Ongoing Instability Research Articles

Demographic and Clinical Characteristics of Refugee Children Utilizing Healthcare Services of Türkiye (2021-2022): A Single-Centre Study

BACKGROUND: The number of refugees in the world has been increasing due to ongoing wars, political instability, violence, poverty and climate change. Türkiye has the world’s largest refugee population and half of the refugees are children. The aim of this study is to describe healthcare utilization patterns of the pediatric refugee population admitted to emergency, outpatient and inpatient services to enable hospitals to be better prepared to treat large numbers of refugee children. METHODS: This was a retrospective observational study using data from medical records of refugee children who had visited the _University of Health Sciences Sancaktepe Training and Research Hospital_, Istanbul, in pediatric emergency, outpatient and inpatient services between 1 June 2021 and 1 June 2022. RESULTS: 4383 refugee children including emergency (81.9%), outpatient (15.1%) and inpatient clinics (3%) were analyzed. The most frequently seen diseases for each service were upper respiratory infection and gastroenteritis in emergency; vitamin D deficiency and malnutrition in outpatient; lower respiratory infection, fever and intoxication in inpatient services. Most of the visits were non-urgent visits. COVID-19 disease was found in 1.3% of all children. CONCLUSION: Since the child refugee population has been less studied than the adult population, there is little data available on the health status of these pediatric refugees. This study demonstrates refugee children’s visits to the hospital, and especially the Emergency Department (ED), are increasing. Identifying the reasons for non-emergency ED use might provide additional insights and new approaches to serve the health care needs of this vulnerable population.

Abstract IA020: Micronuclei are a nexus of DNA damage signaling and genomic instability

Abstract Micronuclei have classically been considered inert biomarkers of genomic instability arising from failed DNA damage repair and chromosome segregation errors in mitosis. Work from several groups including our own have now demonstrated that micronuclei are active contributors to the cellular response to DNA damage by driving chromothripsis and through induction of anti-viral gene expression programs mediated by the cGAS-STING pathway. We now show that the specific DNA damage type leading to micronuclei formation influences the capacity for cGAS localization and activation. This arises in part due to discrete chromatin features, present prior to DNA damage induction, that are retained in micronuclei several days after their formation. Together these data demonstrate that micronuclei connect the pre-damage chromatin status and the chromatin context of micronuclei-inciting lesions to the long-term signaling outcomes important for anti-tumor immunity. This finding implies that micronuclei represent archives for the nature of DNA repair failure and downstream signaling consequences. Based on this premise we will present our efforts in micronuclear proteomics where we uncover common features of micronuclei including splicing deficiencies. Such deficiencies presage exacerbated MN-associated DNA damage that is upstream of chromothripsis. These studies have direct implications for how cells sense the aftermath of DNA damage and how micronuclei contribute to ongoing genomic instability. Citation Format: Shane M. Harding. Micronuclei are a nexus of DNA damage signaling and genomic instability [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr IA020.

The Mutational Spectrum of Pre- and Post-Neoadjuvant Chemotherapy Triple-Negative Breast Cancers.

The response of triple-negative breast cancer (TNBC) patients to pre-operative (neoadjuvant chemotherapy) is a critical factor of their outcome. To determine the effects of chemotherapy on the tumor genome and to identify mutations associated with chemoresistance and sensitivity, we performed whole exome sequencing on pre/post-chemotherapy tumors and matched lymphocytes from 26 patients. We observed great inter-tumoral heterogeneity with no gene mutated recurrently in more than four tumors besides TP53. Although the degree of response to chemotherapy in residual tumors was associated with more subclonal changes during chemotherapy, there was minimal evolution between pre/post-tumors. Indeed, gene sets enriched for mutations in pre- and post-chemotherapy tumors were very similar and reflected genes involved in the biological process of neurogenesis. Somatically mutated genes present in chemosensitive tumors included COL1A2, PRMD15, APOBEC3B, PALB2 and histone protein encoding genes, while BRCA1, ATR, ARID1A, XRCC3 and genes encoding for tubulin-associated proteins were present in the chemoresistant tumors. We also found that the mutational spectrum of post-chemotherapy tumors was more reflective of matching metastatic tumor biopsies than pre-chemotherapy samples. These findings support a portrait of modest ongoing genomic instability with respect to single-nucleotide variants induced by or selected for by chemotherapy in TNBCs.

Sense of community among young adults before and after moving into Permanent Supportive Housing: A mixed-methods longitudinal analysis

Amidst chronic stressors and ongoing instability, many young people who have experienced homelessness and housing instability find communities and settings which offer support and care. Permanent Supportive Housing (PSH) is one setting which aims to provide stability and community to those who have experienced homelessness, but it has not been widely studied with young adults (ages 18–25 upon moving into PSH). This paper employs a longitudinal convergent mixed methods approach – with quantitative and qualitative survey data over 1.5 years – to explore how young adult residents (N = 27 at T1; N = 20 at T2, N = 13 at T3) experience sense of community before and after moving into PSH. Using McMillan and Chavis’ (1986) four-part Psychological Sense of Community (PSOC) framework to frame data collection and analysis, we find that residents’ sense of community is shaped by an ongoing negotiation of personal and collective needs. Building community takes time and requires opportunities for voices to be heard (and shape change), along with ongoing personal growth – especially related to substance use recovery. Our findings offer insights for future PSH settings for young people – as well as other residential and community settings which aim to support young people. We suggest the need for future research which explores the tension of policy decision making, about substance use for example, in low-barrier support services like PSH.

Cellular Responses to Widespread DNA Replication Stress

Replicative DNA polymerases are blocked by nearly all types of DNA damage. The resulting DNA replication stress threatens genome stability. DNA replication stress is also caused by depletion of nucleotide pools, DNA polymerase inhibitors, and DNA sequences or structures that are difficult to replicate. Replication stress triggers complex cellular responses that include cell cycle arrest, replication fork collapse to one-ended DNA double-strand breaks, induction of DNA repair, and programmed cell death after excessive damage. Replication stress caused by specific structures (e.g., G-rich sequences that form G-quadruplexes) is localized but occurs during the S phase of every cell division. This review focuses on cellular responses to widespread stress such as that caused by random DNA damage, DNA polymerase inhibition/nucleotide pool depletion, and R-loops. Another form of global replication stress is seen in cancer cells and is termed oncogenic stress, reflecting dysregulated replication origin firing and/or replication fork progression. Replication stress responses are often dysregulated in cancer cells, and this too contributes to ongoing genome instability that can drive cancer progression. Nucleases play critical roles in replication stress responses, including MUS81, EEPD1, Metnase, CtIP, MRE11, EXO1, DNA2-BLM, SLX1-SLX4, XPF-ERCC1-SLX4, Artemis, XPG, FEN1, and TATDN2. Several of these nucleases cleave branched DNA structures at stressed replication forks to promote repair and restart of these forks. We recently defined roles for EEPD1 in restarting stressed replication forks after oxidative DNA damage, and for TATDN2 in mitigating replication stress caused by R-loop accumulation in BRCA1-defective cells. We also discuss how insights into biological responses to genome-wide replication stress can inform novel cancer treatment strategies that exploit synthetic lethal relationships among replication stress response factors.

Single Cell Whole Genome Measurement of Genomic Heterogeneity and Clonal Evolution in Multiple Myeloma

Background: Sequencing studies have advanced our understanding of the genomic underpinnings of Multiple Myeloma (MM). While whole genome sequencing (WGS) has emerged as a comprehensive approach for profiling the genomic landscape of MM, WGS has limited sensitivity in defining the intrapatient genomic heterogeneity. Single cell RNA approaches can capture phenotypic heterogeneity but fail to recover most of the key genomic drivers. To overcome these historical limitations, we utilized a newer single cell whole genome direct library preparation (scWGS DLP+; Lacks et al. Cell 2019) sequencing technology able to detect early changes and study clonal population dynamics, providing a more precise understanding of the emergence and clinical impact of genomic events during MM evolution. Methods: scWGS DLP+ was applied to CD138 + Plasma Cells (PC) isolated from bone marrow samples of MM patients. Using newly developed computational approaches, we characterized the Single Nucleotide Variants (SNVs), copy number changes and complex Structural Variants (SVs) at a single cell level and use this information to reconstruct the evolutionary histories of each patient's myeloma. Results: We applied DLP to 7 MM patients obtaining 800-1600 single cell whole genomes per patient. All canonical IgH translocations identified by FISH were recovered in the scWGS data. Single cell copy number heterogeneity was observed in all but 1 patient, including heterogeneity affecting known drivers. The number of subclones ranged from 1 to 15, with an average of 6 subclones detected per patient (≥10 cells, ≥5MB distinct segmental difference). This is in striking contrast with bulk WGS where we are usually able to define no more than one or two subclones. Gain of 1q (3 copies) was observed in all patients but was either rare (1-3%, 3 patients) or clonal (>99%, 4 patients), with two clonal 1q patients exhibiting convergent subclonal 1q amplification (>3 copies). Loss of previously gained chromosomes was observed including loss of ancestrally gained chromosome 15 in hypodiploid Patient 2, and sporadic loss of 1q in patients with ubiquitous 1q gain. For 3 of 7 patients, hypodiploidy (HRD) had arisen before the most recent clonal expansion. HRD clones continued to diversify, accruing multiple additional events on HRD chromosomes including large or focal gains, or deletions subsequent to a gain. Interestingly, one case had 1 small hypodiploid clone co-existing with a completely different major clone with 1q and t(14;20) IgH translocation, suggesting the existence of two distinct clonal plasma cell populations (one malignant and one likely bening). Two of the 7 patients harbored both small (<20 cells) whole genome doubled (WGD) subclones, and small numbers of highly aneuploid likely produced by multi-polar cell division post WGD. We explored two patient's evolutionary histories in detail, highlighting the unique resolution of scWGS DLP+ to detect CNV but also SNV, mutational signatures and SVs. Patient 3 exhibited 4 distinct subclones with distant evolutionary origin as evidenced by the relatively small number of shared SNV. APOBEC signature mutations were detected in all 4 subclones suggesting APOBEC mutagenesis was still ongoing across the cell populations in this patient. In Patient 1, a complex SV on chromosome 17 resulted in loss of most of 17q and an amplification of 17q segments. The heterogeneous structure of chromosome 17 across clones suggests a late onset of this complex event and ongoing instability. Chromosome 16 exhibited a pattern of cell specific arm loss likely resulting from telomere loss. Interestingly, a minor clone showed complex amplification of 16p affecting TNFRSF17, suggesting that chromosome 16 is at an earlier stage of a process of instability that starts with cell specific arm loss, and ends with clonal expansion of a complex amplification SV targeting a gene with fitness benefit. Discussion: Applied to Multiple Myeloma, scWGS shows higher clonal heterogeneity than previously described with multiple clones exhibiting diverse genetic alterations. The findings underscore the genomic complexity and dynamic nature of MM, highlighting the need for sensitive techniques like scWGS to capture the full spectrum and chronological order of genomic events.

Political instability and hiv/aids response in the south west and north west regions of Cameroon: a qualitative study

BackgroundPolitically motivated violence and insecurity continue to be a major threat to progress in HIV epidemic control and a significant contributor to health inequality. Despite a decreasing HIV/AIDS disease burden, the Republic of Cameroon in West Africa is experiencing ongoing political instability in her North and South West Regions. Our study used qualitative methods to better understand key frontline health care providers’ (fHCP) perceptions of the effects of political instability on HIV/AIDS response gains in Cameroon since 2018, as well as lessons learned for overcoming them.MethodsBetween July and August 2022, semi-structured, in-depth key informant interviews involving 10 purposively selected participants were conducted in the two regions. Interviews were recorded and transcribed verbatim, coded thematically, and analyzed manually.ResultsSix overarching themes emerged from the transcribed key informant interviews. They were as follows: Challenge with access to and availability of health care services (HIV care, commodity supply chain) in the smaller communities; Impact on continuity of treatment; Increased risk of new HIV infections; The socioeconomic impact of the crisis on the quality of life; The impact of the crisis on fHCPs’ physical and mental health and the health system’; and Coping mechanisms.ConclusionsFrontline healthcare workers have acknowledged the significant impact the current political instability has had in hindering the development and advancement of a successful local response to HIV/AIDS in the two impacted regions of Cameroon. Coordinated efforts must be made to strengthen the health sector in areas such as HIV healthcare decentralization, supply chain, and protecting frontline healthcare workers from political quagmires in order to lessen the impact of the nation’s socio-political crisis on the HIV/AIDS response and, more generally, on the entire health sector.

Outcome Analysis of Posterior Cruciate Ligament Injuries: A Narrative Review.

The primary posterior stabilizer of the knee is the posterior cruciate ligament (PCL), the largest intra-articular ligament in the human knee. One of the four primary ligaments of the knee joint, the PCL, serves to support the tibia on the femur. An extreme force applied anteriorly to the proximal tibia of the flexed knee results in trauma to the PCL. Dashboard injuries, which occur when the knee is driven into the dashboard after a collision with a motor vehicle, are frequent causes. Grade 1 and 2 acute injuries are often addressed conservatively due to the PCL's natural capacity for mending. If a grade 3 injury occurs, a cautious trial can be conducted on elderly or low-demand patients. When standard treatment for isolated grade 3 injuries has failed, surgery is advised. Single-bundle or double-bundle techniques using either transtibial tunnel or tibial inlay techniques are among the reconstruction approaches. Restoring the natural kinematics of the knee and forestalling persistent posterior and mixed rotatory knee laxity are the ultimate goals of treating PCL injuries through a personalized strategy. These injuries may become more common in the future as more people participate in sports. As a result of ongoing instability, discomfort, diminished function, and the emergence of inflammatory and degenerative disorders of joints, PCL rips are becoming more well-acknowledged as a cause of morbidity and decreased function.

Genomic signatures of past and present chromosomal instability in Barrett’s esophagus and early esophageal adenocarcinoma

The progression of precancerous lesions to malignancy is often accompanied by increasing complexity of chromosomal alterations but how these alterations arise is poorly understood. Here we perform haplotype-specific analysis of chromosomal copy-number evolution in the progression of Barrett’s esophagus (BE) to esophageal adenocarcinoma (EAC) on multiregional whole-genome sequencing data of BE with dysplasia and microscopic EAC foci. We identify distinct patterns of copy-number evolution indicating multigenerational chromosomal instability that is initiated by cell division errors but propagated only after p53 loss. While abnormal mitosis, including whole-genome duplication, underlies chromosomal copy-number changes, segmental alterations display signatures of successive breakage-fusion-bridge cycles and chromothripsis of unstable dicentric chromosomes. Our analysis elucidates how multigenerational chromosomal instability generates copy-number variation in BE cells, precipitates complex alterations including DNA amplifications, and promotes their independent clonal expansion and transformation. In particular, we suggest sloping copy-number variation as a signature of ongoing chromosomal instability that precedes copy-number complexity. These findings suggest copy-number heterogeneity in advanced cancers originates from chromosomal instability in precancerous cells and such instability may be identified from the presence of sloping copy-number variation in bulk sequencing data.

Ebro Valley Gypsum Escarpment Near Zaragoza (NE Spain)—Combination of Highly Valuable Rock Record, Dynamic Geomorphosites and Associated Cultural Heritage

The 40-km-long escarpment of the Ebro River valley to the north-west of Zaragoza (NE Spain) is a remarkable geomorphological feature and an important geoheritage locality. Being 30 to 150 m high, the escarpment exposes a complex evaporate-clastic succession of Early to Middle Miocene age, with alternating gypsum and mudstone/marl units, as well as halite beds at depth. The escarpment is a highly dynamic feature, extensively shaped by mass movements of different types, especially in sections where it is directly undercut by the Ebro River. It also hosts abundant evidence of salt and gypsum dissolution, contributing to ongoing instability. Diverse cultural heritage is associated with the escarpment, including an ancient Celtiberian settlement, medieval castles, abandoned villages, rock-cut churches and dwellings and ancient salt mines. Twenty-six possible geosites are identified, with six considered as most representative described in detail. Opportunities to develop the area for geotourism are presented, but these will be associated with challenges of properly managing steep, dynamic and fragile terrain.

Contradictions of economic policy in the context of new risks and challenges in the development of the world economy

The relevance of the problems considered in the article is associated with the growth of uncertainty and increased turbulence in the development of the world economy in recent years, as well as with the ambiguous impact of this instability on the economies of individual countries. These new trends have actualized the problems of economic policy, the analysis of which is the purpose of our study. These problems are connected both with the restoration of the previous growth rates and the choice of optimal instruments of fiscal and monetary policy, as well as counteracting the volatility of world prices and the instability inherent in commodity markets. One of the objectives of the study is to assess the approaches of individual countries in terms of their response to the crisis phenomena of recent years, to determine the main directions for counteracting the growth in the debt burden of countries, tools to curb inflation in the context of unprecedentedly tight financial conditions, as well as mechanisms for macroprudential regulation. As one of the results of the study, the author proves the growing differentiation of economic policies in the context of individual countries, limiting the sustainable recovery of the world economy, which is exacerbated by the ongoing instability of international trade and disruptions in global value chains. In addition, the author concluded that volatile world energy and food prices make traditional economic policies more uncertain and force countries to use alternative economic regulation tools, in particular, those related to changing the practice of applying policy rates to curb inflation, new approaches to the implementation of the tasks of the climate agenda and labor market policy.

Maggot therapy could provide affordable and efficacious wound care in Lebanon and other low- and middle-income countries

The poor economic situation, ongoing political instability, and the 2020 Beirut explosion have seriously eroded the capacity of the Lebanese healthcare system. Insecure fuel supplies and the rationing of electricity to a few hours per day make matters worse. New strategies are required to deliver healthcare that is more resilient in the face of ongoing disruption. Maggot therapy for the treatment of chronic and infected wounds could make a meaningful difference in Lebanon. When placed in a wound, medicinal maggots remove dead tissue, control infection and stimulate wound healing. It is an inexpensive, easy to use, and highly efficacious therapy, even under austere conditions. This review provides an introduction to maggot therapy and briefly explains its therapeutic benefits before discussing the role it can play in the Lebanese healthcare system. Finally, the prerequisites and enablers for successful integration of maggot therapy into the Lebanese healthcare system are outlined.

Pakistan’s Intractable Corruption Provides Terror Groups Agency

This paper discusses the challenges faced by Pakistan, a country in South Asia, with a focus on corruption as a major contributor to the ongoing instability, particularly in relation to terrorism. Corruption has created conditions that are conducive to terrorism by creating economic and political instability, weakening the rule of law, and undermining the legitimacy of government institutions. Terrorist groups, including the Taliban, TTP, and LeT, exploit public frustration to recruit vulnerable individuals, offer financial incentives, and social services. Corruption has led to a lack of accountability, lack of resources, and a breakdown of trust between the government and the people. Furthermore, corruption has contributed to the high turnover of government leadership in Pakistan. The paper also looks at the historical lack of public trust in Pakistan's government, marked by military coups, political instability, and economic challenges. The paper concludes that unless the issue of corruption is addressed, Pakistan will continue to face significant challenges that undermine its social, political, and economic landscape.

Acoustic emission monitoring and analyses for avalanche release and slab fracturing events observed in Great Himalaya

ABSTRACT The acoustic emission (AE) monitoring of failures, fractures and instabilities evolving within a snowpack may provide vital information about the avalanche formation preceding release processes. In this work, AE activity was collected continuously over five years from the snowpack built on avalanche starting zone in Great Himalaya, and the analyses are presented in the context of an avalanche release and two slab fracturing events detected successfully during this study period. For non-invasive detection of AE activity from snow, a specialised sensor-arrestor array was deployed over the avalanche slope. In our investigations, an abnormal AE activity was observed both during the slab fracturing as well as the avalanche occurrence periods. For AE-based direct assessment of snow instability, a method is proposed to estimate instability index (βin), based on AE count and amplitude values of a hit, and it is applied for analyses of avalanche formation preceding release and slab fracturing cases. The prominent AE attributes including βin-variations are also analysed at appropriate window scales for a smooth representation of the ongoing instability and failure processes underneath the slab. The AE spectral analyses of avalanche release and slab fracturing reveal the dominant frequencies around 45–47 kHz and 34–43 kHz, respectively. A progressively increasing behaviour was observed with an abrupt increase in the relevant AE parameters and also the βin-values, nearly 13 hours before the avalanche release, and it continued until the avalanche released which can be associated to the instability development prior to avalanche release.

Presentation, care and outcomes of patients with NSTEMI according to World Bank country income classification: Prospective international multicentre cohort study of the ESC EORP NSTEMI registry

Abstract Funding Acknowledgements Type of funding sources: None. Background The majority of NSTEMI burden resides outside high income countries (HICs). Care that conforms to the European Society of Cardiology (ESC) guidelines has been demonstrated to improve outcomes,2-6 but places a financial burden on healthcare systems.7 Whether care quality and outcomes vary by country economic prosperity is unknown. The EURObservational Research Programme (EORP) NSTEMI registry was designed and implemented to identify patterns in NSTEMI care and outcomes across the heterogeneous context of ESC country members and affiliated countries. Purpose We describe presentation, care and outcomes of NSTEMI by World Bank country income classification. Methods Prospective cohort study (11 March 2019 to 6 March 2021) including 2947 adult patients with NSTEMI from 287 centres in 59 countries. For each patient demographic features, therapeutic methods, treatment delays, risk stratification and medication prescription during admission and on discharge were recorded. Quality of care was evaluated based on 12 guideline-recommended care interventions. The all-or-none scoring composite performance measure was used to define receipt of optimal care. Outcomes included in-hospital repeat myocardial infarction, acute heart failure and death, and 30-day mortality. Results Patients admitted with NSTEMI in low-lower middle income countries (LLMICs), compared to patients in HICs, were younger (median age 58 years [IQR 51-65] vs 68 [59-77]), more commonly diabetic (48.6% vs 34.2%) but with a lower burden of other comorbidities (Table 1). Of patients with NSTEMI in LLMICs, 76.7% met very high risk criteria for an immediate invasive strategy. Compared to patients in HICs, the proportion of patients in LLMICs presenting in Killip Class III or IV was three-fold higher; and ongoing chest pain, life-threatening arrhythmias, and hemodynamic instability were at least twice as common. Invasive coronary angiography use increased with ascending income classification (LLMICs, 79.2%; upper middle income countries [UMICs], 83.7%; HICs, 91.0%), but overall care quality did not (≥80% of eligible interventions achieved: LLMICS, 64.8%; UMICs 69.6%; HICs 55.1%) (Figure 1). Rates of acute heart failure (LLMICS, 21.3%; UMICs, 12.1%; 3.2%; HICs, 6.8%; p<0.001), repeat myocardial infarction (LLMICS: 2.5%; UMICs: 1.5%; HICs: 0.9%; p=0.04), in-hospital mortality (LLMICS, 3.6%; UMICs: 2.8%; HICs: 1.0%; p<0.001) and 30 day mortality (LLMICs, 4.9 %; UMICs, 3.9%; HICs, 1.5%; p<0.001) exhibited an inverse economic gradient. Conclusions Patients with NSTEMI in LLMICs present at a younger age, with fewer comorbidities, at a more advanced stage of acute disease, and have worse outcomes compared with HICs. Overall care did not vary by income classification, but there was a shortfall in provision of interventional procedures in LLMICs. A cardiovascular health narrative is needed to address this inequity across economic boundaries.

Timing of invasive coronary angiography in non-ST-elevation acute coronary syndrome-an updated individual patient data meta-analysis.

The optimal timing of invasive coronary angiography in non-ST-elevation acute coronary syndrome (NSTE-ACS) was subject of several randomized controlled trials (RCTs) since more than 20 years. American and European guidelines recommend an early invasive strategy <24 h for high-risk NSTE-ACS patients with a global registry of acute coronary events (GRACE) risk score >140 but without evidence for ongoing ischaemia or haemodynamic instability.1,2 However, scientific evidence supporting this recommendation is sparse. Butt et al.3 analysed the effect of the GRACE risk score on all-cause mortality in a post-hoc analysis of the very early versus deferred invasive evaluation using computerized tomography (VERDICT) trial. We combined the published VERDICT data with an existing database of our previous meta-analysis (Supplementary material online for further details, Table S1, Table S2, and Figure S1r).4 Consecutively, we updated our previous GRACE risk score subgroup analysis to synthetize up-to-date scientific evidence from the currently available data. The methodology is described in the Supplementary material online in detail. In short, we performed one-stage as well as two-stage meta-analyses. Both approaches led to the same result that an early invasive strategy does reduce the risk of all-cause mortality in patients with a GRACE risk score >140 but not in patients with a GRACE risk score ≤140 or the unselected population of NSTE-ACS patients (Figure 1). While some heterogeneity is present in the total population (I2 = 30%), it is absent in each subgroup stratum (I2 = 0%; Supplementary material online, Figure S2). The reported finding is driven by the addition of data from the VERDICT trial. Exclusion of this trial leads to a similar finding as reported in our previous meta-analysis (see Supplementary material online, Table S3 and Supplementary material online, Figure S3).4

Malaysia in 2022

Malaysia held a general election in 2022 that was expected to resolve ongoing political instability. Instead, it produced a hung parliament, reflecting a deeply divided electorate and growing support for Islamist politics. Following a royal intervention, Anwar Ibrahim’s progressive coalition formed a unity government with the long-dominant UMNO and East Malaysian parties; this unprecedented arrangement faces evolving social, political, and economic challenges that will test its stability and the very nature of Malaysian politics.

British Society for Haematology guideline for anticoagulantmanagement of pregnant individuals with mechanical heart valves.

British Society for Haematology guideline for anticoagulantmanagement of pregnant individuals with mechanical heart valves.

Pilgrimage, Precarity, and Pandemics

Pilgrimage, Precarity, and Pandemics

Climate change increased extreme monsoon rainfall, flooding highly vulnerable communities in Pakistan

As a direct consequence of extreme monsoon rainfall throughout the summer 2022 season Pakistan experienced the worst flooding in its history. We employ a probabilistic event attribution methodology as well as a detailed assessment of the dynamics to understand the role of climate change in this event. Many of the available state-of-the-art climate models struggle to simulate these rainfall characteristics. Those that pass our evaluation test generally show a much smaller change in likelihood and intensity of extreme rainfall than the trend we found in the observations. This discrepancy suggests that long-term variability, or processes that our evaluation may not capture, can play an important role, rendering it infeasible to quantify the overall role of human-induced climate change. However, the majority of models and observations we have analysed show that intense rainfall has become heavier as Pakistan has warmed. Some of these models suggest climate change could have increased the rainfall intensity up to 50%. The devastating impacts were also driven by the proximity of human settlements, infrastructure (homes, buildings, bridges), and agricultural land to flood plains, inadequate infrastructure, limited ex-ante risk reduction capacity, an outdated river management system, underlying vulnerabilities driven by high poverty rates and socioeconomic factors (e.g. gender, age, income, and education), and ongoing political and economic instability. Both current conditions and the potential further increase in extreme peaks in rainfall over Pakistan in light of anthropogenic climate change, highlight the urgent need to reduce vulnerability to extreme weather in Pakistan.