Rapid spin changes around a magnetar fast radio burst.

Magnetars are neutron stars with extremely high magnetic fields (≳1014 gauss) that exhibit various X-ray phenomena such as sporadic subsecond bursts, long-term persistent flux enhancements and variable rotation-period derivative1,2. In 2020, a fast radio burst (FRB), akin to cosmological millisecond-duration radio bursts, was detected from the Galactic magnetar SGR 1935+2154 (refs. 3-5), confirming the long-suspected association between some FRBs and magnetars. However, the mechanism for FRB generation in magnetars remains unclear. Here we report the X-ray observation of two glitches in SGR 1935+2154 within a time interval of approximately nine hours, bracketing an FRB that occurred on 14 October 20226,7. Each glitch involved a significant increase in the magnetar's spin frequency, being among the largest abrupt changes in neutron-star rotation8-10 observed so far. Between the glitches, the magnetar exhibited a rapid spin-down phase, accompanied by an increase and subsequent decline in its persistent X-ray emission and burst rate. We postulate that a strong, ephemeral, magnetospheric wind11 provides the torque that rapidly slows the star's rotation. The trigger for the first glitch couples the star's crust to its magnetosphere, enhances the various X-ray signals and spawns the wind that alters magnetospheric conditions that might produce the FRB.

Increased plasma DR-70 (fibrinogen-fibrin degradation products) concentrations as a diagnostic biomarker in dogs with neoplasms.

BACKGROUND: Tumor biomarkers have used widely in clinical oncology in human medicine. Only a few studies have evaluated the clinical utility of tumor biomarkers for veterinary medicine. A test for fibrinogen and fibrin degradation products (DR-70) has been proposed as an ideal biomarker for tumors in humans. The clinical value of DR-70 for veterinary medicine however has yet to be determined. OBJECTIVES: Investigate the diagnostic value of DR-70 concentrations by comparing them between healthy dogs and dogs with tumors. ANIMALS: Two hundred sixty-three dogs with different types of tumors were included. Sixty healthy dogs also were recruited for comparison. METHODS: The DR-70 concentrations were measured in all recruited individuals by ELISA. Clinical conditions were categorized based on histopathology, cytology, ultrasound examination, radiology, clinical findings, and a combination of these tests. RESULTS: The median concentration of DR-70 was 2.130 ± 0.868 µg/mL in dogs with tumors, which was significantly higher than in healthy dogs (1.202 ± 0.610 µg/mL; P < .0001). With a cut-off of 1.514 µg/mL, the sensitivity and specificity of DR-70 were 84.03% and 78.33%, respectively. The area under curve was 0.883. The DR-70 concentration can be an effective tumor biomarker in veterinary medicine. CONCLUSIONS AND CLINICAL IMPORTANCE: Increased DR-70 concentrations were not affected by tumor type, sex, age, or body weight. However, in dogs with metastatic mast cell tumors and oral malignant melanoma, DR-70 concentrations were significantly increased. Additional studies, including more dogs with nonneoplastic diseases, are needed to further evaluate the usefulness of DR-70 as a tumor biomarker.

Association of Influenza Vaccination With Risk of Bell Palsy Among Older Adults in Taiwan.

Importance: Annual administration of the influenza vaccine (fluVc) is currently the most effective method of preventing the influenza virus in older adults. However, half of adults older than 65 years remain unvaccinated in Taiwan, possibly because of concern about adverse events, such as Bell palsy (BP). Currently, studies on the association between fluVc and risk of BP are inconsistent. Objective: To determine whether the incidence of BP increases following fluVc in older adults. Design, Setting, and Participants: A self-controlled case series study design was used. Days 1 through 7, days 8 through 14, days 15 through 30, and days 31 through 60 following fluVc were identified as risk intervals, and days 61 through 180 were considered the control interval. A total of 4367 vaccinated individuals aged 65 years or older who developed BP within 6 months following fluVc were enrolled. Population-based retrospective claims data were obtained between 2010 and 2017; data were analyzed from April 2022 through September 2022. Exposure: Government-funded seasonal fluVc. Main Outcomes and Measures: The outcome of interest was BP onset in risk intervals compared with control intervals. Three or more consecutive diagnoses of BP within 60 days following fluVc were used as the definition of a patient with BP. Poisson regression was used to analyze the incidence rate ratio (IRR) of risk intervals compared with control intervals. Results: In total, 13 261 521 patients who received the fluVc were extracted from the National Health Insurance Research Database in Taiwan from January 1, 2010, to December 31, 2017. Of those, 7 581 205 patients older than 65 years old met the inclusion criteria. The number of patients with BP diagnosed within 6 months following fluVc enrolled for risk analysis was 4367 (mean [SD] age, 74.19 [5.97] years; 2349 [53.79%] female patients). The incidence rate of BP among all observed fluVc older adults was 57.87 per 100 000 person-years. The IRRs for BP on days 1 through 7, days 8 through 14, and days 15 through 30 were 4.18 (95% CI, 3.82-4.59), 2.73 (95% CI, 2.45-3.05), and 1.67 (95% CI, 1.52-1.84), respectively. However, there was no increase during days 31 through 60 (IRR, 1.06; 95% CI, 0.97-1.16). The postvaccination risk of BP was consistent across all subgroups stratified by sex, age group, and baseline conditions. Conclusions and Relevance: The present self-controlled case series indicated that the risk of BP in individuals older than 65 years increased within the first month, especially within the first week, following fluVc. But overall, the adverse event rate of BP was low, and considering the morbidity and mortality of influenza infection, the benefits of fluVc still outweigh the risks.

Gene therapy with a synthetic adeno-associated viral vector improves audiovestibular phenotypes in Pjvk-mutant mice.

Recessive PJVK mutations that cause a deficiency of pejvakin, a protein expressed in both sensory hair cells and first-order neurons of the inner ear, are an important cause of hereditary hearing impairment. Patients with PJVK mutations garner limited benefits from cochlear implantation; thus, alternative biological therapies may be required to address this clinical difficulty. The synthetic adeno-associated viral vector Anc80L65, with its wide tropism and high transduction efficiency in various inner ear cells, may provide a solution. We delivered the PJVK transgene to the inner ear of Pjvk mutant mice using the synthetic Anc80L65 vector. We observed robust exogenous pejvakin expression in the hair cells and neurons of the cochlea and vestibular organs. Subsequent morphologic and audiologic studies demonstrated significant restoration of spiral ganglion neuron density and hair cells in the cochlea, along with partial recovery of sensorineural hearing impairment. In addition, we observed a recovery of vestibular ganglion neurons and balance function to WT levels. Our study demonstrates the utility of Anc80L65-mediated gene delivery in Pjvk mutant mice and provides insights into the potential of gene therapy for PJVK-related inner ear deficits.

Comparative Transcriptome Analysis of Organ-Specific Adaptive Responses to Hypoxia Provides Insights to Human Diseases.

The common carp is a hypoxia-tolerant fish, and the understanding of its ability to live in low-oxygen environments has been applied to human health issues such as cancer and neuron degeneration. Here, we investigated differential gene expression changes during hypoxia in five common carp organs including the brain, the gill, the head kidney, the liver, and the intestine. Based on RNA sequencing, gene expression changes under hypoxic conditions were detected in over 1800 genes in common carp. The analysis of these genes further revealed that all five organs had high expression-specific properties. According to the results of the GO and KEGG, the pathways involved in the adaptation to hypoxia provided information on responses specific to each organ in low oxygen, such as glucose metabolism and energy usage, cholesterol synthesis, cell cycle, circadian rhythm, and dopamine activation. DisGeNET analysis showed that some human diseases such as cancer, diabetes, epilepsy, metabolism diseases, and social ability disorders were related to hypoxia-regulated genes. Our results suggested that common carp undergo various gene regulations in different organs under hypoxic conditions, and integrative bioinformatics may provide some potential targets for advancing disease research.

Incidental Finding of Moderna COVID-19 Vaccination-Related Axillary Lymphadenopathy on 201Tl Myocardial Perfusion Imaging.

ABSTRACT: We presented here a 71-year-old man with a history of thyroid cancer post total thyroidectomy and 131I ablation and right renal cell carcinoma post right partial nephrectomy. He reported persistent chest tightness and pain after the first dose of the Moderna COVID-19 (mRNA-1273) vaccine. Thus, coronary heart disease was suspected, and the patient was referred for MPI (myocardial perfusion imaging). Focal 201Tl uptake in the left axillary region was found incidentally on MPI, and SPECT/CT revealed enlarged benign-looking lymph nodes. The diagnostic is in favor of reactive hyperplasia after the intramuscular injection of vaccine into left deltoid muscle.

Meis1, Hi1α, and GATA1 are integrated into a hierarchical regulatory network to mediate primitive erythropoiesis.

During development, erythroid cells are generated by two waves of hematopoiesis. In zebrafish, primitive erythropoiesis takes place in the intermediate cell mass region, and definitive erythropoiesis arises from the aorta-gonad mesonephros. TALE-homeoproteins Meis1 and Pbx1 function upstream of GATA1 to specify the erythroid lineage. Embryos lacking Meis1 or Pbx1 have weak gata1 expression and fail to produce primitive erythrocytes. Nevertheless, the underlying mechanism of how Meis1 and Pbx1 mediate gata1 transcription in erythrocytes remains unclear. Here we show that Hif1α acts downstream of Meis1 to mediate gata1 expression in zebrafish embryos. Inhibition of Meis1 expression resulted in suppression of hif1a expression and abrogated primitive erythropoiesis, while injection with in vitro-synthesized hif1α mRNA rescued gata1 transcription in Meis1 morphants and recovered their erythropoiesis. Ablation of Hif1α expression either by morpholino knockdown or Crispr-Cas9 knockout suppressed gata1 transcription and abrogated primitive erythropoiesis. Results of chromatin immunoprecipitation assays showed that Hif1α associates with hypoxia-response elements located in the 3'-flanking region of gata1 during development, suggesting that Hif1α regulates gata1 expression in vivo. Together, our results indicate that Meis1, Hif1α, and GATA1 indeed comprise a hierarchical regulatory network in which Hif1α acts downstream of Meis1 to activate gata1 transcription through direct interactions with its cis-acting elements in primitive erythrocytes.

Enhanced x-ray emission coinciding with giant radio pulses from the Crab Pulsar.

Giant radio pulses (GRPs) are sporadic bursts emitted by some pulsars that last a few microseconds and are hundreds to thousands of times brighter than regular pulses from these sources. The only GRP-associated emission outside of radio wavelengths is from the Crab Pulsar, where optical emission is enhanced by a few percentage points during GRPs. We observed the Crab Pulsar simultaneously at x-ray and radio wavelengths, finding enhancement of the x-ray emission by 3.8 ± 0.7% (a 5.4σ detection) coinciding with GRPs. This implies that the total emitted energy from GRPs is tens to hundreds of times higher than previously known. We discuss the implications for the pulsar emission mechanism and extragalactic fast radio bursts.

Enhanced Over-Representation Analysis for the Differential Regulation of Birc5a and HIF2α-Knockdown Approaches.

Hypoxia-inducible factors (HIFs) and survivin (Birc5) genes are often considered important cancer drug targets for molecularly targeted therapy, as both genes play important roles in the cellular differentiation and development of neuronal cells. Pathway enrichment analysis is predominantly applied when interpreting the correlated behaviors of activated gene clusters. Traditional enrichment analysis is evaluated via p-values only, regardless of gene expression fold-change levels, gene locations, and possible hidden interactions within a pathway. Here, we combined these factors to retrieve significant pathways, as compared with traditional approaches. We performed RNA-seq analyses on Birc5a and HIF2α knocked down in zebrafish during the embryogenesis stage. Regarding Birc5a, two additional biological pathways, sphingolipid metabolism and herpes simplex infection, were identified; whereas for HIF2α, four biological pathways were re-identified, including ribosome biogenesis in eukaryotes, proteasome, purine metabolism, and complement and coagulation cascades. Our proposed approaches identified additional significant pathways directly related to cell differentiation or cancer, also providing comprehensive mechanisms for designing further biological experiments.

Incidental Finding of Bilateral Thalamic Glioma on 99mTc TRODAT-1 SPECT/CT.

ABSTRACT: 99mTc-TRODAT-1 SPECT/CT has been used to evaluate parkinsonian disorders. We present an interesting case of a 63-year-old woman with progressive tremulousness over the left side of the body for 6 months. Bilateral thalamic glioma with reduced uptake was shown on 99mTc-TRODAT-1 SPECT/CT. Secondary parkinsonism was impressed in this case.

Prognostic Value of 18F-FDG PET/CT Volume-Based Metabolic Parameters in Patients with Node-Negative Stage II Esophageal Squamous Cell Carcinoma.

Esophageal squamous cell carcinoma (ESCC) is a major cancer prevalent in Asian males. Pretreatment tumor burden can be prognostic for ESCC. We studied the prognostic value of metabolic parameters of 2-deoxy-2-[18F] fluoro-D-glucose positron emission tomography/computed tomography (18F-FDG PET/CT) and the serum squamous cell carcinoma antigen (SCC-Ag) level in node-negative stage II ESCC patients. Eighteen males underwent staging evaluation were included. The volume-based metabolic parameters derived from 18F-FDG PET/CT, including metabolic tumor volume (MTV) and total lesion glycolysis (TLG), were obtained using the PET Volume Computer Assisted Reading application. The Spearman correlation coefficients were calculated to assess the relationship between metabolic parameters and pretreatment serum SCC-Ag levels. Based on the 5-year follow-up, patients were sub-divided into the demised and the stable groups. Potential prognostic value was assessed by independent t-test and the Mann-Whitney U test. The association of overall survival was assessed using univariate and multivariate Cox regression analyses. The demised group showed significant higher values in serum SCC-Ag, as well as in MTV and TLG, but not SUVmax and SUVmean. The SUVmax, MTV, TLG, and serum SCC-Ag showed significant association with overall survival. Our findings suggest potential usage of pretreatment volume-based metabolic parameters of 18F-FDG PET/CT and serum SCC-Ag as prognostic factors for node-negative stage II ESCC patients.

Detection of Recurrent Cervical Cancer and Prediction of Its Patient Survival with Serum Squamous-Cell Carcinoma-Antigen and 2-[18F] Fluoro-2-Deoxy-d-Glucose-Positron Emission Tomography/Computed Tomography.

AIM: To evaluate the usefulness of serum squamous-cell carcinoma antigen (SCC-Ag) and 2-[18F]fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography (FDG-PET/CT) for the detection of recurrent squamous-cell carcinoma (SqCC) of the uterine cervix, and its prediction of patient survival. METHODS: FDG-PET/CT was performed for patients with serum SCC-Ag levels elevated to ≥1.5 ng/mL (Group 1) and those with suspicious recurrences without any increase in serum SCC-Ag levels (Group 2). The results were analyzed on the basis of histological data, disease progression and/or clinical follow-up. Recurrence was defined as evidence of recurrent lesions within 6 months of FDG-PET/CT. The outcome was determined using medical records. RESULTS: In total, 88 consecutive patients with cervical SqCC cancer with suspected recurrence (62 in Group 1 and 26 in Group 2) were enrolled. Recurrences were observed in 55 patients (77.4% (48/62) in Group 1 vs. 26.9% (7/26) in Group 2, p < 0.001). The overall sensitivity, specificity and accuracy of serum SCC-Ag were 87.3%, 57.6% and 76.1%, respectively, and those of FDG-PET/CT were 98.2%, 90.9% and 95.5%, respectively; the corresponding values were 97.9%, 92.9% and 96.8% for Group 1 and 100%, 89.5% and 92.3% for Group 2. Surgical resection was performed for 16 patients. At the end of the study, 40.3% (25/62) of Group 1 patients and 88.5% (23/26) of Group 2 patients were alive (p < 0.001). The survival of patients who underwent surgical resection for recurrent tumors was higher than that of patients who did not undergo resection (62.5% (10/16) vs. 17.9% (7/39), p = 0.001). Metabolic tumor volume (MTV) and total lesion glycolysis (TLG) derived from FDG-PET/CT showed significantly different in-patient survival. CONCLUSIONS: Serum SCC-Ag could predict tumor recurrence and the survival of patients with SqCC cervical cancer. As such, the surgical resection of limited recurrent disease, as determined using FDG-PET/CT, might improve the survival of patients with cervical cancer. MTV and TLG may serve as a prognostic biomarker of survival in patients with recurrent cervical cancer.

Efficient in Utero Gene Transfer to the Mammalian Inner Ears by the Synthetic Adeno-Associated Viral Vector Anc80L65.

Sensorineural hearing loss is one of the most common sensory disorders worldwide. Recent advances in vector design have paved the way for investigations into the use of adeno-associated vectors (AAVs) for hearing disorder gene therapy. Numerous AAV serotypes have been discovered to be applicable to inner ears, constituting a key advance for gene therapy for sensorineural hearing loss, where transduction efficiency of AAV in inner ear cells is critical for success. One such viral vector, AAV2/Anc80L65, has been shown to yield high expression in the inner ears of mice treated as neonates or adults. Here, to evaluate the feasibility of prenatal gene therapy for deafness, we assessed the transduction efficiency of AAV2/Anc80L65-eGFP (enhanced green fluorescent protein) after microinjection into otocysts in utero. This embryonic delivery method achieved high transduction efficiency in both inner and outer hair cells of the cochlea. Additionally, the transduction efficiency was high in the hair cells of the vestibules and semicircular canals and in spiral ganglion neurons. Our results support the potential of Anc80L65 as a gene therapy vehicle for prenatal inner ear disorders.

Comparison of FDG-PET/CT for Cancer Detection in Populations With Different Risks of Underlying Malignancy.

Background/Aim: Whole-body positron-emission tomography/computed tomography with the glucose analog 2-[ 18 F]fluoro-2-deoxy-D-glucose (FDG-PET/CT) has been used to screen examinees for underlying malignancy in many countries. The aim of this study was to compare the potential value of FDG-PET/CT application in asymptomatic individuals with those with suspected malignancy. Patients and Methods: A total of 9,408 examinees underwent whole-body FDG-PET/CT at our hospital from July 2006 to August 2013. Three thousand and seven hundred asymptomatic individuals and 848 individuals with laboratory and clinical/radiologicaI suspicion of malignancy who had undergone FDG-PET/CT for cancer screening were recruited. The final confirmation of cancer and outcomes were based on a pathological report and continuous follow-up. Results: Forty-five out of 3,700 asymptomatic individuals (1.2%) had proven malignancy, and 42 of them (93.3%) were found by FDG-PET/CT. Two hundred and twelve out of 848 with suspected malignancy (25%) had proven malignancy, and 196 of them (92.5%) were detected by FDG-PET/CT. Most of these cancers in asymptomatic individuals were clinically at an early stage. The discovery rate in asymptomatic individuals and those with suspected malignancy was 1.1% and 23.1%, respectively. The overall survival of patients with cancer diagnosed with PET/CT was higher than those with suspected malignancy (78.6% vs. 48.5%, p<0.001). Patients with a resectable lesion, early-stage disease, and lower maximal standardized uptake value had significantly better survival than those without. Conclusion: FDG-PET/CT is useful in the early diagnosis of cancer and thus might improve the survival rates of these patients. Considering the costs and risk of radiation exposure, it would be better used as a priority in patients with laboratory and clinical/radiologic suspicion of malignancy.

Consumption of betel quid contributes to sensorineural hearing impairment through arecoline-induced oxidative stress.

Betel quid is one of the most widely used psychoactive substances, and is consumed by approximately 10% of the world's population. In addition to its carcinogenicity, betel quid has also been reported to affect many organs, including the brain, heart, lungs, gastrointestinal tract, and reproductive organs. As betel quid contains several neurotoxic ingredients, we hypothesize that it also possesses ototoxicity and may lead to sensorineural hearing impairment (SNHI). In this study, we investigated the contribution of betel quid consumption to SNHI in a large clinical cohort, and validated the pathogenetic mechanisms in ex vivo tissue explants. We enrolled a total of 2364 volunteers, and determined their audiologic results based on Z-scores converted from their original frequency-specific hearing thresholds. Using generalized linear regression, we identified a positive correlation between betel quid consumption and the Z-scores across different frequencies. Subsequently, we explored the toxicity of arecoline, the main neuroactive component of betel quid, on tissue explants from murine cochleae. Arecoline reduced cell activity in the explant cultures and induced apoptosis in the hair cells, probably through the effects of oxidative stress. These findings have expanded the potential hazards of betel quid to common neurological disorders, and provide insights into preventive strategies against SNHI caused by neurotoxic substances.

Crossing fitness canyons by a finite population.

We consider the Wright-Fisher model of the finite population evolution on a fitness landscape defined in the sequence space by a path of nearly neutral mutations. We study a specific structure of the fitness landscape: One of the intermediate mutations on the mutation path results in either a large fitness value (climbing up a fitness hill) or a low fitness value (crossing a fitness canyon), the rest of the mutations besides the last one are neutral, and the last sequence has much higher fitness than any intermediate sequence. We derive analytical formulas for the first arrival time of the mutant with two point mutations. For the first arrival problem for the further mutants in the case of canyon crossing, we analytically deduce how the mean first arrival time scales with the population size and fitness difference. The location of the canyon on the path of sequences has a crucial role. If the canyon is at the beginning of the path, then it significantly prolongs the first arrival time; otherwise it just slightly changes it. Furthermore, the fitness hill at the beginning of the path strongly prolongs the arrival time period; however, the hill located near the end of the path shortens it. We optimize the first arrival time by applying a nonzero selection to the intermediate sequences. We extend our results and provide a scaling for the valley crossing time via the depth of the canyon and population size in the case of a fitness canyon at the first position. Our approach is useful for understanding some complex evolution systems, e.g., the evolution of cancer.

Incidental Thyroid Nodule Noted on Intra-arterial Hepatic MAA Scan Before 90Y-SIRT.

We report a case of a 61-year-old man who had recurrent hepatocellular carcinoma admitted for series evaluation before Y selective internal radiotherapy (SIRT). Intra-arterial hepatic Tc macroaggregated albumin scan before Y-SIRT revealed a 2.7-cm incidental low-density thyroid nodule with hot uptake. TcO4 scan revealed corresponding hot uptake in the thyroid nodule with near background uptake of normal thyroid tissue, favored autonomous nodule. After Y-microsphere SIRT, bremstrallung imaging revealed no Y-microsphere deposition to thyroid.

The role of renoscintigraphy and surgery in the management of Page kidney: A case report.

RATIONALE: Page kidney is an uncommon condition that hypertension occurs secondary to microvascular ischemia and alternation of small-vessel hemodynamics due to external compression of renal parenchyma and activation of the renin-angiotensin-aldosterone system. There are no specific guidelines for the management of Page kidney in the literatures. PATIENT CONCERNS: A 17-year-old teenager who had Fontan procedure for tricuspid and pulmonary atresia in early childhood suffered from sudden onset of severe left flank pain during cardiac catheterization procedure. Left renal artery active bleeding with renal parenchyma compression in association with renin-mediated hypertension led to the diagnosis of Page kidney. DIAGNOSES: Page kidney was diagnosed in this case. INTERVENTIONS: Urgent embolization was performed to treat left renal artery active bleeding. Because of decreased renal function with elevation of serum creatinine, inadequate blood pressure control with antihypertensive medication, and poor renal blood flow of left kidney, open drainage of perirenal hematoma was done 5 days after catheterization procedure. OUTCOMES: After the operation, glomerular filtration rate improved immediately, and left flank pain and hypertension resolved at discharge. LESSONS: The choice of the therapies for Page kidney depended on the clinical presentation of each case. This case pointed out the significance of renoscintigraphy and surgery in the management of Page kidney.

Application of whole-body FDG-PET for cancer screening in a cohort of hospital employees.

Whole-body positron emission tomography/computed tomography with the glucose analog 2-[F]fluoro-2-deoxy-D-glucose (FDG-PET/CT) has been extensively used to screen for underlying malignancies in asymptomatic individuals. We were able to survey a cohort of hospital employees using FDG-PET/CT and to report the results herein.A total of 116 hospital employees older than 55 years old were offered whole-body FDG-PET in our hospital. Ninety-seven employees (83.6%) completed the assessment from February 2014 to August 2014 in our PET center. The final confirmation of cancer was based on pathologic examination and follow-up after more than 1 year.Among the 97 participants, 92 were asymptomatic and 5 presented with previously diagnosed cancers. Six of the 92 asymptomatic participants (6.6%) with significant nodular lesions were referred for histological or cytological evaluation of the possibility of malignancy, and 1 case was considered clinically important and required surgical resection. The cancer discovery rate was 3.3% (3/92) with positive predictive value of 50% (3/6). In the 5 participants with previously identified cancers, no recurrence or metastasis was detected.The offer of whole-body FDG-PET for cancer screening was welcomed with enthusiasm by most of the hospital employees. PET/CT combines the merits of PET and CT and can be administered to and provide benefits to a select group of hospital employees.

The rich phase structure of a mutator model.

We propose a modification of the Crow-Kimura and Eigen models of biological molecular evolution to include a mutator gene that causes both an increase in the mutation rate and a change in the fitness landscape. This mutator effect relates to a wide range of biomedical problems. There are three possible phases: mutator phase, mixed phase and non-selective phase. We calculate the phase structure, the mean fitness and the fraction of the mutator allele in the population, which can be applied to describe cancer development and RNA viruses. We find that depending on the genome length, either the normal or the mutator allele dominates in the mixed phase. We analytically solve the model for a general fitness function. We conclude that the random fitness landscape is an appropriate choice for describing the observed mutator phenomenon in the case of a small fraction of mutators. It is shown that the increase in the mutation rates in the regular and the mutator parts of the genome should be set independently; only some combinations of these increases can push the complex biomedical system to the non-selective phase, potentially related to the eradication of tumors.