Sensory and psychological correlates of postsurgical pain in adolescents with idiopathic scoliosis undergoing spinal fusion surgery: a preliminary analysis

OBJECTIVE: Chronic pain, including persistent postsurgical pain, reduces patients' quality of life, mood, and productivity. It presents a significant economic burden to society, yielding an estimated $600 billion annual cost due to health care and lost work productivity. Moderate to severe chronic pain affects 5% of children and adolescents. The current body of knowledge has demonstrated a consensus opinion that psychological factors and sensory factors are correlated with pain in the adult population. However, more research is necessary to determine what role depression and sensory function play in predicting severity of persistent postsurgical pain in children and adolescents. Thus, the present study seeks to explore how, if at all, post-operative pain and functional disability at 1 month postsurgery is correlated with pre-operative depression and sensory profile. METHODS: Eligible candidates were Adolescent Idiopathic Scoliosis (AIS) patients aged 10-17 who have been recommended to undergo spinal fusion surgery at Boston Children's Hospital (BCH). Fifteen participants were included in this study. Prior to surgery, all participants completed the Children's Depression Inventory: Short Form (CDI:S) via REDCap and underwent Quantitative Sensory Testing (QST) on their palmar thenar eminence (non-surgical site) and their lower back (surgical site). Participants' light touch detection thresholds and sharp prick pain threshold scores were determined using von Frey hairs. Participants' pressure-pain sensation threshold scores were determined using a pressure algometer. Warm and cool detection thresholds and hot and cold pain thresholds were measured using a thermode strapped to the skin. At 1 month postsurgery, participants completed the Functional Disability Inventory (FDI) and reported their pain scores, including their current pain, average and worst pain in the last week, average and worst pain in the last month, and average and worst pain in the last six months. Each presurgical variable was compared with each postsurgical variable using Pearson correlations at a significance level of p < 0.05. Additionally, postsurgical FDI scores were compared with postsurgical pain scores using Pearson correlations. RESULTS: Due to the small sample size (N = 15), the results should be considered preliminary. Preoperative CDI:S scores were not found to be correlated with postoperative pain and functional disability at 1 month postsurgery. Several preoperative QST variables were found to be correlated with postsurgical pain at 1 month. Namely, light touch detection threshold on the hand was negatively correlated with current pain (p < 0.05), average pain in the last week (p < 0.05), worst pain in the last week (p < 0.05), average pain in the last month (p < 0.05), and worst pain in the last month (p < 0.05). Warm detection threshold on the hand was negatively correlated with four different post-operative pain measures taken at one month post-surgery: worst pain in the last week (p < 0.05), worst pain in the last month (p < 0.05), average pain in the last six months (p < 0.05), and worst pain in the last six months (p < 0.05). Finally, heat pain threshold on the hand was negatively correlated with worst pain in the last 6 months at 1 month postsurgery (p < 0.05). Furthermore, postsurgical scores on the FDI were positively correlated with current pain at the 1-month post-surgical time point (p < 0.01), average pain in the last week at the 1-month post-surgical time point (p < 0.05), and worst pain in the last week at the 1-month post-surgical time point (p < 0.05). CONCLUSIONS: This study provides preliminary evidence of a correlation between heat sensitivity and poor postsurgical pain outcomes in the AIS population. Contrary to what was expected, hyposensitivity to light touch was correlated with worse pain outcomes. It is unclear why this is the case, and further research on the somatosensory profiles of pain patients is needed to examine this phenomenon. One of the most important findings in the present study is the correlation between post-operative pain and functional disability. The present study contributes to the small but growing body of knowledge surrounding the correlates of pediatric postsurgical pain. The use of QST provides an objective, quantifiable measure of patients' somatosensory profile. Furthermore, the present study contributes to the expansive research base that has shown the detrimental effects of chronic pain, highlighting the correlation between pain and functional disability in the AIS population following spinal fusion surgery

SER-109: An Oral Investigational Microbiome Therapeutic for Patients with Recurrent Clostridioides difficile Infection (rCDI)

Clostridioides difficile infection (CDI) is classified as an urgent health threat by the Centers for Disease Control and Prevention (CDC), and affects nearly 500,000 Americans annually. Approximately 20–25% of patients with a primary infection experience a recurrence, and the risk of recurrence increases with subsequent episodes to greater than 40%. The leading risk factor for CDI is broad-spectrum antibiotics, which leads to a loss of microbial diversity and impaired colonization resistance. Current FDA-approved CDI treatment strategies target toxin or toxin-producing bacteria, but do not address microbiome disruption, which is key to the pathogenesis of recurrent CDI. Fecal microbiota transplantation (FMT) reduces the risk of recurrent CDI through the restoration of microbial diversity. However, FDA safety alerts describing hospitalizations and deaths related to pathogen transmission have raised safety concerns with the use of unregulated and unstandardized donor-derived products. SER-109 is an investigational oral microbiome therapeutic composed of purified spore-forming Firmicutes. SER-109 was superior to a placebo in reducing CDI recurrence at Week 8 (12% vs. 40%, respectively; p \u3c 0.001) in adults with a history of recurrent CDI with a favorable observed safety profile. Here, we discuss the role of the microbiome in CDI pathogenesis and the clinical development of SER-109, including its rigorous manufacturing process, which mitigates the risk of pathogen transmission. Additionally, we discuss compositional and functional changes in the gastrointestinal microbiome in patients with recurrent CDI following treatment with SER-109 that are critical to a sustained clinical response

The Drosophila afadin homologue Canoe regulates linkage of the actin cytoskeleton to adherens junctions during apical constriction

Cadherin-based adherens junctions (AJs) mediate cell adhesion and regulate cell shape change. The nectin–afadin complex also localizes to AJs and links to the cytoskeleton. Mammalian afadin has been suggested to be essential for adhesion and polarity establishment, but its mechanism of action is unclear. In contrast, Drosophila melanogaster’s afadin homologue Canoe (Cno) has suggested roles in signal transduction during morphogenesis. We completely removed Cno from embryos, testing these hypotheses. Surprisingly, Cno is not essential for AJ assembly or for AJ maintenance in many tissues. However, morphogenesis is impaired from the start. Apical constriction of mesodermal cells initiates but is not completed. The actomyosin cytoskeleton disconnects from AJs, uncoupling actomyosin constriction and cell shape change. Cno has multiple direct interactions with AJ proteins, but is not a core part of the cadherin–catenin complex. Instead, Cno localizes to AJs by a Rap1- and actin-dependent mechanism. These data suggest that Cno regulates linkage between AJs and the actin cytoskeleton during morphogenesis

Nunca invisibles: insurgent memory and self-representation by female ex-combatants in Colombia

As part of attempts to end more than half century of armed conflict, transitional justice and memory initiatives have proliferated in Colombia, providing recognition and redress to victims of violence. Yet, alongside the focus on victims, former insurgents in Colombia have also called for the inclusion of their own narratives of the conflict in public memory initiatives. Responding to recent memory studies scholarship, which has begun to reorient the field away from a narrow focus on past trauma, this article analyses the construction of ‘insurgent memory’ in Colombia through the 2018 documentary Nunca Invisibles: Mujeres Farianas, Adiós a la guerra. Emerging from a grassroots memory project led by women from the FARC, I explore how the film challenges the predominant framing of ex-combatant women as victims in transitional justice and DDR scholarship. Situating this in a longer history of memory projects by female combatants, the article analyses how such projects, whilst articulating a discourse of peace and reconciliation, vindicate a narrative of female revolutionary activism and a political identity that is often erased in post-conflict “reintegration” processes. In doing so, I demonstrate the importance of creative, grassroots processes in enabling ex-combatants to represent themselves and move beyond the limitations of official memory and transitional justice frameworks

MicroRNA profiling of the pubertal mouse mammary gland identifies miR-184 as a candidate breast tumour suppressor gene

INTRODUCTION: The study of mammalian development has offered many insights into the molecular aetiology of cancer. We previously used analysis of mammary morphogenesis to discover a critical role for GATA-3 in mammary developmental and carcinogenesis. In recent years an important role for microRNAs (miRNAs) in a myriad of cellular processes in development and in oncogenesis has emerged. METHODS: microRNA profiling was conducted on stromal and epithelial cellular subsets microdissected from the pubertal mouse mammary gland. miR-184 was reactivated by transient or stable overexpression in breast cancer cell lines and examined using a series of in vitro (proliferation, tumour-sphere and protein synthesis) assays. Orthotopic xenografts of breast cancer cells were used to assess the effect of miR-184 on tumourigenesis as well as distant metastasis. Interactions between miR-184 and its putative targets were assessed by quantitative PCR, microarray, bioinformatics and 3' untranslated region Luciferase reporter assay. The methylation status of primary patient samples was determined by MBD-Cap sequencing. Lastly, the clinical prognostic significance of miR-184 putative targets was assessed using publicly available datasets. RESULTS: A large number of microRNA were restricted in their expression to specific tissue subsets. MicroRNA-184 (miR-184) was exclusively expressed in epithelial cells and markedly upregulated during differentiation of the proliferative, invasive cells of the pubertal terminal end bud (TEB) into ductal epithelial cells in vivo. miR-184 expression was silenced in mouse tumour models compared to non-transformed epithelium and in a majority of breast cancer cell line models. Ectopic reactivation of miR-184 inhibited the proliferation and self-renewal of triple negative breast cancer (TNBC) cell lines in vitro and delayed primary tumour formation and reduced metastatic burden in vivo. Gene expression studies uncovered multi-factorial regulation of genes in the AKT/mTORC1 pathway by miR-184. In clinical breast cancer tissues, expression of miR-184 is lost in primary TNBCs while the miR-184 promoter is methylated in a subset of lymph node metastases from TNBC patients. CONCLUSIONS: These studies elucidate a new layer of regulation in the PI3K/AKT/mTOR pathway with relevance to mammary development and tumour progression and identify miR-184 as a putative breast tumour suppressor

Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BACKGROUND Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations. METHODS The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56 604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model-a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates-with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality-which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds. FINDINGS The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2-100·0) per 100 000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1-290·7] per 100 000 population) and Latin America and the Caribbean (195·4 deaths [182·1-211·4] per 100 000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4-48·8] per 100 000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3-37·2] per 100 000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7-9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles. INTERPRETATION Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere. FUNDING Bill & Melinda Gates Foundation

Probiotic Therapy for Irritable Bowel Syndrome

It is estimated that 20% of Americans suffer from Irritable Bowel Syndrome (IBS) which is a functional gastrointestinal disorder characterized by abdominal pain, constipation and diarrhea (National Digestive Diseases Information Clearinghouse, 2011). Many IBS sufferers have attempted to manage their symptoms through probiotic therapy, which is the ingestion of microorganisms, similar to those normally present in the gastrointestinal tract, to achieve health benefits (American Gastroenterological Association, 2011). The information about probiotics for IBS was confusing and conflicting. This paper examined the evidence for the relationship between IBS symptoms and gastrointestinal microorganisms, the species of bacteria that are identified as probiotics, and the efficacy of utilizing probiotic therapy to manage IBS symptoms. It addressed the following question; "Does the current research provide evidence for the efficacy of probiotic therapy for the treatment of IBS symptoms?" A variety of Internet sources and 20 research articles were examined and a summary of the research suggested (a) there is likely a relationship between gastrointestinal microorganisms and IBS symptonls; (b) the term "probiotics" encompasses a variety of species of bacteria; (c) although a variety of bacteria species have been studied, there is not yet conclusive evidence about the most effective species to treat IBS symptoms; (d) the genera Bifidobacterium and Lactobacillus have been the most studied and produced the most favorable data; and (e) few adverse effects are reported in the literature. Further research is necessary to establish guidelines for the use of probiotics to manage IBS symptonls