Proximate Cause Research Articles

Greenery hypothesis: An evolutionary explanation for why presence/absence of green affects humans

Abstract A growing body of empirical evidence shows that experiences of nature provide people with diverse psychological benefits, including improved cognitive function and mental health. While our understanding of the proximate causes of these positive psychological responses of humans to nature has advanced, the ultimate (evolutionary) drivers behind them remain poorly understood. In this study, we provide a summary of several widely accepted evolutionary hypotheses originating from Biophilia, reviewing their challenges and limitations. Subsequently, we propose a new evolutionary psychological hypothesis—the greenery hypothesis—that integrates recent findings in evolutionary psychiatry with many experimental results unexplained by existing hypotheses/theories. Our proposed hypothesis states that humans have adapted to periodic severe drought and re‐watering cycles by developing both negative and positive psychological responses to the absence or presence of greenery within the landscape as cues to optimise their own behavioural activity. The greenery hypothesis holds the potential to yield several insights into the fundamental understanding of human psychological responses to nature exposure with significant implications for various related fields, including psychiatry, urban planning, and biodiversity conservation and restoration. Read the free Plain Language Summary for this article on the Journal blog.

Community mobilisation approaches to preventing adolescent multiple risk behaviour: a realist review

BackgroundAdolescent multiple risk behaviour (MRB) is a global health issue. Most interventions have focused on the proximal causes of adolescent MRB such as peer or family influence, with systematic reviews reporting mixed evidence of effectiveness. There is increasing recognition that community mobilisation approaches could be beneficial for adolescent health. There are gaps in the current literature, theory and implementation that would benefit from a realist approach. We use a theory-driven evidence synthesis to assess how and why community mobilisation interventions work/do not work to prevent adolescent MRB and in what contexts.MethodsThis realist review used a six-stage iterative process, guided by the RAMESES framework. We systematically searched PubMed, MEDLINE, PsycINFO, Web of Science, CINAHL and Sociological s, from their inception to 2021. Studies were screened for relevance to the programme theory, assessed for rigour and included based on a priori criteria. Two independent reviewers selected, screened and extracted data from included studies. A realist logic of analysis was used to develop context-mechanism-outcome configurations that contributed to our programme theory.FindingsWe reviewed 35 documents describing 22 separate community mobilisation intervention studies. Most studies (n = 17) had a quality assessment score of three or four (out of four). We analysed the studies in relation to three middle range theories. To uphold our theory that these interventions work by creating a social environment where adolescents are less likely to engage in MRB, interventions should: (1) embed a framework of guiding principles throughout the community, (2) establish community readiness with population data and (3) ensure a diverse coalition with the support of intervention champions. Mechanisms such as empowerment through coalition ownership over the delivery of the intervention, cohesion across the community and motivation to work collaboratively to improve adolescent health are triggered to achieve social environment shifts. However, certain contexts (e.g. limited funding) restrict intervention success as these mechanisms are not fired.ConclusionsFor community mobilisation interventions to reduce adolescent MRB, the coalitions within them must seek to alter the social environment in which these behaviours occur. Mechanisms including empowerment, cohesion and motivation lead to this shift, but only under certain contexts.Systematic review registrationPROSPERO CRD42020205342

Military AI, sacred violence, and war in the Middle East

Israel’s commitment to a policy of collective punishment, disproportionate response, outright assassination and ethnic cleansing are the culmination of a long process. It has its origins in the expropriations organized by colonial powers, as does the state of Israel itself, but the proximate causes are the recent turn in politics to Biblical Jewish fundamentalism and an irrational enthusiasm for new military technologies, especially AI. These have led to important changes in official Israeli Defense Forces (IDF) policies, including a fundamental degradation of their ethical code.

An efficient and robust ABC approach to infer the rate and strength of adaptation.

Inferring the effects of positive selection on genomes remains a critical step in characterizing the ultimate and proximate causes of adaptation across species, and quantifying positive selection remains a challenge due to the confounding effects of many other evolutionary processes. Robust and efficient approaches for adaptation inference could help characterize the rate and strength of adaptation in nonmodel species for which demographic history, mutational processes, and recombination patterns are not currently well-described. Here, we introduce an efficient and user-friendly extension of the McDonald-Kreitman test (ABC-MK) for quantifying long-term protein adaptation in specific lineages of interest. We characterize the performance of our approach with forward simulations and find that it is robust to many demographic perturbations and positive selection configurations, demonstrating its suitability for applications to nonmodel genomes. We apply ABC-MK to the human proteome and a set of known virus interacting proteins (VIPs) to test the long-term adaptation in genes interacting with viruses. We find substantially stronger signatures of positive selection on RNA-VIPs than DNA-VIPs, suggesting that RNA viruses may be an important driver of human adaptation over deep evolutionary time scales.

Abstract A025: Adaptive therapy: Leveraging evolutionary dynamics for colorectal cancer management in vivo

Abstract Therapeutic resistance to chemotherapy is frequently the proximate cause of cancer treatment failure and, ultimately, patient mortality. Evolutionary therapies have been developed to address this problem and potentially reduce toxicities. The most successful strategy to date, adaptive therapy (AT), is designed to use chemosensitive cells to out-compete and suppress the chemoresistant cells. However, detailed observations to elucidate the mechanisms of AT's success are lacking. Typically, AT involves lowering the dose of the chemotherapy, thereby reducing toxicity and preserving the immune system. We are evaluating AT for the first time in colorectal cancer, using syngeneic orthotopic xenograft models. This project marks several firsts: 1) sensitive and resistant clones will be tracked longitudinally, 2) AT will be tested with a targeted therapy (MRTX1133), 3) AT will be tested in an immune competent model, 4) multiple drugs will be used for AT, and 5) extinction therapy will be tested in mice. We will employ genetic barcodes and differential luciferase tagging to track the tumor cell subpopulations longitudinally. Currently, we are conducting an in-vivo pilot experiment to validate our protocol, emphasizing tumor engraftment efficacy and tracking cell subpopulations. Additionally, we are investigating the potential of Lactobacillus acidophilus to inhibit tumor growth, augment chemotherapy, and bolster immune response in colorectal cancer. Citation Format: Harley I. Richker, Gissel Marquez-Alcaraz, Carlo Maley. Adaptive therapy: Leveraging evolutionary dynamics for colorectal cancer management in vivo [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr A025.

Climate Change Contributions to Increasing Compound Flooding Risk in New York City

Abstract Efforts to meaningfully quantify the changes in coastal compound surge- and rainfall-driven flooding hazard associated with tropical cyclones (TCs) and extratropical cyclones (ETCs) in a warming climate have increased in recent years. Despite substantial progress, however, obtaining actionable details such as the spatially and temporally varying distribution and proximal causes of changing flooding hazard in cities remains a persistent challenge. Here, for the first time, physics-based hydrodynamic flood models driven by rainfall and storm surge simultaneously are used to estimate the magnitude and frequency of compound flooding events. We apply this to the particular case of New York City. We find that sea level rise (SLR) alone will increase the TC and ETC compound flooding hazard more significantly than changes in storm climatology as the climate warms. We also project that the probability of destructive Sandy-like compound flooding will increase by up to 5 times by the end of the century. Our results have strong implications for climate change adaptation in coastal communities.

Facial and genital color ornamentation, testosterone, and reproductive output in high-ranking male rhesus macaques

Males in many vertebrate species have colorful ornaments that evolved by sexual selection. The role of androgens in the genesis and maintenance of these signals is unclear. We studied 21 adult high-ranking male rhesus macaques from nine social groups in the free-ranging population on Cayo Santiago, Puerto Rico, and analyzed facial and genital skin luminance and redness, fecal androgens, rates of mating behaviors, and offspring sired. Facial and genital coloration varied in relation to age, mating behavior, reproductive success, and testosterone concentration. Our results indicate that skin coloration in high-ranking male rhesus macaques is a sexually-selected trait mediated by androgens. These results add to the growing literature on the proximate and ultimate causes of male sexual signals and highlight the need to examine how these characteristics change with age in other species.

Cholesterol lowering depletes atherosclerotic lesions of smooth muscle cell-derived fibromyocytes and chondromyocytes.

Drugs that lower plasma apolipoprotein B (ApoB)-containing lipoproteins are central to treating advanced atherosclerosis and provide partial protection against clinical events. Previous research showed that lowering ApoB-containing lipoproteins stops plaque inflammation, but how these drugs affect the heterogeneous population of plaque cells derived from smooth muscle cells (SMCs) is unknown. SMC-derived cells are the main cellular component of atherosclerotic lesions and the source of structural components that determine the size of plaques and their propensity to rupture and trigger thrombosis, the proximate cause of heart attack and stroke. Using lineage tracing and single-cell techniques to investigate the full SMC-derived cellular compartment in progressing and regressing plaques in mice, here we show that lowering ApoB-containing lipoproteins reduces nuclear factor kappa-light-chain-enhancer of activated B cells signaling in SMC-derived fibromyocytes and chondromyocytes and leads to depletion of these abundant cell types from plaques. These results uncover an important mechanism through which cholesterol-lowering drugs can achieve plaque regression.

Genetically Encoded Lizard Color Divergence for Camouflage and Thermoregulation.

Local adaptation is critical in speciation and evolution, yet comprehensive studies on proximate and ultimate causes of local adaptation are generally scarce. Here, we integrated field ecological experiments, genome sequencing, and genetic verification to demonstrate both driving forces and molecular mechanisms governing local adaptation of body coloration in a lizard from the Qinghai-Tibet Plateau. We found dark lizards from the cold meadow population had lower spectrum reflectance but higher melanin contents than light counterparts from the warm dune population. Additionally, the colorations of both dark and light lizards facilitated the camouflage and thermoregulation in their respective microhabitat simultaneously. More importantly, by genome resequencing analysis, we detected a novel mutation in Tyrp1 that underpinned this color adaptation. The allele frequencies at the site of SNP 459# in the gene of Tyrp1 are 22.22% G/C and 77.78% C/C in dark lizards and 100% G/G in light lizards. Model-predicted structure and catalytic activity showed that this mutation increased structure flexibility and catalytic activity in enzyme TYRP1, and thereby facilitated the generation of eumelanin in dark lizards. The function of the mutation in Tyrp1 was further verified by more melanin contents and darker coloration detected in the zebrafish injected with the genotype of Tyrp1 from dark lizards. Therefore, our study demonstrates that a novel mutation of a major melanin-generating gene underpins skin color variation co-selected by camouflage and thermoregulation in a lizard. The resulting strong selection may reinforce adaptive genetic divergence and enable the persistence of adjacent populations with distinct body coloration.

Do Not Turn a Blind Eye on Forensic Biochemistry: Using Vitreous Electrolytes to Reveal Renal Insufficiency as Cause of Death.

In both medical and forensic autopsy, the kidneys may be overlooked grossly and histologically. As both acute and chronic kidney dysfunction have major implications on morbidity and mortality, it is essential to consider the kidneys as a pathologic source for both immediate and proximate cause of death. For decades, vitreous humor has been used as a measure of postmortem electrolyte analysis to help understand ionic disturbances carried over from the antemortem period. Renal insufficiency from both acute and chronic kidney dysfunction can be ascertained from vitreous investigations and should be a consideration for cause of death. Here, we present 4 cases in which vitreous analysis was used to determine the cause of death. In highlighting these cases, we support the use of biochemical testing in autopsy while demonstrating how it can help elucidate an often overlooked means of mortality. Importantly, it can help with the formulation of clinicopathologic correlations between antemortem and postmortem findings.

High temporal resolution of hydrogen peroxide (H2O2) dynamics during heat stress does not support a causative role in coral bleaching

Human-induced climate change is causing ocean warming that triggers the breakdown of the coral–algal symbiosis. The proximate cause of this phenomenon, known as coral bleaching, is commonly attributed to the overproduction of reactive oxygen species (ROS) by the thermally stressed photosynthetic algal symbionts. However, direct evidence that algal ROS production (e.g., in the form of H2O2) and coral physiological stress are the ultimate cause of bleaching remains ambiguous. Here, we investigated the temporal dynamics of H2O2 and oxygen (O2) concentrations during thermally induced coral bleaching to disentangle cause from consequence. Microsensors at the tissue interface of Pocillopora damicornis measured H2O2 and O2 concentrations while exposing single nubbins to baseline temperatures (30 °C) and to minor (33 °C), moderate (36 °C), and high (39 °C) levels of acute heat stress using the Coral Bleaching Automated Stress System (CBASS). We show that a temporary decline in O2 concentration, accompanied by a declining photosynthetic efficiency and loss of Symbiodiniaceae and pigmentation, is the initial response to moderate thermal stress. This response was neither provoked nor followed by an increased H2O2 concentration at the coral tissue interface. A steady light-independent increase of H2O2 was only detected during high heat stress, resulting in the complete and permanent loss of photosynthetic activity. Our findings do not support a direct connection between algal photodamage and an increase in H2O2 concentration during thermally induced bleaching and suggest that more research on the function of H2O2 is warranted. This notion is further substantiated by the observation of an additional source of H2O2, likely oxidative bursts, that were common at the baseline temperature and under minor heat stress, while their occurrence decreased at moderate and high heat stress. Resolving the multifaceted and dynamic roles of H2O2 in coral bleaching is critical to better understand the response of the coral holobiont to thermal stress and identifying the processes underlying the breakdown of the coral–algal symbiosis.

P19 The role of policy and key stakeholder decision-making in the propagation, and deceleration, of resistance evolution

Abstract Background Antimicrobials have an intangible value on reducing global health burden of infection, yet current valuation methods do not holistically capture the enablement of healthcare as a result of antimicrobials. A lack of incentive and subsequent investment into the novel antimicrobial pipeline demonstrates the urgent need for collaboration amongst those influencing the decision-making process, namely key stakeholders such as governmental bodies, industry and academia. Studies into resistance evolution focus almost entirely on proximate causes, such as the number of antibiotics used in clinical settings, or the understanding of evolutionary pathways to resistance under controlled laboratory conditions. Comparatively, the association between resistance evolution and policy decisions from governments, industry and regulatory bodies is poorly understood. Objectives The primary aim was to evaluate the multifactorial associations between β-lactam development and evolution of β-lactam resistance to inform the current and future antibiotic development pipeline. Methods To undertake this narrative report, we focussed on β-lactam antibiotics, given their clear development timeline and continuous molecular refinement to meet arising clinical and microbiological needs. As such, the evolution of resistance to β-lactams poses a significant threat to mortality, quality of life, and societal function. This report consists of six historical case studies, all of which have significantly influenced the antimicrobial resistance landscape since Fleming’s discovery of penicillin in 1928. We include lesser-known events in our narrative, such as the establishment of the National Research and Development Corporation (NRDC), which propelled the mass commercialization of penicillin, and the subsequent emergence of penicillinases. Pivotal events such as the emergence of ESBL and MBLs into clinical settings also provide insight into the historical decision-making process by key stakeholders such as governmental bodies, industry and academia. Literature reviews were conducted with a focus on the initial introduction of a particular β-lactam into the clinic and when resistance arose. Key stakeholder activities and policy decisions made during these time periods influenced the formation of case studies. Results The case studies are as follows: (i) the influence of the NRDC in accelerated antimicrobial development; (ii) the introduction of the β-lactamase inhibitor—the influence of short-term clinical and financial benefit on prescribing behaviour; (iii) the ‘golden era’ of antibiotics—cephalosporin development and the consequences of short-term market forces; (iv) knowledge of MBL resistance prior to introduction of carbapenems in clinical settings; (v) consequences of controlled manufacturing for the global supply of piperacillin/tazobactam; and (vi) early surveillance studies and the beginning of the antimicrobial stewardship agenda. Conclusions In each case study we provide insight into how key stakeholders can improve practices by learning from past experiences, to inform the future stewardship agenda. We built a case for the need to incorporate evolutionary microbiology into policy and industrial decision-making in order to improve the mitigation of antimicrobial resistance.

Information Technology and the Complexity Cycle

Aim/Purpose: In this paper we propose a framework identifying many of the unintended consequences of information technology and posit that the increased complexity brought about by IT is a proximate cause for these negative effects. Background: Builds upon the three-world model that has been evolving within the informing science transdiscipline. Methodology: We separate complexity into three categories: experienced complexity, intrinsic complexity, and extrinsic complexity. With the complexity cycle in mind, we consider how increasing complexity of all three forms can lead to unintended consequences at the individual, task and system levels. Examples of these consequences are discussed at the individual level (e.g., deskilling, barriers to advancement), the task level (e.g., perpetuation of past practices), as well as broader consequences that may result from the need to function in an environment that is more extrinsically complex (e.g., erosion of predictable causality, shortened time horizons, inequality, tribalism). We conclude by reflecting on the implications of attempting to manage or limit increases of complexity. Contribution: Shows how many unintended consequences of IT could be attributed to growing complexity. Findings: We find that these three forms of complexity feed into one another resulting in a positive feedback loop that we term the Complexity Cycle. As examples, we analyze ChatGPT, blockchain and quantum computing, through the lens of the complexity cycle, speculating how experienced complexity can lead to greater intrinsic complexity in task performance through the incorporation of IT which, in turn, increases the extrinsic complexity of the economic/technological environment. Recommendations for Practitioners: Consider treating increasing task complexity as an externality that should be considered as new systems are developed and deployed. Recommendation for Researchers: Provides opportunities for empirical investigation of the proposed model. Impact on Society: Systemic risks of complexity are proposed along with some proposals regarding how they might be addressed. Future Research: Empirical investigation of the proposed model and the degree to which cognitive changes created by the proposed complexity cycle are necessarily problematic.

A Spatio-Temporal Groundwater Fluoride Contamination Assessment to Infer the Hydro-geochemical Analysis of Punjab Satluj Floodplain

Punjab Satluj Floodplain is a Hydro-geologically, ecologically, and economically very precious resource-rich landscape. This area is fragile due to flood risk; since its inception, it has attracted lots of economic and sociocultural activities that adversely affect hydro-geochemical conditions. Spatial and statistical analysis of land use and land cover change reveals that from 1975 to 2011, this landscape experienced 56.55 % land use and land cover transformation. Maximum transformation is noticed in the agricultural and built-up areas. In 1975, agricultural and built-up areas covered 47057.11 hectares (45.13 %) and 469.5 hectares (0.45 %), respectively, of the Punjab Satluj floodplain, which was expanded and covered 91011.36 hectares (87.28 %) and 6495.7 hectares (6.24 %) respectively in 2011. Adversities of these values can be estimated from the groundwater contamination analysis that reveals the specific electrical conductance (EC), nitrate (NO3), potassium (K), calcium (Ca), magnesium (Mg), sodium (Na), and fluoride (F) contamination in the water exceed its permissible consumption limits and effects ecological health. The present research work is the epigram of the hydrogeochemical condition of the Punjab Satluj floodplain concerning the spatial distribution of fluoride contamination and its proximate causes.

The research On Illegality and Medical Fault Presumption: On the Application of the Article 1222 Paragraph 1of the Civil Code of the PRC

Fault determination has always been a difficult and controversial issue in the determination of medical tort liability. Article 1222 of the Civil Code stipulates three situations for medical fault estimation and establishes objective standards for medical fault estimation, which has positive significance in overcoming the abstraction and uncertainty of the fault determination standard for “medical level” in Article 1221.
 In judicial practice, Article 1222 (1) of the Civil Code can simplify the difficulty of determining the fault of medical torts, but there are also some problems. The judgment standards for medical violations of “duty of care” and “illegality” are often confused, the administrative and civil legal liabilities arising from medical violations are often confused, and the legal responsibilities of medical institutions and medical personnel in medical torts are not distinguished, There is even a trend of ‘illegal is wrong’.
 This article analyzes the nature and circumstances of illegal medical behavior, and demonstrates the relationship between violating diagnostic and treatment norms and illegal behavior. It further suggests establishing a presumption rule of “illegal” and “fault”, limiting the presumption of “illegal” medical behavior to “fault” in private language and excluding public law provisions; Establish hierarchical application rules when violating the “diagnostic and treatment norms” to presume “fault”, thereby reducing the impact of the current confusion of diagnostic and treatment norms on the presumption of fault; The presumption principle of “illegality is fault” applies to violations of licensing laws and regulations; Violating the legal provisions of diagnosis and treatment and applying the principle of “proximate cause” presumption; The rule of presumption of evidence applies to violations of medical record laws and regulations. Through the above rules, objective evaluation of medical behavior and fair division of medical damage liability can be achieved.

Stillbirth of a mandrill (Mandrillus sphinx) in the wild: perinatal behaviors and delivery sequences

Birth is a fundamental event in the life of animals, including our own species. More reports of wild non-human primate births and stillbirths are thus needed to better understand the evolutionary pressures shaping parturition behaviors in our lineage. In diurnal non-human primates, births generally occur at night, when individuals are resting. Consequently, they are difficult to observe in the wild and most of the current knowledge regarding perinatal behaviors comes from rare daytime births. Information about stillbirths is even rarer and their proximate causes are generally unknown. Here, we present detailed observations of a daytime birth of a stillborn wild mandrill (Mandrillus sphinx). During this event, which lasted an entire day, we recorded the behaviors of the parturient female ad libitum, using video recordings and photos. The 5-year-old female was primiparous and of low dominance rank. The length of her pregnancy was shorter than usual and the partum phase was extremely long compared to other birth reports in non-human primates. The female disappeared shortly after this event and was assumed to have died. We discuss the possible causes of this stillbirth including the infant’s presentation at birth and maternal inexperience.

Partial migration in Magellanic penguins

We studied the migration of Magellanic penguins near the southern tip of the breeding distribution, and for the first time found evidence of partial migration for this species within the same colony. Forty‐three percent of the penguins studied stayed within ~ 290 km of the colony (residents), while others went northwards as far as 2000 km. All penguins spent the same amount of time at sea and traveled similar total distances, but residents experienced colder waters (2°C lower) and habitats with lower Chlorophyll‐a concentrations than migrants. The two habitats are inhabited by different prey items, consequently offering the penguins distinct prey options. We have shown high variability in the non‐breeding dispersion behavior of Magellanic penguins within the same colony; nonetheless, further research is required to understand the proximate and ultimate causes, and the consequences, of this behavior.

Landscape changes and livelihood outcomes in rural tea farming communities: A case study in Fuding City, Fujian Province, Southeast China

Landscape changes driven by cash crop plantations have been prevalent in tropical and subtropical regions worldwide in recent decades. Investigating the landscape changes and concluding livelihood outcomes are fundamental to figure out the solutions for rural sustainability. This paper examined the landscape changes which was caused by land use changes in tea plantations as well as investigated the resultant livelihood impacts, based on a case study in Fuding City, Southeast China. A questionnaire survey of 114 rural households in four sampled villages was conducted. Results demonstrated that expansion and intensification of tea plantations were two major proximate causes of landscape changes in recent decade. Our survey indicated that some existing intensively-managed tea plantations had derived from intensification and expansion of tea plantations, respectively. We identified four underlying driving forces of landscape changes, including economic benefit, governmental policies, wildlife destruction on grain crops, and rural return migration. Our study confirmed that landscape changes have significant positive effects on farmers’ livelihoods, including increasing employment and incomes, raising living standards, enhancing livelihood assets and livelihood sustainability. Especially, the aged rural populations could have a relatively decent living standard. Meanwhile, the excessive expansion of tea plantations may impair livelihood resilience. Lastly, three policy suggestions based on different time scales have been put forward to promote rural households’ livelihood sustainability and resilience.

Brain volume changes caused by anti‐amyloid beta drugs and association with ARIA

AbstractBackgroundThe potential benefit of anti‐Aβ drugs to cognition in Alzheimer’s disease (AD) remains under active debate. Anti‐Aβ drugs also frequently cause accelerated changes to brain volume. This is concerning because loss of brain tissue is the proximate cause of cognitive dysfunction in AD and volume changes are supportive and objective evidence of disease progression.MethodPubMed, Embase and Clinicaltrial.gov databases were searched to evaluate brain volume changes caused by different sub‐classes of anti‐amyloid beta (Aβ) drugs trialed in patients with Alzheimer’s disease. The inclusion criteria for this systematic review and meta‐analysis were: (1) randomized controlled trials of patients treated with anti‐Aβ drugs that have demonstrated to favorably change at least one biomarker of pathological Aβ; and (2) detailed MRI data sufficient to assess the volumetric changes in at least one brain region. Amyloid‐Related Imaging Abnormalities (ARIA) were investigated when reported in clinical trials. Of the 145 trials reviewed, 31 were included in the final analyses (n = 8062 to 10279).ResultA meta‐analysis on the highest dose of each trial on hippocampus, ventricle, and whole brain revealed drug‐induced acceleration of volume changes that varied by anti‐Aβ drug class. Secretase inhibitors accelerated atrophy to the hippocampus (mean difference: ‐37.1 µL [‐19.6% relative to change in placebo]; 95% confidence interval: ‐47.0 to ‐27.1) and whole brain (‐3.3mL [‐21.8% relative to change in placebo]; 95% confidence interval: ‐4.1 to 2.5). Conversely, ARIA‐inducing monoclonal antibodies accelerated ventricular enlargement (mean difference: +2.1mL [+38.7% relative to change in placebo]; 95% confidence interval: 1.5 to 2.8) where a striking correlation between ventricular volume and ARIA frequency was observed (r = 0.86, p = 6.22×10−7).ConclusionThese findings reveal the potential for anti‐Aβ therapies to compromise long‐term brain health by accelerating brain atrophy and provide new insight into the adverse impact of ARIA. Six recommendations emerge from these findings.

School Education in Post-18th Amendment Balochistan: A Political Economy Perspective

In the wake of devolution of education to provinces through the 18th Constitutional Amendment, there has been a noticeable increase in public spending on school education. Moreover, certain reforms have been introduced in education planning, management and monitoring. These measures have enhanced availability of physical infrastructure and reading and writing material for schools and improved education monitoring. There is also evidence of marginal improvements in overall literacy rate and reading and arithmetic skills.
 Notwithstanding the limited gains, the reforms and increased public spending have not translated into commensurate improvements in schooling and learning outcomes. Analysis of proximate causes indicates that learning outcomes are not improving because the various elements of education system are not aligned around the goal of learning. In contrast, expansion of schooling appears to have remained a strategic objective of education delivery but it hasn’t experienced significant improvement either because of the existence of serious policy incoherence among various elements of education system. Prevalence of centralised, politically-influenced, discretionary and outdated planning and management practices combined with ineffectiveness of accountability mechanisms across the education delivery chain have undermined the effectiveness of well-intended reforms.
 A deeper exploration of these issues through the “political settlement” lens reveals that education outcomes aren’t recording major improvements because elite interest is aligned neither with the goal of learning nor access. Instead, elite interest is aligned more around patronage politics. Short-term, clientelist, political objectives govern education provision, owing to the highly fragile, exclusive, fragmented and personalised nature of political settlement. The predatory nature of political settlement has adversely affected both the design and implementation of reform initiatives.