Smouldering-Associated Worsening in Multiple Sclerosis: An International Consensus Statement on Definition, Biology, Clinical Implications, and Future Directions.

Despite therapeutic suppression of relapses, multiple sclerosis (MS) patients often experience subtle deterioration, which extends beyond the definition of "progression independent of relapsing activity." We propose the concept of smouldering-associated-worsening (SAW), encompassing physical and cognitive symptoms, resulting from smouldering pathological processes, which remain unmet therapeutic targets. We provide a consensus-based framework of possible pathological substrates and manifestations of smouldering MS, and we discuss clinical, radiological, and serum/cerebrospinal fluid biomarkers for potentially monitoring SAW. Finally, we share considerations for optimizing disease surveillance and implications for clinical trials to promote the integration of smouldering MS into routine practice and future research efforts. ANN NEUROL 2024;96:826-845.

Integration of metabolic flux with hepatic glucagon signaling and gene expression profiles in the conscious dog.

Glucagon rapidly and profoundly stimulates hepatic glucose production (HGP), but for reasons that are unclear, this effect normally wanes after a few hours, despite sustained plasma glucagon levels. This study characterized the time course of glucagon-mediated molecular events and their relevance to metabolic flux in the livers of conscious dogs. Glucagon was either infused into the hepato-portal vein at a sixfold basal rate in the presence of somatostatin and basal insulin, or it was maintained at a basal level in control studies. In one control group, glucose remained at basal, whereas in the other, glucose was infused to match the hyperglycemia that occurred in the hyperglucagonemic group. Elevated glucagon caused a rapid (30 min) and largely sustained increase in hepatic cAMP over 4 h, a continued elevation in glucose-6-phosphate (G6P), and activation and deactivation of glycogen phosphorylase and synthase activities, respectively. Net hepatic glycogenolysis increased rapidly, peaking at 15 min due to activation of the cAMP/PKA pathway, then slowly returned to baseline over the next 3 h in line with allosteric inhibition by glucose and G6P. Glucagon's stimulatory effect on HGP was sustained relative to the hyperglycemic control group due to continued PKA activation. Hepatic gluconeogenic flux did not increase due to the lack of glucagon's effect on substrate supply to the liver. Global gene expression profiling highlighted glucagon-regulated activation of genes involved in cellular respiration, metabolic processes, and signaling, as well as downregulation of genes involved in extracellular matrix assembly and development.NEW & NOTEWORTHY Glucagon rapidly stimulates hepatic glucose production, but these effects are transient. This study links the molecular and metabolic flux changes that occur in the liver over time in response to a rise in glucagon, demonstrating the strength of the dog as a translational model to couple findings in small animals and humans. In addition, this study clarifies why the rapid effects of glucagon on liver glycogen metabolism are not sustained.

Effect of BvAgNP on growth, development, and glyoxalase gene expression analysis in Mammillaria bombycina and Selenicereus undatus.

BACKGROUND: Silver nanoparticles (AgNPs) have been used in plant tissue culture as growth stimulants, promoting bud initiation, germination, and rooting. In prior studies, AgNPs were synthesized and characterized by green synthesis using extracts from Beta vulgaris var. cicla (BvAgNP), and their functionality as seed disinfectant and antimicrobial was verified. In this study, we evaluated the effect of BvAgNP on the growth and development of Mammillaria bombycina and Selenicereus undatus in vitro, as well as the expression of glyoxalase genes. METHODS: Explants from M. bombycina and S. undatus in vitro were treated with 25, 50, and 100 mg/L of BvAgNP. After 90 days, morphological characteristics were evaluated, and the expression of glyoxalase genes was analyzed by qPCR. RESULTS: All treatments inhibited rooting for M. bombycina and no bud initiation was observed. S. undatus, showed a maximum response in rooting and bud generation at 25 mg/L of BvAgNP. Scanning electron microscopy (SEM) results exhibited a higher number of vacuoles in stem cells treated with BvAgNP compared to the control for both species. Expression of glyoxalase genes in M. bombycina increased in all treatments, whereas it decreased for S. undatus, however, increasing in roots. CONCLUSIONS: This study presents the effects of BvAgNP on the growth and development of M. bombycina and S. undatus, with the aim of proposing treatments that promote in vitro rooting and bud initiation.

Rheumatoid meningitis: a case series report and review of modern therapeutic schemes and outcome.

INTRODUCTION: Rheumatoid meningitis (RM) is an extremely rare extra-articular complication of rheumatoid arthritis (RA), with approximately 165 cases reported world-wide. RM exhibits a broad range of symptoms, with stroke-like episodes and seizures being the most common manifestations. The primary differential diagnoses include vascular and infectious diseases. The influence of immunomodulatory medications on the pathophysiology of RM remains unclear. There are no consensus guidelines on therapeutic regimen. METHODS: We present four patients with prior history of RA that developed different neurological syndromes in correlation to radiological leptomeningitis. Clinical presentations, comorbid conditions, supplementary diagnostic assessments, treatments, and prognosis are provided. A literature review of recent immunosuppressive management in RM patients was performed. RESULTS: Three patients presented to hospital with recurrent focal seizures. Only two suffered meningism, reporting headache and fever. Magnetic resonance imaging (MRI) showed different grades of leptomeningitis across all cases. Notably, three cases demonstrated bilateral involvement extending to the pachymeninges. Two patients exhibited pronounced CSF mononuclear inflammation while extended microbiological evaluations yielded negative results. Two patients required biopsy for confirmation. The initiation of immunosuppressive therapy marked a turning point for three patients who previously exhibited progressive deterioration. Mortality was absent in all cases. CONCLUSIONS: Our experience remarks the elusive nature of RM. Rigorous exclusionary diagnostics are imperative to differentiate RM from mimicking conditions. Clinical manifestations oscillate between transient episodes and progressive neurological impairments, punctuated by frequent epileptic seizures. In scenarios where clinical worsening persists or where clinical and radiological evaluations are inconclusive, aggressive immunosuppressive therapy is recommended.

Casiopeina III-ia: A Copper Compound with Potential Use for Treatment of Infections Caused by Leishmania mexicana.

INTRODUCTION: Casiopeina III-ia (CasIII-ia) is a mixed chelate copper (II) compound capable of interacting with free radicals generated in the respiratory chain through redox reactions, producing toxic reactive oxygen species (ROS) that compromise the viability of cancer cells, bacteria and protozoa. Due to its remarkable effect on protozoa, this study evaluated the effect of CasIII-ia on Leishmania mexicana amastigotes and its potential use as a treatment for cutaneous leishmaniasis in the murine model. METHODS: We analyzed the leishmanicidal effect of CasIII-ia on L. mexicana amastigotes and on their survival in bone marrow-derived macrophages. Furthermore, we evaluated the production of ROS in treated parasites and the efficacy of CasIII-ia in the treatment of mice infected with L. mexicana. RESULTS: Our results show that CasIII-ia reduces parasite viability in a dose-dependent manner that correlates with increased ROS production. A decrease in the size of footpad lesions and in parasite loads was observed in infected mice treated with the intraperitoneal administration of CasIII-ia. CONCLUSIONS: We propose CasIII-ia as a potential drug for the treatment of cutaneous leishmaniasis.

Improved biosensing of Legionella by integrating filtration and immunomagnetic separation of the bacteria retained in filters.

A novel approach is presented that combines filtration and the direct immunomagnetic separation of the retained bacteria Legionella in filters, for further electrochemical immunosensing. This strategy allows for the separation and preconcentration of the water-borne pathogen from high-volume samples, up to 1000 mL. The limit of detection of the electrochemical immunosensor resulted in 100 CFU mL-1 and improved up to 0.1 CFU mL-1 when the preconcentration strategy was applied in 1 L of sample (103-fold improvement). Remarkably, the immunosensor achieves the limit of detection in less than 2.5 h and simplified the analytical procedure. This represents the lowest concentration reported to date for electrochemical immunosensing of Legionella cells without the need for pre-enrichment or DNA amplification. Furthermore, the study successfully demonstrates the extraction of bacteria retained on different filtering materials using immunomagnetic separation, highlighting the high efficiency of the magnetic particles to pull out the bacteria directly from solid materials. This promising feature expands the applicability of the method beyond water systems for detecting bacteria retained in air filters of air conditioning units by directly performing the immunomagnetic separation in the filters.

Sedoanalgesia With Ketamine in the Emergency Department: Factors Associated With Unsatisfactory Effectiveness.

OBJECTIVE: Ketamine is a safe and widely used sedative and analgesic in children. The purpose of this study is to evaluate the response to sedoanalgesia for painful procedures in the pediatric emergency department. METHODS: A retrospective study was conducted in children younger than 16 years who underwent painful procedures with intravenous/intranasal ketamine between January 2016 and December 2022. We collected demographic variables, effectiveness, route of administration, indication, dose, sedation strategy, duration of procedure, and associated adverse effects. RESULTS: A total of 671 ketamine sedation procedures (411 males/260 females) were included, with a mean age of 7.2 years. Closed reduction was the most common painful procedure (53.8%), followed by burn healing (24.6%). Ketamine was administered intravenously in 93.4% of procedures and intranasally in 6.6%. The result of sedoanalgesia was satisfactory in 84.9% and unsatisfactory in 15.1%. The percentage of cases with unsatisfactory analgesia was higher with intranasal administration (36.4%; P < 0.001). In the intravenous group, the percentage of cases with unsatisfactory effectiveness (28.7%) was higher for patients younger than 2 years of age ( P < 0.001). Arthrocentesis procedures were associated with the highest percentage of unsatisfactory sedoanalgesia failures among patients receiving intravenous ketamine (39.3%; P < 0.001). Intranasal ketamine patients who received a dose between 3.6 and 4 mg/kg had a significantly higher percentage of unsatisfactory sedoanalgesia (66.7%; P = 0.048). Patients receiving intravenous ketamine had significantly higher rates of unsatisfactory sedoanalgesia when the initial dose interval was 1.6 to 2 mg/kg (11.8%; P = 0.002) and when the final total dose was also 1.6 to 2 mg/kg (17.6%; P = 0.002). CONCLUSIONS: This study concludes that intravenous/intranasal ketamine can provide safe and successful analgesia in pediatric patients in the ED. At intravenous doses of 1-1.5 mg/kg, good effectiveness was achieved in almost 90% of cases. Arthrocentesis had the highest percentage of unsatisfactory results. Repeat dosing should be considered for procedures longer than 20 minutes.

Establishing Normal Serum Values of Neurofilament Light Chains and Glial Fibrillary Acidic Protein Considering the Effects of Age and Other Demographic Factors in Healthy Adults.

Multiple studies have shown the importance of blood-based biomarkers indicating axonal damage (serum neurofilament light chains [sNfL]) or astroglia activation (serum glial fibrillary acidic protein [sGFAP]) for monitoring different neurological diseases. However, normal values of these variables remain to be clearly defined, partly due to the influence of different demographic factors. We investigated demographic differences in a cohort of healthy volunteers. A cross-sectional study was conducted including 116 healthy controls with ages between 18 and 69 years (67.5% females; n = 79). sNfL and sGFAP concentrations were measured using single-molecule arrays. Age and body mass index affected sNfL values, and age was found to be the most important factor. The normal values changed with age, and we established normal values for individuals younger than 45 years as <10 pg/mL and for controls older than 45 years as <15 pg/mL. We established normal values at <10 pg/mL for individuals younger than 45 years and <15 pg/mL for older individuals. Alternatively, a Z-score of 1.5 was relevant for all controls. sGFAP was only affected by age. Differences in normal values were evident by 55 years. The highest normality limit for sGFAP was 140 pg/mL for controls under 55 years and 280 for older controls. We defined normal levels for sNfL and sGFAP and their corresponding age-associated changes. These data may contribute to the application of such variables in clinical practice.

Toxicological Evaluation of Kaempferol and Linearolactone as Treatments for Amoebic Liver Abscess Development in Mesocricetus auratus.

Several studies with kaempferol (KP) and linearolactone (LL) have demonstrated their antiparasitic activity. However, the toxicity of these treatments is unknown. Therefore, this study aimed to evaluate the possible toxicological effects of intraperitoneal (i.p.) administration of KP or LL on the amoebic liver abscess model (ALA) in Mesocricetus auratus. An ALA was induced in male hamsters with 1.5 × 105Entamoeba histolytica (E. histolytica) trophozoites inoculated in the left hepatic lobe. The lesion evolved for 4 days, and then KP (5 mg/kg body weight/day) or LL (10 mg/kg body weight/day) was administered for 4 consecutive days. Then, magnetic resonance imaging (MRI), paraclinical analyses, and necropsy for histopathological evaluation were performed. There was similar ALA inhibition by KP (19.42%), LL (28.16%), and metronidazole, the antiamoebic control (20.87%) (p ≤ 0.05, analysis of variance [ANOVA]). There were hepatic and renal biochemical alterations in all treatment groups, mainly for KP (aspartate aminotransferase: 347.5 ± 37.5 U/L; blood urea nitrogen: 19.4 ± 1.9 g/dL; p ≤ 0.05, ANOVA). Lesions found in the organs were directly linked to the pathology. In conclusion, KP and LL decreased ALA development and exerted fewer toxicological effects compared with metronidazole. Therefore, both compounds exhibit therapeutic potential as an alternative treatment of amoebiasis caused by E. histolytica. However, additional clinical studies in different contexts are required to reaffirm this assertion.

In Vivo, In Vitro and In Silico Anticancer Activity of Ilama Leaves: An Edible and Medicinal Plant in Mexico.

Ilama leaves are an important source of secondary metabolites with promising anticancer properties. Cancer is a disease that affects a great number of people worldwide. This work aimed to investigate the in vivo, in vitro and in silico anticancer properties of three acyclic terpenoids (geranylgeraniol, phytol and farnesyl acetate) isolated from petroleum ether extract of ilama leaves. Their cytotoxic activity against U-937 cells was assessed using flow cytometry to determine the type of cell death and production of reactive oxygen species (ROS). Also, a morphological analysis of the lymph nodes and a molecular docking study using three proteins related with cancer as targets, namely, Bcl-2, Mcl-1 and VEGFR-2, were performed. The flow cytometry and histomorphological analysis revealed that geranylgeraniol, phytol and farnesyl acetate induced the death of U-937 cells by late apoptosis and necrosis. Geranylgeraniol and phytol induced a significant increase in ROS production. The molecular docking studies showed that geranylgeraniol had more affinity for Bcl-2 and VEGFR-2. In the case of farnesyl acetate, it showed the best affinity for Mcl-1. This study provides information that supports the anticancer potential of geranylgeraniol, phytol and farnesyl acetate as compounds for the treatment of cancer, particularly with the potential to treat non-Hodgkin's lymphoma.

The role of duty, gender and intergenerational care in grandmothers' parenting of grandchildren: a phenomenological qualitative study.

OBJECTIVES: The aim of this study was to describe grandmothers' experiences of taking care of their grandchildren in terms of their care-giving tasks, motivations and emotions. METHODS: A qualitative phenomenological study was conducted. Purposive sampling was used, based on the relevance of the research question. Seventeen participants were included, women ≥ 65 years old, grandmothers who care for their grandchildren at least 10 h per week and who attended the Nursing units of the Primary Care Health Centers (Madrid Public Health Service). Seventeen in-depth interviews were conducted. The interviews were audio-recorded, transcribed verbatim and thematic analysis was carried out from the perspective of hermeneutic phenomenology. For the analysis, the Excel program was used to organize and share the coding process. Also, we followed COREQ guidelines. RESULTS: Four main themes were identified: (a) Care out of obligation, where participants feel an obligation to help their children by caring for grandchildren, regardless of their number, and prefer to do so voluntarily; (b) Care out of responsibility, where grandmothers see their role as a responsibility that includes saving costs by caring for grandchildren and facilitating their children's work life balance; (c) Care as a social duty, reflecting a moral commitment inherited from their mothers to help future generations; and (d) Construction of care from a gender perspective, where grandmothers, as women, primarily assume the care and upbringing of grandchildren. DISCUSSION: Our results contribute to increase knowledge about childcare provided by grandmothers to their grandchildren. Grandmothers become fundamental pillars of families by helping their children balance family and work. Behind this care there is a strong sense of obligation, duty and generational responsibility. Grandmothers' help presents differences in the distribution of tasks and care by sex. Identifying factors that motivate grandmothers to care for their grandchildren helps nurses to perform higher quality comprehensive care.

Intensive care unit patients' experiences of receiving music therapy sessions during invasive procedures: A qualitative phenomenological study.

BACKGROUND: Excessive noise in intensive care units poses a significant challenge, impacting both patients and staff by elevating stress, disrupting recovery, and impeding effective communication among healthcare professionals. Despite the World Health Organization recommending noise levels below 35 dB, alarms in these units often surpass these limits, contributing to consistently high noise levels. OBJECTIVES: The aim of this study is to explore intensive care unit patients' experiences with music therapy sessions during invasive procedures. METHODS: This study was conducted using a qualitative hermeneutic phenomenological methodology grounded in Heideggerian philosophy. Interventions were conducted with a music therapist, and 14 in-depth interviews were collected. Reflexive inductive thematic analysis was performed. RESULTS/FINDINGS: From the thematic analysis extracted from the 14 personal interviews, three themes were described that represent the bulk of the experiences and emotions of the study participants following the completion of the music therapy sessions. The most noteworthy results are described in the following, organised according to each theme: (i) music therapy against noise, sounds, and light; (ii) music therapy in the face of invasive tests and techniques; and (iii) music therapy as a strategy and tool. CONCLUSIONS: Music therapy has significant potential to enhance the quality of life for patients in the intensive care unit. Music therapy can promote relaxation, reduce stress and anxiety, alleviate pain and discomfort, and improve emotional and physical wellbeing during patients' stay and invasive procedures.

Dose-dependent progression of multiple low-dose streptozotocin-induced diabetes in mice.

This study investigated the effects of different multiple low doses of streptozotocin (STZ), namely 35 and 55 mg/kg, on the onset and progression of diabetes in mice. Both doses are commonly used in research, and although both induced a loss of beta cell mass, they had distinct effects on whole glucose tolerance, beta cell function, and gene transcription. Mice treated with 55 mg/kg became rapidly glucose intolerant, whereas those treated with 35 mg/kg had a slower onset and remained glucose tolerant for up to a week before becoming equally glucose intolerant as the 55 mg/kg group. Beta cell mass loss was similar between the two groups, but the 35 mg/kg-treated mice had improved glucose-stimulated insulin secretion in gold-standard hyperglycemic clamp studies. Transcriptomic analysis revealed that the 55 mg/kg dose caused disruptions in nearly five times as many genes as the 35 mg/kg dose in isolated pancreatic islets. Pathways that were downregulated in both doses were more downregulated in the 55 mg/kg-treated mice, whereas pathways that were upregulated in both doses were more upregulated in the 35 mg/kg-treated mice. Moreover, we observed a differential downregulation in the 55 mg/kg-treated islets of beta cell characteristic pathways, such as exocytosis or hormone secretion. On the other hand, apoptosis was differentially upregulated in 35 mg/kg-treated islets, suggesting different transcriptional mechanisms in the onset of STZ-induced damage in the islets. This study demonstrates that the two STZ doses induce distinctly mechanistic progressions for the loss of functional beta cell mass.

Heterozygous midnolin knockout attenuates severity of nonalcoholic fatty liver disease in mice fed a Western-style diet high in fat, cholesterol, and fructose.

Although midnolin has been studied for over 20 years, its biological roles in vivo remain largely unknown, especially due to the lack of a functional animal model. Indeed, given our recent discovery that the knockdown of midnolin suppresses liver cancer cell tumorigenicity and that this antitumorigenic effect is associated with modulation of lipid metabolism, we hypothesized that knockout of midnolin in vivo could potentially protect from nonalcoholic fatty liver disease (NAFLD) which has become the most common cause of chronic liver disease in the Western world. Accordingly, in the present study, we have developed and now report on the first functional global midnolin knockout mouse model. Although the overwhelming majority of global homozygous midnolin knockout mice demonstrated embryonic lethality, heterozygous knockout mice were observed to be similar to wild-type mice in their viability and were used to determine the effect of reduced midnolin expression on NAFLD. We found that global heterozygous midnolin knockout attenuated the severity of NAFLD in mice fed a Western-style diet, high in fat, cholesterol, and fructose, and this attenuation in disease was associated with significantly reduced levels of large lipid droplets, hepatic free cholesterol, and serum LDL, with significantly differential gene expression involved in cholesterol/lipid metabolism. Collectively, our results support a role for midnolin in regulating cholesterol/lipid metabolism in the liver. Thus, midnolin may represent a novel therapeutic target for NAFLD. Finally, our observation that midnolin was essential for survival underscores the broad importance of this gene beyond its role in liver biology.NEW & NOTEWORTHY We have developed and now report on the first functional global midnolin knockout mouse model. We found that global heterozygous midnolin knockout attenuated the severity of nonalcoholic fatty liver disease (NAFLD) in mice fed a Western-style diet, high in fat, cholesterol, and fructose, and this attenuation in disease was associated with significantly reduced levels of large lipid droplets, hepatic free cholesterol, and serum LDL, with significantly differential gene expression involved in cholesterol/lipid metabolism.

Central and peripheral myeloid-derived suppressor cell-like cells are closely related to the clinical severity of multiple sclerosis.

Multiple sclerosis (MS) is a highly heterogeneous demyelinating disease of the central nervous system (CNS) that needs for reliable biomarkers to foresee disease severity. Recently, myeloid-derived suppressor cells (MDSCs) have emerged as an immune cell population with an important role in MS. The monocytic-MDSCs (M-MDSCs) share the phenotype with Ly-6Chi-cells in the MS animal model, experimental autoimmune encephalomyelitis (EAE), and have been retrospectively related to the severity of the clinical course in the EAE. However, no data are available about the presence of M-MDSCs in the CNS of MS patients or its relation with the future disease aggressiveness. In this work, we show for the first time cells exhibiting all the bona-fide phenotypical markers of M-MDSCs associated with MS lesions, whose abundance in these areas appears to be directly correlated with longer disease duration in primary progressive MS patients. Moreover, we show that blood immunosuppressive Ly-6Chi-cells are strongly related to the future severity of EAE disease course. We found that a higher abundance of Ly-6Chi-cells at the onset of the EAE clinical course is associated with a milder disease course and less tissue damage. In parallel, we determined that the abundance of M-MDSCs in blood samples from untreated MS patients at their first relapse is inversely correlated with the Expanded Disability Status Scale (EDSS) at baseline and after a 1-year follow-up. In summary, our data point to M-MDSC load as a factor to be considered for future studies focused on the prediction of disease severity in EAE and MS.

SARS-CoV-2 Virus in Cancer Patients: A New Unknown in an Unsolved Equation.

INTRODUCTION: Cancer patients are more susceptible to infections, and infection can be more severe than in patients without cancer diagnosis. We conducted this retrospective study in patients admitted for SARS-CoV-2 infection in order to find differences in inflammatory markers and mortality in cancer patients compared to others. METHODS: We reviewed the electronic records of patients admitted for SARS-CoV-2 infection confirmed by PCR from March to September 2020. Data on socio-demographics, comorbidities, inflammatory makers, and cancer-related features were analyzed. RESULTS: 2,772 patients were admitted for SARS-CoV-2, to the Hospital Universitario Ramón y Cajal in Madrid during this period. Of these, 2,527 (91%) had no history of neoplastic disease, 164 (5.9%) patients had a prior history of cancer but were not undergoing oncological treatment at the time of infection, and 81 (2.9%) were in active treatment. Mortality in patients without a history of cancer was 19.5%, 28.6% for patients with a prior history of cancer, and 34% in patients with active cancer treatment. Patients in active oncology treatment with the highest mortality rate were those diagnosed with lung cancer (OR 5.6 95% CI: 2.2-14.1). In the multivariate study, active oncological treatment (OR 2.259 95% CI: 1.35-3.77) and chemotherapy treatment (OR 3.624 95% CI: 1.17-11.17), were statistically significant factors for the risk of death for the whole group and for the group with active oncological treatment, respectively. CONCLUSION: Cancer patients on active systemic treatment have an increased risk of mortality after SARS-CoV-2 infection, especially with lung cancer or chemotherapy treatment.

Pooling sputum testing to diagnose tuberculosis using xpert MTB/RIF and xpert ultra: a cost-effectiveness analysis.

BACKGROUND: The World Health Organization (WHO) recommends the diagnosis of tuberculosis (TB) using molecular tests, such as Xpert MTB/RIF (MTB/RIF) or Xpert Ultra (Ultra). These tests are expensive and resource-consuming, and cost-effective approaches are needed for greater coverage. METHODS: We evaluated the cost-effectiveness of pooling sputum samples for TB testing by using a fixed amount of 1,000 MTB/RIF or Ultra cartridges. We used the number of people with TB detected as the indicator for cost-effectiveness. Cost-minimization analysis was conducted from the healthcare system perspective and included the costs to the healthcare system using pooled and individual testing. RESULTS: There was no significant difference in the overall performance of the pooled testing using MTB/RIF or Ultra (sensitivity, 93.9% vs. 97.6%, specificity 98% vs. 97%, p-value > 0.1 for both). The mean unit cost across all studies to test one person was 34.10 international dollars for the individual testing and 21.95 international dollars for the pooled testing, resulting in a savings of 12.15 international dollars per test performed (35.6% decrease). The mean unit cost per bacteriologically confirmed TB case was 249.64 international dollars for the individual testing and 162.44 international dollars for the pooled testing (34.9% decrease). Cost-minimization analysis indicates savings are directly associated with the proportion of samples that are positive. If the TB prevalence is ≥ 30%, pooled testing is not cost-effective. CONCLUSION: Pooled sputum testing can be a cost-effective strategy for diagnosis of TB, resulting in significant resource savings. This approach could increase testing capacity and affordability in resource-limited settings and support increased testing towards achievement of WHO End TB strategy.

A Controversial Old Topic Revisited: Should Diagnostic Hysteroscopy Be Routinely Performed Prior to the First IVF Cycle? A Systematic Review and Updated Meta-analysis.

OBJECTIVE: This systematic review and meta-analysis aimed to analyze the impact of performing diagnostic hysteroscopy before the first in vitro fertilization (IVF) cycle on the clinical pregnancy rate and live birth. DATA SOURCES: PubMed-MEDLINE, Embase, Web of Science, The Cochrane Library, Gynecology and Fertility Specialized Register of Controlled Trials, and Google Scholar were consulted from inception to June 2022 using combinations of the relevant Medical Subject Headings terms and keywords. The search included major clinical trial registries such as ClinicalTrials.gov and the European EudraCT registry without language restrictions. In addition, manual cross-reference searches were also performed. METHODS OF STUDY SELECTION: All randomized and controlled clinical trials, prospective and retrospective cohort studies, and case-control studies comparing the probability of pregnancy and live birth among patients who underwent diagnostic hysteroscopy with possible treatment of any abnormal findings before the IVF cycle and patients who underwent the IVF cycle directly have been considered for inclusion. Studies with insufficient information on the results of interest or without the necessary information to perform the pooled analysis, those without a control group or with end points considered different than those of interest, were excluded. The review protocol was registered in PROSPERO (CRD42022354764). TABULATION, INTEGRATION, AND RESULTS: A total of 12 studies were included in the quantitative synthesis, reporting the reproductive outcomes of 5056 patients undergoing ART treatment for the first time. Selected studies included 6 randomized controlled trials, 1 prospective cohort study, 3 retrospective cohort studies, and 2 case-control studies. The likelihood of clinical pregnancy of patients undergoing hysteroscopy before IVF was significantly higher than those without hysteroscopy (odds ratio [OR], 1.49; 95% confidence CI 1.16-1.91; I2 = 69%). (odds ratio [OR], 1.51; 95% confidence interval [CI], 1.22-1.88; I2 59%). Eight studies included live birth rate; no statistically significant differences were found between the 2 groups for this outcome (OR,1.24; 95% CI, 0.94-1.64; I2 = 62%). Subsequently, a sensitivity analysis was performed, including only randomized clinical trials. Clinical pregnancy OR of patients undergoing hysteroscopy before starting the IVF cycle remained significantly higher than the control group (OR,1.62, 95% CI, 1.15-2.29; I2 = 62%). Risk of bias assessment was performed using the Grading of Recommendations Assessment, Development, and Evaluation. CONCLUSION: The available scientific evidence suggests that performing routine hysteroscopy before the first IVF attempt improves the clinical pregnancy rate; however, the live birth rate is unaffected.

Tuberculosis incidence in foreign-born people residing in European countries in 2020.

BackgroundEuropean-specific policies for tuberculosis (TB) elimination require identification of key populations that benefit from TB screening.AimWe aimed to identify groups of foreign-born individuals residing in European countries that benefit most from targeted TB prevention screening.MethodsThe Tuberculosis Network European Trials group collected, by cross-sectional survey, numbers of foreign-born TB patients residing in European Union (EU) countries, Iceland, Norway, Switzerland and the United Kingdom (UK) in 2020 from the 10 highest ranked countries of origin in terms of TB cases in each country of residence. Tuberculosis incidence rates (IRs) in countries of residence were compared with countries of origin.ResultsData on 9,116 foreign-born TB patients in 30 countries of residence were collected. Main countries of origin were Eritrea, India, Pakistan, Morocco, Romania and Somalia. Tuberculosis IRs were highest in patients of Eritrean and Somali origin in Greece and Malta (both > 1,000/100,000) and lowest among Ukrainian patients in Poland (3.6/100,000). They were mainly lower in countries of residence than countries of origin. However, IRs among Eritreans and Somalis in Greece and Malta were five times higher than in Eritrea and Somalia. Similarly, IRs among Eritreans in Germany, the Netherlands and the UK were four times higher than in Eritrea.ConclusionsCountry of origin TB IR is an insufficient indicator when targeting foreign-born populations for active case finding or TB prevention policies in the countries covered here. Elimination strategies should be informed by regularly collected country-specific data to address rapidly changing epidemiology and associated risks.

Frailty as a Superior Predictor of Dysphagia and Surgically Placed Feeding Tube Requirement After Anterior Cervical Discectomy and Fusion Relative to Age.

Frailty is a measure of physiological reserve that has been demonstrated to be a discriminative predictor of worse outcomes across multiple surgical subspecialties. Anterior cervical discectomy and fusion (ACDF) is one of the most common neurosurgical procedures in the United States and has a high incidence of postoperative dysphagia. To determine the association between frailty and dysphagia after ACDF and compare the predictive value of frailty and age. 155,300 patients with cervical stenosis (CS) who received ACDF were selected from the 2016-2019 National Inpatient Sample (NIS) utilizing International Classification of Disease, tenth edition (ICD-10) codes. The 11-point modified frailty index (mFI-11) was used to stratify patients based on frailty: mFI-11 = 0 was robust, mFI-11 = 1 was prefrail, mFI-11 = 2 was frail, and mFI-11 = 3 + was characterized as severely frail. Demographics, complications, and outcomes were compared between frailty groups. A total of 155,300 patients undergoing ACDF for CS were identified, 33,475 (21.6%) of whom were frail. Dysphagia occurred in 11,065 (7.1%) of all patients, and its incidence was significantly higher for frail patients (OR 1.569, p < 0.001). Frailty was a risk factor for postoperative complications (OR 1.681, p < 0.001). Increasing frailty and undergoing multilevel ACDF were significant independent predictors of negative postoperative outcomes, including dysphagia, surgically placed feeding tube (SPFT), prolonged LOS, non-home discharge, inpatient death, and increased total charges (p < 0.001 for all). Increasing mFI-11 score has better prognostic value than patient age in predicting postoperative dysphagia and SPFT after ACDF.