Heterozygous mutations cause genetic instability in a yeast model of cancer evolution.

Genetic instability, a heritable increase in the rate of genetic mutation, accelerates evolutionary adaptation1 and is widespread in cancer2,3. In mammals, instability can arise from damage to both copies of genes involved in DNA metabolism and cell cycle regulation4 or from inactivation of one copy of a gene whose product is present in limiting amounts (haploinsufficiency5); however, it has proved difficult to determine the relative importance of these two mechanisms. In Escherichia coli6, the application of repeated, strong selection enriches for genetic instability. Here we have used this approach to evolve genetic instability in diploid cells of the budding yeast Saccharomyces cerevisiae, and have isolated clones with increased rates of point mutation, mitotic recombination, and chromosome loss. We identified candidate, heterozygous, instability-causing mutations; engineering these mutations, as heterozygotes, into the ancestral diploid strain caused genetic instability. Mutations that inactivated one copy of haploinsufficient genes were more common than those that dominantly altered the function of the mutated gene copy. The mutated genes were enriched for genes functioning in transport, protein quality control, and DNA metabolism, and have revealed new targets for genetic instability7-11, including essential genes. Although only a minority (10 out of 57 genes with orthologues or close homologues) of the targets we identified have homologous human genes that have been implicated in cancer2, the remainder are candidates to contribute to human genetic instability. To test this hypothesis, we inactivated six examples in a near-haploid human cell line; five of these mutations increased instability. We conclude that single genetic events cause genetic instability in diploid yeast cells, and propose that similar, heterozygous mutations in mammalian homologues initiate genetic instability in cancer.

Multimethod analysis of large- and low-tapered single file reciprocating instruments: Design, metallurgy, mechanical performance, and irrigation flow.

AIM: To compare eight large- and low-tapered heat-treated reciprocating instruments regarding their design, metallurgy, mechanical properties, and irrigation flow through an in silico model. METHODOLOGY: A total of 472 new 25-mm E-Flex Rex (25/.04 and 25/.06), Excalibur (25/.05), Procodile (25/.06), Reciproc Blue R25 (25/.08v), WaveOne Gold Primary (25/.07v), and Univy Sense (25/.04 and 25/.06) instruments were evaluated regarding their design (stereomicroscopy, scanning electron microscopy, and 3D surface scanning), metallurgy (energy-dispersive X-ray spectroscopy and differential scanning calorimetry), and mechanical performance (cyclic fatigue, torsional resistance, cutting ability, bending and buckling resistance). Computational fluid dynamics assessment was also conducted to determine the irrigation flow pattern, apical pressure, and wall shear stress in simulated canal preparations. Kruskal-Wallis and one-way anova post hoc Tukey tests were used for statistical comparisons (α = 5%). RESULTS: Instruments presented variations in blade numbers, helical angles, and tip designs, with all featuring non-active tips, symmetrical blades, and equiatomic nickel-titanium ratios. Cross-sectional designs exhibited an S-shaped geometry, except for WaveOne Gold. Univy 25/.04 and Reciproc Blue displayed the smallest and largest core diameters at D3. Univy 25/.04 and E-Flex Rec 25/.04 demonstrated the longest time to fracture (p < .05). Reciproc Blue and Univy 25/.04 exhibited the highest and lowest torque to fracture, respectively (p < .05). Univy 25/.04 and Reciproc Blue had the highest rotation angles, whilst E-Flex Rec 25/.06 showed the lowest angle (p < .05). The better cutting ability was observed with E-Flex Rec 25/.06, Procodile, Excalibur, and Reciproc Blue (p > .05). Reciproc R25 and E-Flex Rec showed the highest buckling resistance values (p < .05), with WaveOne Gold being the least flexible instrument. The impact of instruments' size and taper on wall shear stress and apical pressure did not follow a distinct pattern, although Univy 25/.04 and E-Flex Rec 25/.06 yielded the highest and lowest values for both parameters, respectively. CONCLUSIONS: Low-tapered reciprocating instruments exhibit increased flexibility, higher time to fracture, and greater angles of rotation, coupled with reduced maximum bending loads and buckling strength compared to large-tapered instruments. Nevertheless, low-tapered systems also exhibit lower maximum torque to fracture and inferior cutting ability, contributing to a narrower apical canal enlargement that may compromise the penetration of irrigants in that region.

20-year follow-up of rheumatic mitral stenosis patients after percutaneous mitral commissurotomy: invasive transmitral gradient differential as a predictor of events.

Percutaneous mitral valve commissurotomy (PMC) is a viable alternative to mitral valve (MV) surgery in the treatment of patients with rheumatic mitral stenosis (RMS). In this single-center retrospective study of consecutive patients with RMS submitted to PMC from 1991 to 2008, we analyzed clinical, echocardiographic, and hemodynamic data and events during follow-up (FUP) until December 2021. Major adverse cardiovascular events (MACE) were a combined endpoint of all-cause death, cardiovascular hospitalization, and MV re-intervention. A total of 124 patients were enrolled: 108 (87.1%) were female, with a mean age at PMC of 46 [standard deviation (SD) 11] years. PMC was successful in 91.1%, with a mean reduction in invasive transmitral pressure gradient (TMPG) of 8 (SD 7) mmHg at PMC time. During the mean FUP of 20 (SD 6) years, 51 (41.1%) patients had MV re-intervention (86.3% surgery and 13.7% redo-PMC), 37 (29.8%) were hospitalized, and 30 (24.2%) died. Approximately 75% of patients remained MACE-free after 10 years, and this percentage decreased to around 40% after 20 years; at this time mark, about 8 in 10 patients were alive. A reduction of <5 mmHg in TMPG at PMC time was associated with a 2.7-fold greater rate of MACE compared to a reduction of ≥5 mmHg, independent of MV regurgitation after PMC and moderate disease of other valves (adjusted hazard ratio 2,7; 95% confidence interval 1.395-5.298, p=0.003). In this cohort with favorable long-term results after PMC, a reduction of <5 mmHg in TMPG at PMC time was associated with MACE during FUP. More studies are needed to validate this independent predictor.

Sub-Saharan African information potential to unveil adaptations to infectious disease.

Sub-Saharan Africa is the most promising region of the world to conduct high-throughput studies to unveil adaptations to infectious diseases due to several reasons, namely, the longest evolving time-depth in the Homo sapiens phylogenetic tree (at least two-third older than any other worldwide region); the continuous burden of infectious diseases (still number one in health/life threat); and the coexistence of populations practising diverse subsistence modes (nomadic or seminomadic hunter-gatherers and agropastoralists, and sedentary agriculturalists, small urban and megacity groups). In this review, we will present the most up-to-date results that shed light on three main hypotheses related with this adaptation. One is the hypothesis of coevolution between host and pathogen, given enough time for the establishment of this highly dynamic relationship. The second hypothesis enunciates that the agricultural transition was responsible for the increase of the infectious disease burden, due to the huge expansion of the sedentary human population and the cohabitation with domesticates as main reservoirs of pathogens. The third hypothesis states that the boosting of our immune system against pathogens by past selection may have resulted in maladaptation of the developed hygienic societies, leading to an increase of allergic, inflammatory and autoimmune disorders. Further work will enlighten the biological mechanisms behind these main adaptations, which can be insightful for translation into diagnosis, prognosis and treatment interventions.

Venous thromboembolism-related genetic determinant F11 rs4253417 is a potential prognostic factor in ischaemic stroke.

Ischaemic stroke (IS) and venous thromboembolism (VTE) are two forms of thromboembolism that, although distinct, seem to share numerous risk factors. Concerning genetic risk factors, while many VTE genetic markers have been reported, inclusively by genome-wide association studies (GWAS), the identification and validation of genetic determinants underlying IS pathogenesis have been challenging. Considering that IS and VTE shared biological pathways and aetiological factors, the severity of IS might be also influenced by VTE-related genetic variants. Thus, the present study was designed to analyse the impact of six VTE GWAS-identified genetic variants on the clinical outcome of 363 acute IS patients. Results revealed that the single-nucleotide polymorphism (SNP) F11 rs4253417 was an independent predictor of the 5-year risk of death among patients with total anterior circulation infarct (TACI). Namely, the ones carrying the SNP C allele presented a fourfold increase in the 5-year risk of death compared to TT genotype carriers (CC/CT vs. TT; adjusted HR, 4.240; 95% CI, 1.260-14.270; P = 0.020). This SNP is known to be associated with coagulation factor XI (FXI) levels, thus with implications in haemostasis and inflammation. As such, F11 rs4253417 might be a promising prognostic biomarker among TACI patients to aid in clinical decision-making. However, additional investigation is required to confirm the study's results and dissect the underlying mechanisms.

Somatic CAG expansion in Huntington's disease is dependent on the MLH3 endonuclease domain, which can be excluded via splice redirection.

Somatic expansion of the CAG repeat tract that causes Huntington's disease (HD) is thought to contribute to the rate of disease pathogenesis. Therefore, factors influencing repeat expansion are potential therapeutic targets. Genes in the DNA mismatch repair pathway are critical drivers of somatic expansion in HD mouse models. Here, we have tested, using genetic and pharmacological approaches, the role of the endonuclease domain of the mismatch repair protein MLH3 in somatic CAG expansion in HD mice and patient cells. A point mutation in the MLH3 endonuclease domain completely eliminated CAG expansion in the brain and peripheral tissues of a HD knock-in mouse model (HttQ111). To test whether the MLH3 endonuclease could be manipulated pharmacologically, we delivered splice switching oligonucleotides in mice to redirect Mlh3 splicing to exclude the endonuclease domain. Splice redirection to an isoform lacking the endonuclease domain was associated with reduced CAG expansion. Finally, CAG expansion in HD patient-derived primary fibroblasts was also significantly reduced by redirecting MLH3 splicing to the endogenous endonuclease domain-lacking isoform. These data indicate the potential of targeting the MLH3 endonuclease domain to slow somatic CAG repeat expansion in HD, a therapeutic strategy that may be applicable across multiple repeat expansion disorders.

Care seek behavior for low back pain in southern Brazil during the COVID-19 pandemic: a panel data analysis.

BACKGROUND: During the COVID-19 pandemic, people with low back pain (LBP) might have avoided seeking care for their pain. We aimed to investigate how the COVID-19 pandemic has affected LBP care seeking behavior among adults. METHODS: Data from four assessments of the PAMPA cohort were analyzed. Participants who reported experiencing LBP during wave one both before and during social restrictions (n = 1,753 and n = 1,712, respectively), wave two (n = 2,009), and wave three (n = 2,482) were included. We asked participants about sociodemographic, behavioral, and health factors and outcomes related to LBP. Poisson regression analyses were conducted, and data are presented as prevalence ratios (PR) and respective 95% confidence interval (95%CI). RESULTS: Overall, care seeking behavior decreased by half in the first months of restrictions, from 51.5% to 25.2%. Although there was an increase in care seeking behavior observed in the other two assessments (nearly 10 and 16 months after restrictions), it was insufficient to reach pre-pandemic levels. In the first months of restrictions, a similar scenario was observed for specific care, such as general practitioner and exercise professional care, with proportions of pre-pandemic levels reached after 10 and 16 months. Women were more likely to seek care for LBP 10 and 16 months after restrictions (PR 1.30 95%CI 1.11; 1.52, PR 1.22 95%CI 1.06; 1.39, respectively). Also, those participants who worked, were physically active, and reported pain-related disability and high pain levels were more likely to seek care at all time points assessed. CONCLUSION: Overall, care-seeking behavior for LBP significantly decreased in the first months of restrictions and increased in the following months; however, this behavior remained lower than pre-pandemic levels.

Characterization of four heat-treated reciprocating instruments: Design, metallurgy, mechanical performance, and irrigation flow patterns.

AIM: To compare the design, metallurgy, and mechanical properties of four heat-treated reciprocating instruments coupled with the evaluation of the irrigation flow using an in silico model. METHODOLOGY: New EdgeOne Fire Primary, Easy-File Flex Regular 25, WaveOne Gold Primary and Reciproc Blue R25 instruments (n = 124) were initially evaluated regarding their design through stereomicroscopy, scanning electron microscopy and 3D surface scanning. In addition, energy-dispersive X-ray spectroscopy was utilized to determine their elemental composition, and differential scanning calorimetry tests to evaluate their phase transformation temperatures. Their mechanical performance was further assessed through torsional and bending tests. Using scans obtained from a real tooth and the instruments, a computational fluid dynamics assessment was conducted to determine the irrigation flow pattern, apical pressure, and wall shear stress in simulated canal preparation. Mood's median and One-way anova post hoc Tukey tests were used for statistical comparisons (α = 5%). RESULTS: Reciproc Blue exhibited a superior number of blades (n = 8), whereas EdgeOne Fire had the highest overall volume (4.38 mm3 ) and surface area (32.32 mm2 ). At the 3-mm axial level, EdgeOne Fire displayed the lowest core diameter (0.13 mm), while Reciproc Blue had the highest (0.16 mm). All blades were symmetrical, and the tips of the instruments were non-active but differed from each other. The most irregular surfaces were observed in EdgeOne Fire and Easy-File Flex. All instruments were manufactured from nickel-titanium alloys and exhibited distinct phase transformation temperatures. WaveOne Gold and Reciproc Blue demonstrated the highest maximum torque values (1.87 and 1.62 N cm, respectively), while the lowest was observed on EdgeOne Fire (1.21 N cm) (p < .05). The most flexible (p < .05) were EdgeOne Fire (angle of rotation: 602.6°; maximum bending load: 251.4 g.f) and Reciproc Blue (533.2° and 235.6 g.f). There were no significant differences observed in the irrigation flow among the four domains generated by the tested instruments. CONCLUSIONS: Despite observing variations in the design, phase transformation temperatures, and in the torsional and bending test outcomes among the four heat-treated reciprocating instruments, no significant differences were found in the irrigation flow pattern among the different groups in the simulated root canal preparations.

Accuracy of different digital acquisition methods in complete arch implant-supported prostheses: An in vitro study.

STATEMENT OF PROBLEM: Digital methods such as intraoral scanners for recording the location of implants supporting complete arch prostheses have limitations. Photogrammetry devices should be able to digitize implant positions accurately, but standardized comparisons between different digital acquisition methods are lacking. PURPOSE: The purpose of this in vitro study was to compare the repeatability of different digital acquisition methods for complete arch prostheses supported by 6 and 4 implants. MATERIAL AND METHODS: A master cast was created with 6 and 4 dental implants with multiunit abutments to obtain the master digital casts. The evaluated devices were the industrial high-resolution 12-megapixel scanner (reference) Atos Compact Scan 12M (GOM), the laboratory scanners D2000 (3Shape A/S) and S900 Arti (Zirkonzahn), the photogrammetry devices iCam (iMetric4D) and PIC (PIC Dental), and the intraoral scanners TRIOS 3 (3Shape A/S) and iTero Element 5D (Align Technology). The resulting files were imported to a computer-aided design software program (exocad GmbH) to obtain the implant replicas as standard tessellation language (STL) files. These files were imported into a software program (Geomagic Control X) and superimposed per group through the best-fit algorithm to determine repeatability, defined as the closeness of agreement between each group's scanned results as root mean square (RMS) values. The normality of distribution was tested by the Shapiro-Wilk normality test, and the Kruskal-Wallis test with adjustment with the Bonferroni correction method was used accordingly (α=.05). RESULTS: The repeatability means and 95% confidence intervals for the 4 implant scans were: 1.07 µm (0.86; 1.29) for GOM, 2.05 µm (1.89; 2.21) for D2000, 3.61 µm (3.23; 3.99) for S900, 7.01 µm (6.11; 7.91) for iCam, 5.18 µm (4.6; 5.76) for PIC, 20.52 µm (18.33; 22.72) for TRIOS3, and 20.5 µm (17.37; 23.63) for iTero. Statistically significant differences were found between devices, except for iCam versus PIC, GOM versus S900, iCam versus D2000, PIC versus D2000, and TRIOS3 versus iTero. The repeatability means and 95% confidence intervals for the 6 implant groups were: 1.36 µm (1.08; 1.65) for GOM, 3.17 µm (3.01; 3.33) for D2000, 2.15 µm (2.04; 2.25) for S900, 8.67 µm (8.06; 9.28) for iCam, 13.88 µm (12.62; 15.14) for PIC, 40.32 µm (36.29; 44.36) for TRIOS3, and 38.86 µm (34.01; 43.71) for iTero. Statistically significant differences were detected between devices, except for S900 versus GOM, PIC versus iCam, and iTero versus TRIOS 3. CONCLUSIONS: The results suggest that photogrammetry could be a suitable alternative for recording implant locations of complete arch prostheses supported by 4 or 6 implants, with better repeatability than intraoral scanners. Increasing the number of implants decreased the repeatability of every device tested except the laboratory scanners.

Incidence and clinical results of tendinous injuries in calcaneus and pilon fractures.

PURPOSE: The aims of this study were: (1) to define the incidence of tendinous injuries in calcaneus and pilon fractures with different fracture severity and (2) to determine the clinical impact of such injuries. STUDY DESIGN AND METHODS: CT-scans of 121 patients with calcaneus and pilon fractures were retrospectively analyzed over a 4-year period. The tendinous injuries were identified and correlated with the type of fracture (location and classification). Clinical analysis was performed using the American Orthopedic Foot and Ankle Society (AOFAS) and SF-36 (Short Form-36 Health Survey) scores. RESULTS: Tendinous injuries were observed in 36% of all CT-scans analyzed, with the most common injury being incarceration (n = 20) and dislocation (n = 24). Calcaneus fractures sanders type 3/4 were 9 times more prone to tendon injury (p < 0.001; OR 8.67; 95% CI 2.49-30.24). Pilon fractures Ruedi-Allgower type 2/3 were 8 times more prone to tendon injury (p = 0.005; OR 7.5; 95% CI 1.72-32.80). No significant differences (p > 0.05) were found in AOFAS and SF-36 scores between patients with/without tendon injuries for fractures with the same severity. CONCLUSION: The incidence of tendon injuries in calcaneus/pilon fractures is high and may be underreported. Calcaneus fractures are prone to peroneal tendon injury. In pilon fractures, it is important to look for tibialis posterior tendon injury, especially entrapment. The presence of tendinous injuries does not affect function and pain for the same type of calcaneus and pilon fractures at the long term. LEVEL OF EVIDENCE: Level 3 retrospective study.

Emergency coronary angiography in a 90-plus population: outcomes at 5-year follow-up.

Elderly people represent a vulnerable and increasing population presenting with acute coronary syndrome (ACS). Our goal was to evaluate a group of very old patients who underwent emergency coronary angiography (CA). We retrospectively analyzed a group of very old patients (≥90 years old) who underwent emergency CA from 2008 to 2020. Survival and major adverse cardiovascular events (MACE) (a composite of all-cause death, ischemic stroke, ACS, or hospitalization for acute heart failure) were compared with an aged-matched control population with ACS not submitted to emergency CA. A total of 34 patients were enrolled, 56% of whom were female, with a median age of 92 years old. Almost all patients had ST elevation-ACS. In CA, 65% had multivessel disease, and coronary intervention was performed in 71%. More than one-third evolved in Killip class III/IV, and 70% had left ventricular dysfunction. Regarding mortality, 38% of patients died in the index event versus 25% in the aged-matched control group (p=0.319). During 5 years of follow-up, there was no significant difference in mortality between the 2 groups (Log-rank=0.403) and more than 50% of patients died in 2 years. Comparing MACE occurrence, both groups were similar (Log-rank=0.662), with more than 80% having at least one event in 5 years. Very old patients submitted to emergency CA had a high rate of multivessel disease and left ventricular dysfunction, in-hospital and follow-up mortality, and MACE. Compared to an aged-matched control group not submitted to emergency CA, they showed no survival or MACE benefit during a 5-year follow-up.

Wernicke encephalopathy and beriberi disease presenting as STEMI-equivalent.

Thiamine deficiency is commonly associated with malnutrition, alcoholism and bariatric surgery. Thiamine deficiency can manifest in different ways, especially in developing countries: as peripheric neuropathy, as Wernicke encephalopathy or as beriberi disease. The authors present the case of a 72-year-old male, with a hiatal hernia that led to thiamine deficiency due to malnutrition. The initial clinical manifestation was an ST-elevation myocardial infarct equivalent, an ECG with a shark-fin pattern that evolved to a Wellens type B pattern. The patient evolved with severe altered mental status. A Wernicke encephalopathy diagnosis was confirmed by MRI; the patient was medicated with high-dose thiamine, with quick recovery, both neurologic and cardiac. The clinical history and response to treatment confirm the diagnosis of Wernicke encephalopathy and beriberi disease.

Long-term prognosis of out-of-hospital cardiac arrest due to idiopathic ventricular arrhythmias.

Life-threatening ventricular arrhythmias (VA) may occur in patients with unknown cardiac disease. A sizable part of them remains labeled as Idiopathic VA and limited data is available regarding their natural history. Our aim was to evaluate the long-term clinical outcomes of survivors of an idiopathic life-threatening VA. Patients who survived an idiopathic life-threatening VA referred to an ICD were included and followed for a median follow-up of 7 years. Clinical and device data were collected and a comparison between genders was made. A total of 29 patients, 41% female, mean age of 50 (19) years were studied; all were implanted with an ICD at index hospitalization. At follow-up, an etiological diagnosis was established in 38% of patients. Genetic testing improved the diagnosis and allowed the identification of a distinct clinical entity in 60% of patients (p=0.04, OR=7.0), especially in women. Regarding ICD data, 31% received appropriate therapies with a median time to first appropriate shock of 39 months (IQR 12-46 months). Men had a significantly higher prevalence of appropriated shocks (50% vs 8%, p=0.04), with a similar time to the first arrhythmic event between genders. Two of the patients died, both from non-arrhythmic causes. Etiologic diagnosis and recurrence prediction in patients with idiopathic VA is challenging, even with long-term follow-up and sophisticated diagnostic evaluation.  Genetic testing significantly improved the diagnostic yield, especially in women. Arrhythmia recurrence occurred in about one-third of patients and is significantly higher in men, underscoring the importance of ICD implantation.

The world upside down - after 20 years of follow-up of dextro-transposition of the great arteries.

Dextro-transposition of the great arteries (D-TGA) is a congenital heart disease (CHD) classically palliated with atrial switch (ATR-S) and nowadays corrected with arterial switch (ART-S). Our aim was to observe a group of D-TGA patients followed in an adult CHD outpatient clinic. We analyzed a group of D-TGA patients born between 1974 and 2001. Adverse events were defined as a composite of death, stroke, myocardial infarction or coronary revascularization, arrhythmia, and ventricular, baffle, or significative valvular dysfunction. A total of 79 patients were enrolled, 46% of whom were female, with a mean follow-up of 27±6 years after surgery. ATR-S was performed in 54% and ART-S in 46%; the median age at procedure was 13 months and 10 days, respectively. During follow-up, almost all ART-S remained in sinus rhythm versus 64% of ATR-S (p=0.002). The latter group had a higher incidence of arrhythmias (41% versus 3%, p<0.001), mostly atrial flutter or fibrillation; the median time to first arrhythmia was 23 years. Systemic ventricle systolic dysfunction (SVSD) was more frequent in ATR-S (41% versus 0%, p<0.001); the mean time to SVSD was 25 years. In ART-S, the most frequent complication was significant valvular regurgitation (14%). Regarding time-to-event analysis, 80% and 40% of ATR-S maintained adverse events-free after 20 and 30 years, respectively; the time-to-first adverse event was 23 years, and there was no difference compared to ART-S (Log-rank=0.596). ART-S tended to maintain more preserved biventricular function than ATR-S (Log-rank=0.055). After a long term free of adverse events, ATR-S patients experienced more arrhythmias and SVSD. ART-S complications were predominantly anastomosis-related; SVSD or arrhythmias were rare.

Acute myocardial infarction during late COVID-19 era: patient characteristics, presentation and outcomes.

COVID-19 pandemic has unquestionably influenced care of acute myocardial infarction (AMI). Still, its impact on patients (pts) characteristics, presentation, treatment, and outcomes remains not well established in late pandemic times. To address this issue, we performed a prospective study of type-1 AMI patients admitted in a tertiary care hospital. Pts were enrolled during 6-months in 2019 [n=122; pre-COVID-19 (PC) group] and in 2021 [n=196; late-COVID-19 (C) group]. Data was based on pts interview and review of medical records. Age and gender distribution, as well as ST/non-ST-elevation myocardial infarction (STEMI/NSTEMI) proportion and access to coronariography and revascularization were similar between groups. Group C patients presented more pre-existing established cardiovascular disease (CVD) (43% vs 30%; p=0.03); more frequent description of typical chest pain (94% vs 84%; p=0,002); higher levels of pain intensity, in a 0-10 scale (8±2 vs 7±2; p=0.02); higher frequencies of AMI complications (27% vs 15%; p=0.01) and worse Killip (K) class evolution (K≥2 in 22% C vs13% PC patients; p=0.05). In conclusion, late pandemic AMI patients presented worse in-hospital outcomes in our study, though pre-hospital and hospital care were comparable to pre-pandemic times. COVID patients had a higher burden of pre-existing established CVD and a more typical and intense symptom presentation. Therefore, it can be hypothesized that "sicker" patients continued to look for help when presenting AMI symptoms, while "less sick" patients and the ones with less typical and intense symptoms possibly avoided contact with health care services during late pandemic period.

Cardiovascular toxicity in breast cancer patients - contributors and role of cardioprotective drugs.

Breast cancer (BC) patients treated with anthracyclines and/or anti-HER2-targeted therapies (AHT) are highly associated with cardiovascular toxicity (CVT). Our objective was to evaluate the risk of CVT secondary to cancer treatment and the role of cardioprotective-drugs (CPD) in BC patients. We collected a retrospective cohort of females with BC treated with chemotherapy and/or AHT from 2017 to 2019. CVT was defined as LVEF<50% or decline ≥10% during follow-up. As CPD, we considered renin-angiotensin-aldosterone-system inhibitors and beta-blockers. A subgroup analysis of the AHT patients was also performed. A total of 203 women were enrolled. The majority had high or very-high CVT risk score and normal cardiac function at presentation. As for CPD, 35.5% were medicated pre-chemotherapy. All patients were submitted to chemotherapy; AHT were applied to 41.7%. During a 16 months follow-up, 8.5% developed CVT. There was a significant decrease of GLS and LVEF at 12-months (decrease of 1.1% and 2.2%, p<0.001). AHT and combined therapy were significantly associated with CVT. In the AHT sub-group analysis (n=85), 15.7% developed CVT. Patients previously medicated with CPD had a significative lower incidence of CVT (2.9% vs 25.0%, p=0.006). Patients already on CPD presented a higher LVEF at 6-months follow-up (62.5% vs 59.2%, p=0.017). Patients submitted to AHT and anthracycline therapy had higher risk of developing CVT. In the AHT sub-group, pre-treatment with CPD was significantly associated with a lower prevalence of CVT. These results highlight the importance of cardio-oncology evaluation and strengthen the value of primary prevention.

Is preoperative fat infiltration in lumbar spine muscles associated with worse clinical outcomes after lumbar interbody fusion?

PURPOSE: Lumbar musculature has a fundamental role in spine stability and spinal balance. Muscle atrophy and fat infiltration play an important role in pain pathophysiology. Accordingly, the preoperative condition of lumbar muscles may influence clinical outcomes after surgical treatment. In this context, the aim of this study was to evaluate the association between preoperative lumbar paravertebral muscle fat infiltration and clinical outcomes after lumbar interbody fusion. METHODS: A retrospective study of patients with lumbar pathology submitted to lumbar transforaminal (TLIF) or posterior interbody fusion (PLIF) was performed, with a minimum of two years of follow-up. Preoperative lumbar magnetic resonance imaging (MRI) images were classified for fat infiltration in lumbar multifidus muscle and correlated with clinical outcomes. RESULTS: Seventy-five patients were included: 24 submitted to PLIF and 51 to TLIF. Most patients underwent surgery for spondylolisthesis (67%). Higher degrees of fat infiltration were associated with more advanced age (54.8 vs. 49.1 years old, p = 0.04) and more leg pain after surgery (p = 0.04). No statistically significant differences in other clinical outcomes such as Oswestry Disability Index, visual analogue scale for back and leg pain, self-reported back pain relief, return to work and overall satisfaction were found between different groups of fat infiltration. The improvement in leg pain was associated with improvement in self-reported lumbar pain (p < 0.001). CONCLUSION: Age and preoperative degree of fat infiltration may be important to predict improvement in leg pain after lumbar interbody fusion. The absence of solid literature on this topic and universal assessment methodologies reinforce the need for further studies.

Empirical rescue treatment of Helicobacter pylori infection in third and subsequent lines: 8-year experience in 2144 patients from the European Registry on H. pylori management (Hp-EuReg).

OBJECTIVE: To evaluate the use, effectiveness and safety of Helicobacter pylori empirical rescue therapy in third and subsequent treatment lines in Europe. DESIGN: International, prospective, non-interventional registry of the clinical practice of European gastroenterologists. Data were collected and quality reviewed until October 2021 at Asociación Española de Gastroenterología-Research Electronic Data Capture. All cases with three or more empirical eradication attempts were assessed for effectiveness by modified intention-to-treat and per-protocol analysis. RESULTS: Overall, 2144 treatments were included: 1519, 439, 145 and 41 cases from third, fourth, fifth and sixth treatment lines, respectively. Sixty different therapies were used; the 15 most frequently prescribed encompassed >90% of cases. Overall effectiveness remained <90% in all therapies. Optimised treatments achieved a higher eradication rate than non-optimised (78% vs 67%, p<0.0001). From 2017 to 2021, only 44% of treatments other than 10-day single-capsule therapy used high proton-pump inhibitor doses and lasted ≥14 days. Quadruple therapy containing metronidazole, tetracycline and bismuth achieved optimal eradication rates only when prescribed as third-line treatment, either as 10-day single-capsule therapy (87%) or as 14-day traditional therapy with tetracycline hydrochloride (95%). Triple amoxicillin-levofloxacin therapy achieved 90% effectiveness in Eastern Europe only or when optimised. The overall incidence of adverse events was 31%. CONCLUSION: Empirical rescue treatment in third and subsequent lines achieved suboptimal effectiveness in most European regions. Only quadruple bismuth-metronidazole-tetracycline (10-day single-capsule or 14-day traditional scheme) and triple amoxicillin-levofloxacin therapies reached acceptable outcomes in some settings. Compliance with empirical therapy optimisation principles is still poor 5 years after clinical practice guidelines update. TRIAL REGISTRATION NUMBER: NCT02328131.

Promotion of somatic CAG repeat expansion by Fan1 knock-out in Huntington's disease knock-in mice is blocked by Mlh1 knock-out.

Recent genome-wide association studies of age-at-onset in Huntington's disease (HD) point to distinct modes of potential disease modification: altering the rate of somatic expansion of the HTT CAG repeat or altering the resulting CAG threshold length-triggered toxicity process. Here, we evaluated the mouse orthologs of two HD age-at-onset modifier genes, FAN1 and RRM2B, for an influence on somatic instability of the expanded CAG repeat in Htt CAG knock-in mice. Fan1 knock-out increased somatic expansion of Htt CAG repeats, in the juvenile- and the adult-onset HD ranges, whereas knock-out of Rrm2b did not greatly alter somatic Htt CAG repeat instability. Simultaneous knock-out of Mlh1, the ortholog of a third HD age-at-onset modifier gene (MLH1), which suppresses somatic expansion of the Htt knock-in CAG repeat, blocked the Fan1 knock-out-induced acceleration of somatic CAG expansion. This genetic interaction indicates that functional MLH1 is required for the CAG repeat destabilizing effect of FAN1 loss. Thus, in HD, it is uncertain whether the RRM2B modifier effect on timing of onset may be due to a DNA instability mechanism. In contrast, the FAN1 modifier effects reveal that functional FAN1 acts to suppress somatic CAG repeat expansion, likely in genetic interaction with other DNA instability modifiers whose combined effects can hasten or delay onset and other CAG repeat length-driven phenotypes.

Patterns of CAG repeat instability in the central nervous system and periphery in Huntington's disease and in spinocerebellar ataxia type 1.

The expanded HTT CAG repeat causing Huntington's disease (HD) exhibits somatic expansion proposed to drive the rate of disease onset by eliciting a pathological process that ultimately claims vulnerable cells. To gain insight into somatic expansion in humans, we performed comprehensive quantitative analyses of CAG expansion in ~50 central nervous system (CNS) and peripheral postmortem tissues from seven adult-onset and one juvenile-onset HD individual. We also assessed ATXN1 CAG repeat expansion in brain regions of an individual with a neurologically and pathologically distinct repeat expansion disorder, spinocerebellar ataxia type 1 (SCA1). Our findings reveal similar profiles of tissue instability in all HD individuals, which, notably, were also apparent in the SCA1 individual. CAG expansion was observed in all tissues, but to different degrees, with multiple cortical regions and neostriatum tending to have the greatest instability in the CNS, and liver in the periphery. These patterns indicate different propensities for CAG expansion contributed by disease locus-independent trans-factors and demonstrate that expansion per se is not sufficient to cause cell type or disease-specific pathology. Rather, pathology may reflect distinct toxic processes triggered by different repeat lengths across cell types and diseases. We also find that the HTT CAG length-dependent expansion propensity of an individual is reflected in all tissues and in cerebrospinal fluid. Our data indicate that peripheral cells may be a useful source to measure CAG expansion in biomarker assays for therapeutic efforts, prompting efforts to dissect underlying mechanisms of expansion that may differ between the brain and periphery.