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PubMed1995

Amrinone combined with dobutamine improves hemodynamics and oxygen delivery without down-regulation of cardiac beta-adrenergic receptor density in porcine endotoxemia.

Effects of amrinone (AMR), a phosphodiesterase inhibitor, alone and in combination with dobutamine (DOB), on hemodynamics and O2 delivery were studied during porcine endotoxemia. Pentobarbital-anesthetized pigs were randomly administered either Escherichia coli lipopolysaccharide (endotoxin) or equivolumetric .9% NaCl (control) as a continuous infusion for 4 h. From 2 to 4 h (T = 120-240 min) of endotoxin infusion, pigs were randomly administered one of the following treatments; AMR infusion (40 micrograms/kg/min) (AMRlow); DOB (10 micrograms/kg/min) (DOB); AMR infusion (40 micrograms/kg/min) + DOB (AMRlow+DOB); AMR bolus (.75 mg/kg) followed by AMR infusion (40 micrograms/kg/min) (AMRhigh); or AMR bolus (.75 mg/kg) followed by infusion (40 micrograms/kg/min) + DOB (AMRhigh+DOB). Myocardial samples were obtained at the end of the experiment and flash-frozen for beta-adrenergic receptor analysis. Endotoxin significantly (p < .05) decreased cardiac index, right ventricular ejection fraction, stroke volume index, maximum rate of rise of left ventricular pressure (dP/dtmax), mean arterial pressure, and O2 delivery, and increased pulmonary vascular resistance and mean pulmonary arterial pressure (p < .05). AMRlow+DOB significantly (p < .05) increased cardiac index, dP/dtmax, right ventricular ejection fraction, stroke volume index, O2 delivery and consumption, and decreased mean pulmonary arterial pressure, pulmonary vascular resistance, mean arterial pressure, and systemic vascular resistance. beta-Adrenergic receptor density (Bmax) and binding equilibrium dissociation constant (KD) for [3H]dihydroalprenolol were not affected by endotoxin or any treatment (p < .05). Endotoxin-induced hemodynamic deterioration and decreased O2 delivery was attenuated by AMRlow+DOB. Potential applications of this combination may exist in treatment of septic patients with inadequate myocardial performance and reduction in O2 delivery complicated by pulmonary hypertension.

Amrinone↗

PubMed2007

Successful rescue of refractory, severe antibody mediated rejection with splenectomy.

Antibody-mediated rejection (AMR) commonly occurs after transplantation of ABO-incompatible and sensitized renal transplant. Treatment regimens commonly include a combination of plasmapheresis (PL) and intravenous immunoglobulin (IVIG). However, some cases of AMR remain refractory to treatment. We report a case series of four patients with AMR refractory to standard therapy (ST) who resolved after splenectomy. Four living donor kidney transplant recipients were diagnosed with AMR. Two patients were ABO incompatible, one was cross-match positive and one had no obvious predisposing factors. After failure of therapy with corticosteroids, PL, IVIG, Thymoglobulin, and Rituximab (three patients) or Campath (one patient), AMR was treated with laparoscopic splenectomy. After an average of 11 days of ST, laparoscopic splenectomy was performed for rescue. The urinary output improved immediately in all patients, serum creatinine levels decreased within 48 hr, and ABO titers fell in the ABO-incompatible patient and the cross-match became negative in the two sensitized patients. Splenectomy may play a role in the treatment of AMR refractory to ST.

Adult↗

PubMed2001

Development of a STS marker assay for detecting loss of heterozygosity in rice hybrids.

The RAPD (random amplified polymorphic DNA) markers OPE15750 and OPE15300 were affected by loss of heterozygosity (LOH) in rice hybrids AMR x 'M202' and AMR x 'L202'. The markers were mapped to the same locus at or near the centromere of rice chromosome 2. The two RAPD products were cloned, sequenced, and found to have lengths of 734 bp and 297 bp, respectively. The 297-bp sequence shares a 98% homology with one end of the 734-bp sequence, accounting for the cross-hybridization previously observed between the two clones. Based on the DNA sequence of the 734-bp fragment, a pair of STS (sequence-tagged site) primers was designed and tested. Rice plants homozygous for either OPE15734 or OPE15297 all produced PCR fragments of the same length, 482 bp. However, the two PCR products were discernible by digestion with the restriction enzyme XbaI prior to gel electrophoresis. The STS product from plants homozygous for OPE15734 was cut into two fragments of 239 and 240 bp, which appeared as one single band in an agarose gel; whereas the STS product from plants homozygous for OPE15297 was not cut by XbaI and was characterized by a 482-bp band in the agarose gel. These STS primers were tested in rice hybrids and F2 progenies derived from the hybrids of AMR x 'M202' and AMR x 'L202'. Homozygosity for OPE15297 was confirmed for all F2 panicle rows derived from AMR x 'M202'. In contrast, F2 panicle rows of AMR x 'L202' exhibited two different segregation patterns (genotypes), i.e., either uniformly homozygous for the 240-bp marker (OPE15734/OPE15734) or segregating for the 482- and 240-bp markers (OPE15734/OPE15297). This STS-marker system provides a robust assay for detecting the occurrence of LOH in rice hybrid progenies.

Base Sequence↗

PubMed2006

Effect of temperature on maximum swimming speed and cost of transport in juvenile European sea bass (Dicentrarchus labrax).

This study is an attempt to gain an integrated understanding of the interactions between temperature, locomotion activity and metabolism in the European sea bass (Dicentrarchus labrax). To our knowledge this study is among the few that have investigated the influence of the seasonal changes in water temperature on swimming performance in fish. Using a Brett-type swim-tunnel respirometer the relationship between oxygen consumption and swimming speed was determined in fish acclimatised to 7, 11, 14, 18, 22, 26 and 30 degrees C. The corresponding maximum swimming speed (U(max)), optimal swimming speed (U(opt)), active (AMR) and standard (SMR) metabolic rates as well as aerobic metabolic scope (MS) were calculated. Using simple mathematical functions, these parameters were modelled as a function of water temperature and swimming speed. Both SMR and AMR were positively related to water temperature up to 24 degrees C. Above 24 degrees C SMR and AMR levelled off and MS tended to decrease. We found a tight relationship between AMR and U(max) and observed that raising the temperature increased AMR and increased swimming ability. However, although fish swam faster at high temperature, the net cost of transport (COT(net)) at a given speed was not influence by the elevation of the water temperature. Although U(opt) doubled between 7 degrees C and 30 degrees C (from 0.3 to 0.6 m s(-1)), metabolic rate at U(opt) represented a relatively constant fraction of the animal active metabolic rate (40-45%). A proposed model integrates the effects of water temperature on the interaction between metabolism and swimming performance. In particular the controlling effect of temperature on AMR is shown to be the key factor limiting maximal swimming speed of sea bass.

Analysis of Variance↗

PubMed2005

Deaths associated with anaesthesia in Togo, West Africa.

This study attempts to determine the anaesthetic death rate, the causes of deaths and the avoidable mortality rate (AMR) in consecutive cases. The number of anaesthetics given was 1464: 30 cases died within 24 h. The incidence of 24-h perioperative deaths per 100 anaesthetics was 2.57. In all, 50% of deaths were observed in obstetric surgery; 47% of deaths were associated with cardiovascular management, 30% with respiratory management; 93% of deaths were identified as avoidable. The AMR was 1.5% (anaesthetic AMR: 0.75%, administrative AMR: 0.68%, surgical AMR: 0.07%). Insufficient or no blood available is the only factor for administrative AMR.

Adolescent↗

PubMed2002

Strategies to contain the emergence of antimicrobial resistance: a systematic review of effectiveness and cost-effectiveness.

OBJECTIVES: To conduct a systematic review of the literature to describe and critically appraise studies reporting on the cost and/or effectiveness of interventions proposed to control the emergence of antimicrobial resistance (AMR). METHODS: The search for relevant studies encompassed consultation with world experts in AMR, and electronic bibliographic database search of: Medline (1960-2000); ISI (1981-2000); EMBASE (1988-2000); Grey Literature (1999-2000); Database of Reviews of Effectiveness (DARE) and the NHS Health Economic Evaluation Database (HEED) at York University's Centre for Reviews and Dissemination (CRD) (numerous years); OPAC (1975-2000); and the Cochrane Library Online (1990-2000). Only studies that concerned the effectiveness or cost-effectiveness of measures specifically designed to contain the emergence of AMR were reviewed. Standardised data extraction sheets, based on existing checklists for effectiveness and cost-effectiveness, were used to assess the validity of each study using the 'risk of bias criteria' suggested in the Cochrane Handbook. Only studies categorised as being at low or moderate risk of bias were reported fully. The reliability of the data review process was monitored by comparison of several, random, independent assessments by all authors. The mix of study methods (i.e. including studies based on non-randomised controlled trials) meant that formal meta-analysis was not possible, and thus a qualitative review was performed. RESULTS: In total, 43 studies were reviewed, with 21 classed as being at moderate or low risk of bias and therefore reported in the paper. These studies covered policies on: restricting the use of antimicrobials (five studies, suggesting that restriction policies can alter prescriber behaviour, although with limited evidence of subsequent effect on AMR); prescriber education, feedback and use of guidelines (six studies, with no clear conclusion); combination therapies (seven studies, showing the potential to lower drug-specific resistance, although for an indeterminate time period); vaccination (three studies showing cost/effectiveness). Most of these studies were: from the developed world, principally the USA; hospital-based, with few community level interventions; and concerned with effectiveness, not cost-effectiveness. CONCLUSIONS: Overall, there is an absence of good evidence concerning what is effective, and especially cost-effective, in reducing the emergence of AMR. However, in addition to more research concerning these forms of intervention, the paper highlights four specific areas for further investigation: validating intermediate or surrogate outcome measures to enable better use to be made of the literature on intermediate measures; development and evaluation of 'macro' strategies; research into specific aspects of AMR in developing countries; and empirical and methodological research concerning the economic evaluation of interventions.

Anti-Bacterial Agents↗

PubMed1998

[Mortality trends for acute rheumatic fever and chronic rheumatic heart disease in Venezuela, 1955-1994]

This study reports on deaths due to acute rheumatic fever (ARF) and chronic rheumatic heart disease (CRHD) in Venezuela from 1955 to 1994. Census publications and other official sources provide the population data. Yearly age -and sex- specific mortality rates per 100,000 inhabitants were calculated and adjusted by the direct method to the WHO's standard population. The RF-adjusted mortality rate (AMR) declined: total from 7.68 to 1.08 (-85.9%); male from 7.53 to 0.84 (-88.8%); and female from 7.83 to 1.33 (-83.0%). In all cases female RF-AMRs were higher than male. There was a reduction of 88.5% in the ratio of RF deaths to cardiovascular deaths (ICD-6330-334,400-447; ICD-7330-334,400-447; ICD-8 390-438; ICD-9 390-438). ARF-AMR declined (-93.5%) as did CRHD-AMR (-85.1%). Proportional death by ARF and CRHD in patients 45 years old and younger increased. Venezuela experienced a continuous decline in RF-AMR from 1955 to the l980s, followed by a period of stabilization lasting until l994. The reduction could be the consequence of improvement in socioeconomic status and of RF prevention with penicillin, a standard practice in the health care system. The 1980s and 1990s RF-AMR stabilization could be associated with economic setbacks in Venezuela and changes in the agent's virulence patterns.

Journal Article↗

PubMed2025

Duration of Hospitalization is Associated with the Gut Microbiome in Patients Undergoing Hematopoietic Stem Cell Transplantation: Early Results from a Randomized Trial of Home Versus Hospital Transplantation.

Home-based hematopoietic stem cell transplantation (HCT) is an innovative care model with growing interest, but its impact on the gut microbiome remains unexplored in a randomized setting. We present interim results from the first randomized controlled trials (RCT) evaluating the effect of HCT location-home versus hospital-on gut microbial diversity and antimicrobial resistance (AMR) gene carriage. We hypothesize that patients randomized to undergo home HCT would have higher gut taxonomic diversity and lower AMR gene abundance compared to those undergoing standard hospital HCT. We analyzed stool samples from the first 28 patients enrolled in ongoing Phase II RCTs comparing home (n = 16) and hospital (n = 12) HCT at Duke University using shotgun metagenomic sequencing to compare taxa and AMR gene composition between groups. We also performed a secondary analysis comparing patients who received transplants at outpatient infusion clinics versus inpatient standard HCT to evaluate the influence of hospitalization duration. In the primary RCT analysis, taxonomic and AMR gene α- and β-diversity were comparable between home and hospital groups, reflecting similar durations of hospitalization despite group allocation. In contrast, secondary analyses demonstrated that patients transplanted in outpatient infusion clinics who experienced significantly reduced hospitalization had higher gut taxonomic α-diversity and differential β-diversity, although AMR gene diversity remained unchanged. In summary, randomization by transplant location did not impact the gut microbiota to the same extent as the duration of hospitalization, although secondary analyses were heavily confounded. Even when taxonomic differences were observed, AMR genes were similar between groups. This RCT represents a novel investigation into how care setting influences the gut microbiome during HCT. Our findings suggest that hospital duration, rather than randomization allocation alone, is the primary driver of microbial disruption. These results underscore the potential for reducing hospital duration to mitigate microbiome injury, thereby informing future interventions to reduce infection risk and improve patient outcomes.

Microbiome↗

PubMed1989

Acoustic middle ear reflexes in laboratory animals using clinical equipment: technical considerations.

Acoustic middle ear muscle reflexes (AMR) were examined in nonanesthetized rabbits using clinical oto-impedance devices to determine the feasibility of utilizing clinically available instruments in studies of laboratory animals, particularly with regard to parameters such as probe tone frequency and intensity. The Karolinska Sjukhuset clinical impedance instrument and the Madsen Electronics ZO174 standard clinical impedance meter were used. The results of this study show that reliable AMRs and tympanograms can be obtained from rabbits with both clinical instruments. Probe tone frequencies in the range of 800-1,200 Hz were most effective for eliciting tympanograms and the AMR in rabbits. The probe tone level was also found to be an important factor, with the most reliable sound pressure level being around 70 dB SPL, and below that of the reflex threshold. Both clinical instruments recorded AMR threshold elevations in animals with 7th-nerve and cochlear lesions. AMR decay was observed at 8 and 12 kHz, but no decay was seen in normal-hearing animals up to 4 kHz, suggesting that this frequency may be suitable for detecting and measuring pathological decay in the rabbit. The overall results suggest that standard oto-impedance instruments with a probe tone frequency of 1,000 Hz may be used effectively in experimental studies of several aspects of the AMR in laboratory animals, such as rabbits.

Acoustic Impedance Tests↗

PubMed2006

Amurubicinol-induced eotaxin-3 expression in human NCI-H69 small cell lung carcinoma cells.

We previously demonstrated the doxorubicin-induced expression of urokinase-type plasminogen activator (uPA), interleukin-8 (IL-8), monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-alpha in human RC-K8 lymphoma cells and NCI-H69 small cell lung carcinoma cells in which reactive oxygen species might be involved. Amurubicin hydrochloride (AMR), a novel derivative drug of doxorubicin, was recently introduced to clinical practice for treatment of lung cancer in Japan. Therefore, we investigated the effects of AMR on the expression of uPA and chemokines in NCI-H69 cells. AMR and its active form, amurubicinol hydrochloride (AMROH), both induced the expression of uPA, IL-8 and MCP-1 in H69 cells in a dose-dependent manner. When the cultured supernatant obtained from AMR-treated H69 cells was subcutaneously injected into rabbits, migration of a significant number of eosinophils was observed around the injected site. Antigen levels of eotaxin-3, a major migration-factor of eosinophils, were increased in AMROH-treated cells in parallel with the mRNA levels. The induction was observed below the clinically achievable concentration of AMR or AMROH. Thus, the simultaneous induction of uPA, IL-8, MCP-1 and eotaxin-3 may play a role in the pharmacological action of AMR through induction of the interaction between proinflammatory cells and lung carcinoma cells.

Animals↗

PubMed2006

Enhancement of radiosensitivity by topoisomerase II inhibitor, amrubicin and amrubicinol, in human lung adenocarcinoma A549 cells and kinetics of apoptosis and necrosis induction.

The effects of amrubicin (AMR) and its active metabolite, amrubicinol (AMROH), on the sensitivity of human lung adenocarcinoma A549 cells to ionizing radiation were investigated in vitro. Further, the kinetics of apoptosis and necrosis induction were also analyzed. The cytocidal effects of X-ray irradiation on A549 cells resulted in a low level of radiosensitivity with a D0 value of 12 Gy. The slopes of the survival curves in the exponential phase were plotted on semilogarithmic paper for radiation combined with AMR (2.5 microg/ml) and AMROH (0.02 microg/ml) treatment, and were shown to be approximately parallel to treatment with irradiation alone. The initial shoulder-shape portion of the survival curve for radiation alone, indicating the repair of sublethal damage, was reduced as compared to that for sequential combined treatment with AMR or AMROH. Sequential treatments with AMR or AMROH prior to ionizing radiation resulted in an additive radio-enhancement effect that reduced not only survival, but also the shoulder width. Fractionated irradiation with 2 Gy per fraction of A549 cells was carried out in vitro similar to that commonly performed in clinical radiotherapy and the radio-resistance of the cells was shown to be inhibited by AMR and AMROH. Similar to AMR and AMROH, adriamycin and etoposide (VP-16) are DNA topoisomerase II inhibitors. The effects of these 4 agents on cells that received X-ray irradiation were compared and all of the agents exhibited comparable radio-enhancement effects. The induction of apoptosis was investigated at 48 and 72 h after administration of AMROH, radiation or combined treatment, and apoptosis was not significantly induced after any of the treatments. We also examined the induction of necrosis, and found that the incidence of necrosis following combined treatment was approximately 2 times higher than that with either of the single treatments.

Adenocarcinoma↗

PubMed1991

Enrollee health status under Medicare risk contracts: an analysis of mortality rates.

Previous studies comparing the health status of Medicare beneficiaries enrolled under HMO risk contracts to that of Medicare beneficiaries in fee-for-service (FFS) have generally focused on demonstration projects conducted before 1985. This study examines mortality rates in 1987 for approximately 1 million aged Medicare beneficiaries enrolled in 108 HMOs. We estimated adjusted mortality ratios (AMR) for each HMO and across all HMOs, by dividing the actual number of deaths among HMO enrollees by the "expected" number of deaths. The expected number of deaths was based on death rates among local FFS populations, adjusting for age, sex, Medicaid buy-in status, and institutional status. The AMR for all HMO enrollees pooled together was 0.80. For persons newly enrolled in 1987, the AMR was 0.69; in general, AMRs were higher for beneficiaries who had been enrolled for longer periods of time. Among individual HMOs, none exhibited an AMR substantially above 1.00. Regression analysis indicated lower AMRs for staff model HMOs than for either IPA or group models. Low mortality among Medicare HMO enrollees is consistent with favorable selection or with improvements in the health status of enrollees due to better access or quality of care in HMOs. In either case, health status differences between HMO enrollees and FFS beneficiaries have implications for the appropriateness of Medicare's Adjusted Average Per Capita Cost (AAPCC) payment formula for HMOs.

Aged↗

PubMed1995

On line echocardiography in evaluating left atrial changes in acute mitral regurgitation and in monitoring a catheter-mounted balloon for its correction.

The purpose of this study was to evaluate changes in the left atrial size in acute mitral regurgitation (AMR) and monitor its correction by a catheter-mounted balloon (B). In 16 dogs, pressure changes in the left atrium (LA) were related to LA size and regurgitant mitral flow after the production of AMR by severing the mitral cusps. TEE was used for evaluating LA area (ALA) and the mitral regurgitation flow area (AMRF). TEE was also used in monitoring the position of a catheter-mounted B inserted through the LV apex and positioned on the mitral ring to relieve AMR. The B was inflated during systole and deflated during diastole. The ALA increased by 4.89 +/- 1.21 cm2 (mean +/- 1 SD) (p < 0.001) after AMR, the AMRF increased by 3.01 +/- 0.85 cm2 (p < 0.001) and the mean atrial pressure (LAP) by 9.38 +/- 2.43 mmHg (p < 0.001). In all experiments the position of the B could be confirmed in the 2D image and in 4 the reduction of AMRF by the function of the B was documented by the colour flow Doppler. It is concluded that after AMR the size of the LA increases along with the increase in LA pressure and a phasically inflated balloon and its effect on AMR can be easily identified and monitored by TEE.

Animals↗

PubMed2026

National Antimicrobial Resistance Monitoring System: Three Decades of Advancing Public Health Through Integrated Surveillance of Antimicrobial Resistance.

Antimicrobial resistance (AMR) occurs when bacteria and other microorganisms adapt in ways that make medicines less effective, causing infections that are harder to treat and more likely to spread. According to the Centers for Disease Control and Prevention (CDC), AMR infections affect millions of Americans each year and contribute to thousands of deaths (CDC, 2019). After three decades of operation, the U.S. National Antimicrobial Resistance Monitoring System (NARMS) stands as a model of sustained, collaborative public health surveillance. What began in 1996 as an effort to track resistance in Salmonella and E. coli O157 has evolved into a One Health surveillance network monitoring AMR across the farm-to-fork continuum. Through a partnership among CDC, the Food and Drug Administration (FDA), the U.S. Department of Agriculture (USDA), state and local health departments, and universities, NARMS has become the backbone of foodborne AMR surveillance in the United States. The past decade has been particularly transformative. NARMS explored new sampling to include companion animals, minor livestock, aquaculture, surface water, and wildlife. Whole-genome sequencing (WGS) revolutionized the program's capabilities, enabling timely identification of emerging pathogens and revealing how resistance genes spread. Near real-time public dashboards make NARMS data accessible to researchers, clinicians, regulators, and policymakers. NARMS data shape decisions about new animal drug approvals, guide stewardship programs, and inform clinical treatment guidelines nationwide. As NARMS enters its fourth decade with a 2026-2030 strategic plan, the program will leverage artificial intelligence and metagenomics while expanding surveillance to fill remaining gaps ensuring this vital system continues to protect the food supply and both human and animal health from AMR.

Antimicrobial Resistance (AMR)↗

PubMed1991

Interaction between the blink reflex and the abnormal muscle response in patients with hemifacial spasm: results of intraoperative recordings.

Patients with hemifacial spasm (HFS) have an abnormal muscle response (AMR) that can be elicited by stimulating one branch of the facial nerve and recording electromyographically from muscles innervated by other branches of the facial nerve. In addition, the R1 component of the blink reflex can be elicited from the affected side in patients with HFS who are undergoing microvascular decompression (MVD) operations under inhalation anesthesia. A synkinetic component of the blink reflex response that corresponds to the R1 component can be recorded from the mentalis muscle. In the present study we show that the blink reflex elicited by electrical stimulation of the supraorbital nerve can suppress the AMR elicited by electrical stimulation of the temporal branch of the facial nerve in patients with HFS when the interval between stimulation of the supraorbital nerve and stimulation of the temporal branch of the facial nerve (interstimulus interval, ISI) is such that the blink reflex response would appear later than the AMR if they had been elicited independently. Within a short range of ISIs the two responses suppress each other partially or totally. We find evidence that the suppression of the AMR is the result of an interaction in the facial motonucleus. We believe that the results of the present study support the hypothesis that the facial motonucleus is hyperactive in patients with HFS, and we suggest that the AMR is a result of backfiring from the facial motonucleus and that it may thus be an exaggerated F-response.

Blinking↗

PubMed2026

A One Health approach to Antimicrobial Resistance: Concepts, challenges, and advances in omics.

Antimicrobial resistance (AMR) is a global threat driven by the interplay between microbial evolution and human activity. Antimicrobial use in human and veterinary medicine, as well as in agriculture, accelerates the selection and dissemination of resistant bacteria and genes across interconnected human, animal, and environmental reservoirs. These dynamic exchanges render single-sector interventions ineffective. A One Health approach integrating human, animal, and environmental health is therefore essential to understand and mitigate the emergence and spread of AMR. This chapter focuses on bacterial antimicrobial resistance, addressing key concepts, major challenges, and emerging technologies within a One Health framework. Advances in next-generation sequencing and omics technologies have transformed our capacity to resolve AMR at unprecedented scale and resolution. These tools enable the tracking of resistance genes and high-risk clones across ecosystems, uncover transmission pathways, and identify key drivers of dissemination. Such insights support real-time epidemiological surveillance, outbreak detection, and targeted interventions. However, translating these advances into routine practice remains a major challenge, requiring harmonized methodologies, data integration, and cross-sector coordination. Addressing AMR demands sustained collaboration across disciplines and stakeholders, including clinicians, veterinarians, farmers, researchers, policymakers, industry, and the public. And framing AMR as a shared ecological and societal responsibility underscores the urgency of coordinated global action. We call for the urgent integration of One Health principles into surveillance, policy, and innovation to preserve antimicrobial effectiveness and safeguard future health.

Humans↗

PubMed2026

Genome-Wide and Rare Variant Association Studies of Amblyopia in Admixed American and African Ancestry Groups.

OBJECTIVE: To identify genetic variants associated with amblyopia in African (AFR) and Admixed American (AMR) ancestry groups, expanding on previous studies conducted in European ancestry. DESIGN: Retrospective ancestry-stratified genome-wide association study (GWAS) and gene-level rare variant association study (RVAS). PARTICIPANTS: Participants in the All of Us Research Program from AFR and AMR ancestry groups who had whole-genome sequencing available. Cases and controls were distinguished based on the presence of International Classification of Diseases 9/10/SNOMED diagnosis codes for amblyopia in electronic health records. This yielded ancestry-stratified subsets of 269 cases and 71 585 controls of AMR ancestry and 366 cases and 79 460 controls of AFR ancestry. METHODS: Stratified logistic regression models were adjusted for age, biological sex, and the top 10 principal components of genomic ancestry. GWAS was limited to common variants (minor allele frequency ≥1%), and RVAS was limited to rare variants with coding sequence-altering effects (minor allele frequency >1%, exonic only, excluding synonymous variants) aggregated at the gene level using the SKAT algorithm. Downstream analyses of the significant variants were performed using KEGG and GO pathway analysis and STRING database queries for protein-protein interactions and gene-gene interactions. MAIN OUTCOME MEASURES: Single-nucleotide polymorphisms were determined to have genome-wide significance if P < 5e-8 in the GWAS, and genes were determined to have significant association with amblyopia in the RVAS if P < 8.0 × 10-4. RESULTS: In the AMR GWAS, 245 unique single-nucleotide polymorphisms mapping to 97 distinct loci were identified, notably within neurodevelopmental and axonal guidance genes, including ROBO1, SEMA4B, PTPRD, NRXN1, and CAMK2D. The AFR GWAS identified 11 significant variants corresponding to 6 loci mapping primarily to long noncoding RNAs and pseudogenes. The AMR RVAS identified 15 genes, including axonal transport genes (KIF1B and KIF7) and growth factor signaling genes (EGF, ERBIN, and AKAP17A). The AFR RVAS identified a single gene, DLG2, which encodes the postsynaptic protein PSD-93, which promotes the closure of the sensitive period of neuroplasticity for vision in early childhood. CONCLUSIONS: Genetic risk architectures for amblyopia differ across ancestries but fundamentally converge on neurodevelopmental signaling, cortical synapse assembly, and sensitive period plasticity rather than ocular structural dynamics. FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any materials discussed in this article.

Amblyopia↗

PubMed2004

Firm measures are required to effect any significant decrease in the Japanese age-adjusted mortality rate from malignant neoplasms for the 21st century.

The Japanese have the longest lifespan worldwide, but this has been mostly due to reductions in the mortality rates from diseases other than malignant neoplasms. Changes in the age-adjusted mortality rates (AMRs) for malignant neoplasms in Japan from 1950 to 2000 are analyzed to elucidate the overall trend. The overall AMRs for all malignant neoplasms in men increased from 1950 to 2000, and decreased slowly in women during the same period. Changes since 1990 have been small in both genders, but show a hopeful trend towards a decrease in the total AMR since 1995. These trends reflect a balance between the decreased AMR from gastric (both male and female) and uterine cancers and increases in many other malignant neoplasms. However, in the period 1990-2000, the decrease in the AMR from gastric and uterine cancers has shown a trend towards leveling off. Therefore, improving the trend towards reductions in cancer incidence and mortality in the 21st century and beyond will depend on achieving changes in other cancer sites, which can only be realized through the twofold approach of preventative medicine and research as well as improvements in the levels of diagnosis and therapy. Much more emphasis must therefore be placed on primary prevention, in particular on anti-smoking campaigns, as well as stepping-up research into the etiology of, and novel treatments for other malignant neoplasms, especially colorectal and breast cancers.

Adolescent↗