older and had higher rates of liver disease, suggesting that these individuals remitted due to alcohol-related health conditions that manifested in later life., (© 2023 The Authors. Alcohol: Clinical and Experimental Research published by Wiley Periodicals LLC on behalf of Research Society on Alcohol.)

Background: Endorsement of specific Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) alcohol use disorder (AUD) criteria have been shown to change significantly over time in men in their thirties who have persistent or recurrent AUD. However, few studies have documented whether the endorsement of AUD items changes over time in younger individuals or in women. We evaluated changes in the endorsement of AUD criteria in 377 men and women with persistent or recurrent AUD during their twenties., Methods: Information on AUD-item endorsement over time was available for 223 men and 154 women aged 20-25 with persistent or recurrent AUD in at least three interviews in the Collaborative Study on the Genetics of Alcoholism. The statistical significance of endorsement changes over time was evaluated using the related-sample Cochran's Q test for the full sample and for men and women separately. Additional analyses evaluated sex differences in the patterns of change., Results: In the full sample, the predominant pattern was for a significant increase in the rates of endorsement for six of the seven alcohol dependence criteria but not in the four abuse criteria. A similar pattern was seen within men, but women had significant changes in only three of the seven dependence criteria., Conclusions: Endorsement of the seven alcohol dependence criteria among individuals with persistent or recurrent AUD in their twenties generally increased, but few changes were observed in the rates of endorsement of the four abuse criteria. These results are discussed in terms of how they reflect on the nature of AUD and the DSM criteria., (© 2023 Research Society on Alcohol.)

The present paper highlights how alcohol use disorder (AUD) conceptualizations and resulting diagnostic criteria have evolved over time in correspondence with interconnected sociopolitical influences in the United States. We highlight four illustrative examples of how DSM-defined alcoholism, abuse/dependence, and AUD have been influenced by sociopolitical factors. In doing so, we emphasize the importance of recognizing and understanding such sociopolitical factors in the application of AUD diagnoses. Last, we offer a roadmap to direct the process of future efforts toward the improved diagnosis of AUD, with an emphasis on pursuing falsifiability, acknowledging researchers' assumptions about human behavior, and collaborating across subfields. Such efforts that center the numerous mechanisms and functions of behavior, rather than signs or symptoms, have the potential to minimize sociopolitical influences in the development of diagnostic criteria and maximize the treatment utility of diagnoses.

Recent conceptualizations frame addiction recovery as a complex process involving changes across behavioral, physical, psychological, and social domains. These broad conceptualizations can be difficult to apply directly to research, making detailed models of individual dimensions necessary to guide empirical work and subsequent clinical interventions. We used Kelly and Hoeppner's (2015) biaxial formulation of recovery as a basis for a detailed examination of social processes in recovery using social network approaches. We delineated how appraisal of situational risks and social network resources result in coping actions, and how repeated iterations of this process change a person's social recovery capital over time. In addition, we incorporated the experience of interpersonal trauma and structural oppression, and demonstrated how the model accommodates the complex issues often encountered during recovery. We present a measurable framework that can guide empirical testing of how social processes and social recovery capital change over time during recovery. The model presented here illuminates key factors in the recovery process that have the potential to support trauma- and social-network-informed interventions. We call for research that empirically tests this model in ways that will result in practical, trauma-informed social network interventions for people in recovery., Competing Interests: Conflicts of Interest: No authors report there are no competing interests to declare.

Substance use disorders (SUDs) incur serious social and personal costs. The risk for SUDs is complex, with risk factors ranging from social conditions to individual genetic variation. We examined whether models that include a clinical/environmental risk index (CERI) and polygenic scores (PGS) are able to identify individuals at increased risk of SUD in young adulthood across four longitudinal cohorts for a combined sample of N = 15,134. Our analyses included participants of European (N EUR = 12,659) and African (N AFR = 2475) ancestries. SUD outcomes included: (1) alcohol dependence, (2) nicotine dependence; (3) drug dependence, and (4) any substance dependence. In the models containing the PGS and CERI, the CERI was associated with all three outcomes (ORs = 01.37-1.67). PGS for problematic alcohol use, externalizing, and smoking quantity were associated with alcohol dependence, drug dependence, and nicotine dependence, respectively (OR = 1.11-1.33). PGS for problematic alcohol use and externalizing were also associated with any substance dependence (ORs = 1.09-1.18). The full model explained 6-13% of the variance in SUDs. Those in the top 10% of CERI and PGS had relative risk ratios of 3.86-8.04 for each SUD relative to the bottom 90%. Overall, the combined measures of clinical, environmental, and genetic risk demonstrated modest ability to distinguish between affected and unaffected individuals in young adulthood. PGS were significant but added little in addition to the clinical/environmental risk index. Results from our analysis demonstrate there is still considerable work to be done before tools such as these are ready for clinical applications., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Aim: This study presents a measure of Social Recovery Capital (SRC) derived from the Important People and Activities instrument (IPA)., Methods: The sample comprised young adults who participated in the Collaborative Study on the Genetics of Alcoholism, a high-risk family study of alcohol use disorder (N = 2472). Exploratory and confirmatory factor analysis identified influential items and factor structure, adjusting for family relatedness. The final scale was tested for reliability and validity., Results: Factor analysis retained 10 items loading on three factors (Network Abstinence Behaviors, Basic Network Structure and Network Importance) that together explained 42% of the variance in SRC. The total model showed adequate fit (Comparative Fit Index = 0.95; Tucker Lewis Index = 0.93; Root Mean Square Error of Approximation = 0.06; Standardized Root Mean Squared Residual = 0.05) and acceptable reliability (α = 0.60; McDonald's ω = 0.73) and correlated with validation measures mostly in the weak to moderate range. Due to variable factor scores for reliability and validity, we only recommend using the total score., Conclusion: The SRC-IPA is a novel measure of SRC derived from the IPA that captures social network data and has applications in research and clinical work. Secondary data analyses using the SRC-IPA in studies that collected the IPA can further demonstrate the interaction of SRC with a wide variety of clinical indicators and demographic characteristics, making it a valuable addition to other measures of SRC., (© The Author(s) 2022. Medical Council on Alcohol and Oxford University Press. All rights reserved.)

Background: Early identification of individuals at high risk for alcohol use disorder (AUD) coupled with prompt interventions could reduce the incidence of AUD. In this study, we investigated whether Polygenic Risk Scores (PRS) can be used to evaluate the risk for AUD and AUD severity (as measured by the number of DSM-5 AUD diagnostic criteria met) and compared their performance with a measure of family history of AUD., Methods: We studied individuals of European ancestry from the Collaborative Study on the Genetics of Alcoholism (COGA). DSM-5 diagnostic criteria were available for 7203 individuals, of whom 3451 met criteria for DSM-IV alcohol dependence or DSM-5 AUD and 1616 were alcohol-exposed controls aged ≥21 years with no history of AUD or drug dependence. Further, 4842 individuals had a positive first-degree family history of AUD (FH+), 2722 had an unknown family history (FH?), and 336 had a negative family history (FH-). PRS were derived from a meta-analysis of a genome-wide association study of AUD from the Million Veteran Program and scores from the problem subscale of the Alcohol Use Disorders Identification Test in the UK Biobank. We used mixed models to test the association between PRS and risk for AUD and AUD severity., Results: AUD cases had higher PRS than controls with PRS increasing as the number of DSM-5 diagnostic criteria increased (p-values ≤ 1.85E -05 ) in the full COGA sample, the FH+ subsample, and the FH? subsample. Individuals in the top decile of PRS had odds ratios (OR) for developing AUD of 1.96 (95% CI: 1.54 to 2.51, p-value = 7.57E -08 ) and 1.86 (95% CI: 1.35 to 2.56, p-value = 1.32E -04 ) in the full sample and the FH+ subsample, respectively. These values are comparable to previously reported ORs for a first-degree family history (1.91 to 2.38) estimated from national surveys. PRS were also significantly associated with the DSM-5 AUD diagnostic criterion count in the full sample, the FH+ subsample, and the FH? subsample (p-values ≤6.7E -11 ). PRS remained significantly associated with AUD and AUD severity after accounting for a family history of AUD (p-values ≤6.8E -10 )., Conclusions: Both PRS and family history were associated with AUD and AUD severity, indicating that these risk measures assess distinct aspects of liability to AUD traits., (© 2022 by the Research Society on Alcoholism.)

Background: Research has explored the impact of various medical cannabis policies on substance use treatment admission in recent years, but we know little about factors related to participants' treatment engagement and outcome. To fill this gap in the existing literature, this study used national data to examine the influence of cannabis policies (decriminalized, medical, and recreational) and referral sources (criminal justice vs. voluntary) on treatment completion and length of stay., Methods: Data came from the Treatment Episode Data Set-Discharge (2006-2017) on adults 18+ whose primary drug at treatment admission was cannabis. Difference-in-difference analyses using logistic regression examined the effect of cannabis policies on outpatient treatment completion (yes/no; n = 2,192,807) and length of stay (more/fewer than 90 days; n = 1,863,585) in those with a criminal justice or voluntary referral source., Results: Cannabis policy was not associated with treatment completion in either those with a criminal justice or voluntary referral source. Compared to individuals in states where cannabis use was strictly illegal, those in states with a decriminalization policy were less likely to stay in treatment for 91+ days regardless of the referral source., Conclusions: Cannabis policy appears to have a differential effect on treatment completion versus length of stay, with policy having no impact on successful treatment completion. Specifically, we found that decriminalization policies hinder treatment engagement past 90 days. In this sense, length of stay may be a more useful measure of treatment outcome for research than treatment completion moving forward. Furthermore, our study found that neither medical nor recreational policies affected length of stay or treatment completion, regardless of referral source., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Over 25% of U.S. children are witness to traumatic intrafamilial or community violence each year, and sleep medicine and developmental research jointly suggest that trauma-exposed youth experience more sleep disturbance than their non-exposed counterparts. Sleep medicine literature emphasizes physical and social environmental factors affecting sleep, and trauma literature underscores children's seeking out physically and emotionally safe and predictable environments during trauma recovery. This study employed a hermeneutic phenomenological framing to explore the lived experiences of 65 violence-exposed children and families, and to examine how youths' social and physical sleep environments facilitated or impeded sleep in the aftermath of trauma. Children's sleep experiences following violence exposure shared two primary essences of experience: a) navigating external threats that agitated sleep after trauma; and b) exercising agency over sleep and related environments to restabilize emotional security. Clinicians and social services coordinators working with children and families are uniquely positioned to indicate sleep assessments as part of treatment following trauma, and to also facilitate identification of tangible, sleep-supportive and changeable factors in sleep environments.

Predictive models for recovering from alcohol use disorder (AUD) and identifying related predisposition biomarkers can have a tremendous impact on addiction treatment outcomes and cost reduction. Our sample (N = 1376) included individuals of European (EA) and African (AA) ancestry from the Collaborative Study on the Genetics of Alcoholism (COGA) who were initially assessed as having AUD (DSM-5) and reassessed years later as either having AUD or in remission. To predict this difference in AUD recovery status, we analyzed the initial data using multimodal, multi-features machine learning applications including EEG source-level functional brain connectivity, Polygenic Risk Scores (PRS), medications, and demographic information. Sex and ancestry age-matched stratified analyses were performed with supervised linear Support Vector Machine application and were calculated twice, once when the ancestry was defined by self-report and once defined by genetic data. Multifeatured prediction models achieved higher accuracy scores than models based on a single domain and higher scores in male models when the ancestry was based on genetic data. The AA male group model with PRS, EEG functional connectivity, marital and employment status features achieved the highest accuracy of 86.04%. Several discriminative features were identified, including collections of PRS related to neuroticism, depression, aggression, years of education, and alcohol consumption phenotypes. Other discriminated features included being married, employed, medication, lower default mode network and fusiform connectivity, and higher insula connectivity. Results highlight the importance of increasing genetic homogeneity of analyzed groups, identifying sex, and ancestry-specific features to increase prediction scores revealing biomarkers related to AUD remission.

Little is known about how the structure and composition of women's personal social networks (PSNs) combine to support recovery from substance use disorders, how PSNs change during early recovery, or how known covariates such as trauma, co-occurring mental health disorders, or treatment modality impact this relationship. This study used latent profile and transition analyses with 6 recovery-specific PSN indicators in a sample of women in early recovery ( N =377) to identify three PSN typologies in relation to abstinence outcomes over 12 months, and track transitions between the typologies at 0-6 and 6-12 months. Women in the Highly Connected type (14.3%) had tightly-knit networks, more sober alters, and fewer treatment-related alters. Women in the Treatment-Related type (49.3%) had looser-knit networks with more sober and sobriety-supporting alters and alters they know from treatment. Women in the At-Risk type (36.3%) had more isolates, few sobriety-supporting alters, and more alters with whom they used. Women in the Treatment-Related Sobriety Support type were significantly more likely to maintain sobriety by 12 months ( B =-0.81; OR=2.09, 95% CI [1.23-3.56]) than women in the At Risk type. Higher mean Trauma Symptom Checklist scores were positively related to membership in the At Risk type. The majority of women who transitioned did so by 6 months, with 41.6% transitioning then. Women in the At Risk group had the highest probability of transition ( P =0.55). Being in residential treatment (versus outpatient) predicted lower odds of transitioning ( B = -0.81, p =.06). This study provides a framework for conducting longitudinal latent variable analysis with social network data, and offers a clinically-useful starting point for research on individualized, targeted, and stage-based interventions for women in recovery., Competing Interests: Declaration of Interest: No conflict of interest declared

Background: There are gaps in the literature on service use (help-seeking and treatment utilization) for alcohol problems among those with alcohol use disorder (AUD). First, policy changes and cultural shifts (e.g., insurance) related to AUD have occurred over the last few decades, making it important to study generational differences. Second, multiple studies have found that females receive fewer services than males, and exploring whether these sex differences persist across generations can inform public health and research endeavors. The current study examined service use for alcohol problems among individuals with AUD. The aims were as follows: (i) to describe service use for alcohol problems; (ii) to assess generational differences (silent [b. 1928 to 1945], boomer [b. 1946 to 1964], generation X [b. 1965 to 1980], millennial [b. 1981 to 1996]) in help-seeking and treatment utilization; and (iii) to examine sex differences across generations., Methods: Data were from affected family members of probands who participated in the Collaborative Study on the Genetics of Alcoholism (N = 4,405). First, frequencies for service use variables were calculated across generations. Pearson chi-square and ANOVA were used to test for differences in rates and types of service use across generations, taking familial clustering into account. Next, Cox survival modeling was used to assess associations of generation and sex with time to first help-seeking and first treatment for AUD, and time from first onset of AUD to first help-seeking and first treatment. Interactions between generation and sex were tested within each Cox regression., Results: Significant hazards were found in all 4 transitions. Overall, younger generations used services earlier than older generations, which translated into higher likelihoods of these behaviors. Regardless of generation, younger females were less likely to use services than males., Conclusions: There are generational and sex differences in service use for alcohol problems among individuals with AUD. Policy and clinical implications are discussed., (© 2020 by the Research Society on Alcoholism.)

Women in recovery from substance use disorders often have difficulty establishing recovery-supportive networks. This exploratory study uses qualitative thematic analysis to examine how 88 women in recovery describe the actions they take to manage their personal social networks 12 months after intake into residential substance use treatment. Participants describe disconnecting or limiting contact with recovery-endangering people and adding recovery-supportive people to their networks as primary relationship actions for maintaining recovery. Their actions to build recovery-supportive networks can provide a focus for clinical work to help them become integrated into their communities.

Prenatal cocaine exposure (PCE) may increase adolescent substance use through alterations of neurotransmitter systems affecting fetal brain development. The relationship between PCE and substance use at 15 and 17 years was examined. Subjects (365: 186 PCE; 179 non-cocaine exposed (NCE)) supplied biologic and self-report data using the Youth Risk Behavior Surveillance System (YRBSS) and Computerized Diagnostic Interview Schedule for Children (C-DISC 4) at ages 15 and 17. The relationship between PCE and substance use was assessed using General Estimating Equation (GEE) analyses controlling for confounding factors including violence exposure and preschool lead level. Teens with PCE vs. NCE teens were 2 times more likely to use tobacco (OR=2.1; 95% CI 1.21-3.63; p<.001) and marijuana (OR=1.85; CI 1.18-2.91; p<.001) and have a substance use disorder at age 17 (OR=2.51; CI 1.00-6.28; p<.05). Evaluation of PCE status by gender revealed an association between PCE and marijuana use that was more pronounced for boys than girls at 17 years. Violence exposure was also a significant predictor of alcohol (p<.001), tobacco (p<.05), and marijuana (p<.0006) use and substance abuse/dependence (p<.01). Externalizing behavior at age 12 fully mediated the effects of PCE on substance use disorder at age 17 and partially mediated effects of PCE on tobacco use, but did not mediate effects on marijuana use. The percentage of substance use reported increased between 15 and 17 years, with no differences between the PCE and NCE groups. Data suggest specialized drug use prevention measures for children with PCE may benefit this high risk group., (Copyright © 2017. Published by Elsevier B.V.)

Introduction: Women with substance use disorders enter treatment with limited personal network resources and reduced recovery support. This study examined the impact of personal networks on substance use by 12 months post treatment intake., Methods: Data were collected from 284 women who received substance abuse treatment. At 6 month follow up, composition, support availability and structure of personal networks were examined. Substance use was measured by women's report of any use of alcohol or drugs. Hierarchical multivariate logistic regression was conducted to examine the contribution of personal network characteristics on substance use by 12 months post treatment intake., Results: Higher numbers of substance using alters (network members) and more densely connected networks at 6 month follow-up were associated with an increased likelihood of substance use by 12 months post treatment intake. A greater number of isolates in women's networks was associated with decreased odds of substance use. Women who did not use substances by 12 months post treatment intake had more non-users among their isolates at 6 months compared to those who used substances. No association was found between support availability and likelihood of substance use., Conclusions: Both network composition and structure could be relevant foci for network interventions e.g. helping women change network composition by reducing substance users as well as increasing network connections. Isolates who are not substance users may be a particular strength to help women cultivate within their network to promote sustained sobriety post treatment., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Introduction: Lactate clearance has been implicated as a predictor of mortality among emergency department (ED) patients with severe sepsis or septic shock. We aimed to validate prior studies showing that lactate clearance during the ED stay is associated with decreased mortality., Methods: Retrospective dual-centered cross-sectional study using patients identified in the Yale-New Haven Hospital Emergency Medicine sepsis registry with severe sepsis or septic shock who had initial lactate levels measured in the ED and upon arrival (<24 hours) to the hospital floor. Lactate clearance was calculated as percent of serum lactate change from ED to floor measurement. We compared mortality and hospital interventions between patients who cleared lactate and those who did not., Results: 207 patients (110 male; 63.17±17.9 years) were included. Two reviewers extracted data with 95% agreement. One hundred thirty-six patients (65.7%) had severe sepsis and 71 patients (34.3%) had septic shock. There were 171 patients in the clearance group and 36 patients in the non-clearance group. The 28-day mortality rates were 15.2% in the lactate clearance group and 36.1% in the non-clearance group (p<0.01). Vasopressor support was initiated more often in the non-clearance group (61.1%) than in the clearance group (36.8%, p<0.01) and mechanical ventilation was used in 66.7% of the non-clearance group and 36.3% of the clearance group (p=0.001)., Conclusion: Patients who do not clear their lactate in the ED have significantly higher mortality than those with decreasing lactate levels. Our results are confirmatory of other literature supporting that lactate clearance may be used to stratify mortality-risk among patients with severe sepsis or septic shock.

Introduction: Severe sepsis is a leading cause of non-coronary death in hospitals across the United States. Early identification and risk stratification in the emergency department (ED) is difficult because there is limited ability to predict escalation of care. In this study we evaluated if a sustained shock index (SI) elevation in the ED was a predictor of short-term cardiovascular collapse, defined as vasopressor dependence within 72 hours of initial presentation., Methods: Retrospective dual-centered cross-sectional study using patients identified in the Yale-New Haven Hospital Emergency Medicine sepsis registry., Results: We included 295 patients in the study with 47.5% (n=140) having a sustained SI elevation in the ED. Among patients with a sustained SI elevation, 38.6% (54 of 140) required vasopressors within 72 hours of ED admission contrasted to 11.6% (18 of 155) without a sustained SI elevation (p=0.0001; multivariate modeling OR 4.42 with 95% confidence intervals 2.28-8.55) . In the SI elevation group the mean number of organ failures was 4.0 ± 2.1 contrasted to 3.2 ± 1.6 in the non-SI elevation group (p=0.0001)., Conclusion: ED patients with severe sepsis and a sustained SI elevation appear to have higher rates of short-term vasopressor use, and a greater number of organ failures contrasted to patients without a sustained SI elevation. An elevated SI may be a useful modality to identify patients with severe sepsis at risk for disease escalation and cardiovascular collapse.

To evaluate the utility of sperm tests as indicators of chemical effects on human spermatogenesis, the literature on 4 sperm tests used to assess chemically induced testicular dysfunction was reviewed. The tests surveyed included sperm count, motility, morphology (seminal cytology), and double Y-body (a fluorescence-based test thought to detect Y-chromosomal nondisjunction). There were 132 papers that provided sufficient data for evaluation. These reports encompassed 89 different chemical exposures: 53 were to single agents; 14 to complex mixtures; and 22 to combinations of 2 or more identified agents. Approximately 85% of the exposures were to experimental or therapeutic drugs, 10% were to occupational or environmental agents, and 5% were to drugs for personal use. The most common sperm parameter studied was sperm count (for 87 of the 89 exposures reviewed). Sperm motility was evaluated for 59 exposures, morphology for 44, and double Y-bodies for only 4. The 89 exposures reviewed were grouped into 4 classes: those which adversely effected spermatogenesis, as measured by one or more of the sperm tests (52); those suggestive of improving semen quality (11); those showing inconclusive evidence of adverse effects from exposure (14); and those showing no significant changes (12). Since the reviewed reports had a large variety of study designs, and since every attempt was made to include all reports with interpretable data, these classifications were based on reviewing committee decisions rather than on uniform statistical criteria. This review gives strong evidence that human sperm tests can be used to identify chemicals that affect sperm production, but because of our limited understanding of underlying mechanisms, the extent to which they can detect mutagens, carcinogens or agents that affect fertility remains uncertain. For the very few agents studied with both human and mouse sperm tests, similar test-responses were seen; thus sperm tests in mice and other laboratory mammals may have a potential role in hazard identification. An overall comparison of the 4 human sperm tests suggests that no one test is biologically more responsive than another; all of them may thus be needed when testing for chemically induced changes from agents of unknown activity. This review also gives evidence that sperm tests can be used to assess the extent and the potential reversibility of induced spermatogenic damage. The reviewing committee recommends further studies to determine (a) the dose-response characteristics of the human sperm tests, (b) details of the reversibility of induced changes with time after exposure, (c) the relative responses in the 4 sperm tests in exposed individuals, (d) the mechanism of action, (e) the biological and genetic implications of chemically induced effects, and (f) the comparison of responses among different species for risk assessment. The reviewing committee outlines specific considerations for planning new sperm studies on chemically exposed men.

The literature on the mouse sperm morphology test and on other sperm tests in nonhuman mammals was reviewed (a) to evaluate the relationship of these tests to chemically induced spermatogenic dysfunction, germ-cell mutagenicity, and carcinogenicity, and (b) to make an interspecies comparison to chemicals. A total of 71 papers were reviewed. The mouse sperm morphology test was used to assess the effects of 154 of the 182 chemical agents covered. 4 other murine sperm tests were also used: the induction of acrosomal abnormalities (4 agents), reduction in sperm counts, (6 agents), motility (5 agents), and F1 sperm morphology (7 agents)). In addition, sperm tests for the spermatogenic effects of 35 agents were done in 9 nonmurine mammalian species; these included analyses for sperm count, motility, and morphology, using a large variety of study designs. For the mouse sperm morphology test, 41 agents were judged by the reviewing committee to be positive inducers of sperm-head shape abnormalities, 103 were negative, and 10 were inconclusive. To evaluate the relationship between changes in sperm morphology and germ cell mutagenicity, the effects of 41 agents on mouse sperm shape were compared to available data from 3 different mammalian germ-cell mutational tests (specific locus, heritable translocation, and dominant lethal). The mouse sperm morphology test was found to be highly sensitive to germ-cell mutagens; 100% of the known mutagens were correctly identified as positives in the sperm morphology test. Data are insufficient at present to access the rate of false positives. Although it is biologically unclear why one might expect changes in sperm morphology to be related to carcinogenesis, we found that (a) a positive response in the mouse sperm morphology test is highly specific for carcinogenic potential (100% for the agents surveyed), and (b) overall, only 50% of carcinogens were positive in the test (i.e., sensitivity approximately equal to 50%). Since many carcinogens do not produce abnormally shaped sperm even at lethal doses, negative findings with the sperm test cannot be used to classify agents as noncarcinogens. We conclude that the mouse sperm morphology test has potential use for identifying chemicals that induce spermatogenic dysfunction and perhaps heritable mutations. Insufficient numbers of chemicals agents have been studied by the other sperm tests to permit similar comparisons. A comparison of 25 chemicals tested with sperm counts, motility, and morphology in at least 2 species (including man, mouse and 9 other mammals) demonstrated good agreement in response among species. With further study, interspecies comparisons of chemically induced sperm changes may be useful for predicting and evaluating human effects.

The literature on cell transformation by chemical carcinogens has been critically reviewed. This subject is highly relevant to carcinogenesis in vivo, because the phenotypic changes that are collectively referred to as cell transformation usually involve the acquisition of tumorigenicity on inoculation into suitable rodent hosts. The systems chosen for review fall into 3 categories: cell strains (cells with a limited lifespan); cell lines (cells with an unlimited lifespan); and oncogenic viral-chemical interactions involving cells (Fischer rat embryo cells expressing an endogenous retrovirus, mouse embryo cells expressing the AKR leukemia virus, chemical enhancement of a simian adenovirus, SA7 transformation of Syrian hamster or rat embryo cells). Of the entire literature reviewed, 117 papers have been accepted for data abstraction by pre-defined criteria; these include 41 references to cell strains, 40 in cell lines, and 38 in viral-chemical interactions including cells. Because different systems have been reviewed, it would be meaningless to group all the compounds. The overall summary of the systems is as follows (many compounds have been tested in more than one system and, hence, are duplicated in these totals). (Chart: see text) In general, there is a reasonably good correlation between the results of the cell transformation systems and in vivo carcinogenesis. However, the many deficiencies of the EPA Merged Carcinogen List preclude definitive comparisons. Moreover, a number of 'false negatives' were obtained in systems that did not employ external metabolic activation. Further validation of all systems is required, but it seems very probable that several cell transformation systems will become valuable in assaying (with reasonable time and cost) the carcinogenic potential of environmental chemicals.

An alpha macroglobulin fraction (19S) was isolated from the serum of rats and BC(3)F(1) mice by zonal ultracentrifugation. Both the isologous and heterologous macroglobulin fractions increased survival among BC(3)F(1) mice x-irradiated with 750 roentgens. The mouse macroglobulin fraction also enhanced radiation recovery of hematopoietic tissue as measured by colony-forming assay and iron-59 incorporation into erythropoietic cells. The overall difference in hematopoietic activity in the irradiated (400 roentgens) mice treated with the macroglobulin fraction, in comparison with this activity in the controls, was three- to fivefold in the bone marrow and nine- to tenfold in the spleen between days 4 and 7 after irradiation. This effect was not obtained with the isologous serum protein fraction containing proteins of smaller molecular weight.

The essential role of continuous antigenic stimulation in the development and differentiation of antibody-forming cells as defined in the X-Y-Z immune cell maturation scheme was examined in these studies. Mice were primed with sheep erythrocytes (SRBC) in an attempt to induce maximum immune progenitor cell conversion (X --> Y). Subsequently antigen was depleted at 1 or 4 days after priming with isologous specific antibody in order to interrupt further immune cell differentiation (Y --> Z). It was reasoned that this condition would result in depression of the functional antibody-producing cell compartment as measured in the intact mice and subsequently in enhancement of the sensitized (Y cell) compartment as measured in the spleen cell transfer system. These data were also correlated with systematic studies of the hyperplasia of the spleen germinal centers. The effect of passive antibody on the primary response to SRBC was a marked decrease indirect and indirect hemolysin-producing cells (DPFC and IPFC). However, there was a lack of correlation in the degree of antibody-mediated 19S and 7S immune cell suppression during the primary response, the DPFC being much less depressed than the IPFC. As measured in the transfer system there was an enhanced 19S sensitized cell compartment and a depressed 7S sensitized cell compartment in 1 day passively immunized mice. This was true whether or not transfers were performed 1, 2, or 4 wk after priming. Similarly, there was an enhanced 19S-sensitized cell compartment with little or no effect on the 7S-sensitized. cell compartment in 4 day passively immunized mice. These data suggest that progeny of the antigen-stimulated progenitor cells (X cell), as a consequence of lack of further antigenic stimulation, were forced into maturation arrest. These studies further demonstrate that isologous passive antibody suppresses germinal center growth regardless of whether the antibody is infused 1, 2, or 4 days after priming. In terms of formation of sensitized cells, the marked depression of 7S sensitized cell compartment after passive immunization at 24 hr in contrast to the enhancement of the 19S sensitized cell compartment corresponds to the suppressed growth of germinal centers during the primary response. Thus, if the germinal center is, as suggested, the site of proliferative expansion of immunocompetent cells, these data indicate that the germinal center growth is related to the 7S antibody response and in the formation of "7S memory."