Harmonizing Definitions and Perspectives in Extreme Liver Surgery: A Delphi Experts Consensus.

OBJECTIVE: To propose to our community a common language about extreme liver surgery. BACKGROUND: The lack of a clear definition of extreme liver surgery prevents convincing comparisons of results among centers. METHODS: We used a two-round Delphi methodology to quantify consensus among liver surgery experts. For inclusion in the final recommendations, we established a consensus when the positive responses (agree and totally agree) exceeded 70%. The study steering group summarized and reported the recommendations. In general, a five-point Likert scale with a neutral central value was used, and in a few cases multiple choices. Results are displayed as numbers and percentages. RESULTS: A two-round Delphi study was completed by 38 expert surgeons in complex hepatobiliary surgery. The surgeon´s median age was 58 years old (52-63) and the median years of experience was 25 years (20-31). For the proposed definitions of total vascular occlusion, hepatic flow occlusion and inferior vein occlusion, the degree of agreement was 97%, 81% and 84%, respectively. In situ approach (64%) was the preferred, followed by ante situ (22%) and ex situ (14%). Autologous or cadaveric graft for hepatic artery or hepatic vein repair were the most recommended (89%). The use of veno-venous bypass or portocaval shunt revealed the divergence depending on the case. Overall, 75% of the experts agreed with the proposed definition for extreme liver surgery. CONCLUSION: Obtaining a consensus on the definition of extreme liver surgery is essential to guarantee the correct management of patients with highly complex hepatobiliary oncological disease. The management of candidates for extreme liver surgery involves comprehensive care ranging from adequate patient selection to the appropriate surgical strategy.

Chronic Pain and Depression are Increased in Outpatient Adults with Somatic Symptoms from Secondary Health Care Services.

BACKGROUND: Somatic symptom disorder is described as excessive thoughts, feelings, or behaviors related to physical symptoms. The presence of somatic symptoms has been associated with depression, alexithymia, and the presence of chronic pain. Individuals with somatic symptom disorder are frequent attenders of primary health care services. AIM: We focused on investigating if the presence of psychological symptoms, alexithymia, or pain could be risk factors for somatic symptoms in a secondary health care service. METHODS: A cross-sectional and observational study. A total of 136 Mexican individuals who regularly attend a secondary health care service were recruited. The Visual Analogue Scale for Pain Assessment, the Symptom Checklist 90, and the Patient Health Questionnaire-15 were applied. RESULTS: Of all the participants, 45.2% showed somatic symptoms. We observed that these individuals more frequently presented with complaints of pain (χ2 = 18.4, p < .001), as well as more severe (t = -4.6, p < .001), and prolonged (χ2 = 4.9, p = 0.02). They also exhibited higher severity in all psychological dimensions assessed (p < .001). Finally, cardiovascular disease (t = 2.52, p = .01), pain intensity (t = 2.94, p = .005), and SCL-90 depression (t = 7.58, p < .001) were associated with somatic symptoms. CONCLUSIONS: In this study, we observed a high frequency of somatic symptoms in outpatients attending secondary health care services. They may be accompanied by comorbid cardiovascular conditions, higher pain intensity, and other mental health-related symptoms, which may aggravate the general clinical picture presented by the patient seeking health care. The presence and severity of somatization should be taken into consideration in the first and second level health care services for an early mental state evaluation and treatment of these outpatients to have a better clinical assessment and health outcome.

Cluster of Oseltamivir-Resistant and Hemagglutinin Antigenically Drifted Influenza A(H1N1)pdm09 Viruses, Texas, USA, January 2020.

Four cases of oseltamivir-resistant influenza A(H1N1)pdm09 virus infection were detected among inhabitants of a border detention center in Texas, USA. Hemagglutinin of these viruses belongs to 6B.1A5A-156K subclade, which may enable viral escape from preexisting immunity. Our finding highlights the necessity to monitor both drug resistance and antigenic drift of circulating viruses.

Relationship between Clinic and Ambulatory Blood-Pressure Measurements and Mortality.

BACKGROUND: Evidence for the influence of ambulatory blood pressure on prognosis derives mainly from population-based studies and a few relatively small clinical investigations. This study examined the associations of blood pressure measured in the clinic (clinic blood pressure) and 24-hour ambulatory blood pressure with all-cause and cardiovascular mortality in a large cohort of patients in primary care. METHODS: We analyzed data from a registry-based, multicenter, national cohort that included 63,910 adults recruited from 2004 through 2014 in Spain. Clinic and 24-hour ambulatory blood-pressure data were examined in the following categories: sustained hypertension (elevated clinic and elevated 24-hour ambulatory blood pressure), "white-coat" hypertension (elevated clinic and normal 24-hour ambulatory blood pressure), masked hypertension (normal clinic and elevated 24-hour ambulatory blood pressure), and normotension (normal clinic and normal 24-hour ambulatory blood pressure). Analyses were conducted with Cox regression models, adjusted for clinic and 24-hour ambulatory blood pressures and for confounders. RESULTS: During a median follow-up of 4.7 years, 3808 patients died from any cause, and 1295 of these patients died from cardiovascular causes. In a model that included both 24-hour and clinic measurements, 24-hour systolic pressure was more strongly associated with all-cause mortality (hazard ratio, 1.58 per 1-SD increase in pressure; 95% confidence interval [CI], 1.56 to 1.60, after adjustment for clinic blood pressure) than the clinic systolic pressure (hazard ratio, 1.02; 95% CI, 1.00 to 1.04, after adjustment for 24-hour blood pressure). Corresponding hazard ratios per 1-SD increase in pressure were 1.55 (95% CI, 1.53 to 1.57, after adjustment for clinic and daytime blood pressures) for nighttime ambulatory systolic pressure and 1.54 (95% CI, 1.52 to 1.56, after adjustment for clinic and nighttime blood pressures) for daytime ambulatory systolic pressure. These relationships were consistent across subgroups of age, sex, and status with respect to obesity, diabetes, cardiovascular disease, and antihypertensive treatment. Masked hypertension was more strongly associated with all-cause mortality (hazard ratio, 2.83; 95% CI, 2.12 to 3.79) than sustained hypertension (hazard ratio, 1.80; 95% CI, 1.41 to 2.31) or white-coat hypertension (hazard ratio, 1.79; 95% CI, 1.38 to 2.32). Results for cardiovascular mortality were similar to those for all-cause mortality. CONCLUSIONS: Ambulatory blood-pressure measurements were a stronger predictor of all-cause and cardiovascular mortality than clinic blood-pressure measurements. White-coat hypertension was not benign, and masked hypertension was associated with a greater risk of death than sustained hypertension. (Funded by the Spanish Society of Hypertension and others.).

Applicability of 3D-printed models in hepatobiliary surgey: results from "LIV3DPRINT" multicenter study.

BACKGROUND: Hepatobiliary resections are challenging due to the complex liver anatomy. Three-dimensional printing (3DP) has gained popularity due to its ability to produce anatomical models based on the characteristics of each patient. METHODS: A multicenter study was conducted on complex hepatobiliary tumours. The endpoint was to validate 3DP model accuracy from original image sources for application in the teaching, patient-communication, and planning of hepatobiliary surgery. RESULTS: Thirty-five patients from eight centers were included. Process testing between 3DP and CT/MRI presented a considerable degree of similarity in vascular calibers (0.22 ± 1.8 mm), and distances between the tumour and vessel (0.31 ± 0.24 mm). The Dice Similarity Coefficient was 0.92, with a variation of 2%. Bland-Altman plots also demonstrated an agreement between 3DP and the surgical specimen with the distance of the resection margin (1.15 ± 1.52 mm). Professionals considered 3DP at a positive rate of 0.89 (95%CI; 0.73-0.95). According to student's distribution a higher success rate was reached with 3DP (median:0.9, IQR: 0.8-1) compared with CT/MRI or 3D digital imaging (P = 0.01). CONCLUSION: 3DP hepatic models present a good correlation compared with CT/MRI and surgical pathology and they are useful for education, understanding, and surgical planning, but does not necessarily affect the surgical outcome.

Replicative Fitness of Seasonal Influenza A Viruses With Decreased Susceptibility to Baloxavir.

Susceptibility of influenza A viruses to baloxavir can be affected by changes at amino acid residue 38 in the polymerase acidic (PA) protein. Information on replicative fitness of PA-I38-substituted viruses remains sparse. We demonstrated that substitutions I38L/M/S/T not only had a differential effect on baloxavir susceptibility (9- to 116-fold) but also on in vitro replicative fitness. Although I38L conferred undiminished growth, other substitutions led to mild attenuation. In a ferret model, control viruses outcompeted those carrying I38M or I38T substitutions, although their advantage was limited. These findings offer insights into the attributes of baloxavir-resistant viruses needed for informed risk assessment.

Unilateral or Bilateral Standing Broad Jumps: Which Jump Type Provides Inter-Limb Asymmetries with a Higher Reliability?

This study aimed to compare the between-session reliability of performance and asymmetry variables between unilateral and bilateral standing broad jumps (SBJ). Twenty-four amateur basketball players (12 males and females) completed two identical sessions which consisted of four unilateral SBJs (two with each leg) and two bilateral SBJs. Mean and peak values of force, velocity and power, and impulse were obtained separately for each leg using a dual force platform. Inter-limb asymmetries were computed using the standard percentage difference for the unilateral SBJ, and the bilateral asymmetry index-1 for the bilateral SBJ. All performance variables generally presented an acceptable absolute reliability for both SBJs (CV range = 3.65-9.81%) with some exceptions for mean force, mean power, and peak power obtained with both legs (CV range = 10.00-15.46%). Three out of 14 variables were obtained with higher reliability during the unilateral SBJ (CVratio ≥ 1.18), and 5 out of 14 during the bilateral SBJ (CVratio ≥ 1.27). Asymmetry variables always showed unacceptable reliability (ICCrange = -0.40 to 0.58), and slight to fair levels of agreement in their direction (Kappa range = -0.12 to 0.40) except for unilateral SBJ peak velocity [Kappa = 0.52] and bilateral SBJ peak power [Kappa = 0.51]) that showed moderate agreement for both SBJs. These results highlight that single-leg performance variables can be generally obtained with acceptable reliability regardless of the SBJ variant, but the reliability of the inter-limb asymmetries in the conditions examined in the present study is unacceptable to track individual changes in performance.

Differences in attitude toward prevention of suicide between nursing and medicine students: A study in Mexican population.

The aim of the present study was to evaluate the attitude toward suicide prevention in medicine and nursing students attending University in south Mexico, considering their family and personal history of suicide. Demographic features and self-reported personal and family history of suicide were evaluated in 355 Mexican students at the Health Sciences School. Their views toward suicide prevention was assessed using the Attitude Toward Suicide Prevention scale. Comparisons between medicine and nursing students were performed, as well as between had or had-not previous personal or family history of suicide. Our results support that nursing students showed the most negative attitude toward suicide prevention. Therefore, training programs and strategies encouraging a better attitude in suicide prevention are necessary to be implemented. It is also necessary to consider cultural, ethnic and family backgrounds of the students/of the population when developing new strategies.

Susceptibility of Influenza A, B, C, and D Viruses to Baloxavir1.

Baloxavir showed broad-spectrum in vitro replication inhibition of 4 types of influenza viruses (90% effective concentration range 1.2-98.3 nmol/L); susceptibility pattern was influenza A ˃ B ˃ C ˃ D. This drug also inhibited influenza A viruses of avian and swine origin, including viruses that have pandemic potential and those resistant to neuraminidase inhibitors.

Assessing baloxavir susceptibility of influenza viruses circulating in the United States during the 2016/17 and 2017/18 seasons.

The anti-influenza therapeutic baloxavir targets cap-dependent endonuclease activity of polymerase acidic (PA) protein. We monitored baloxavir susceptibility in the United States with next generation sequencing analysis supplemented by phenotypic one-cycle infection assay. Analysis of PA sequences of 6,891 influenza A and B viruses collected during 2016/17 and 2017/18 seasons showed amino acid substitutions: I38L (two A(H1N1)pdm09 viruses), E23G (two A(H1N1)pdm09 viruses) and I38M (one A(H3N2) virus); conferring 4-10-fold reduced susceptibility to baloxavir.

Avian Influenza A(H7N2) Virus in Human Exposed to Sick Cats, New York, USA, 2016.

An outbreak of influenza A(H7N2) virus in cats in a shelter in New York, NY, USA, resulted in zoonotic transmission. Virus isolated from the infected human was closely related to virus isolated from a cat; both were related to low pathogenicity avian influenza A(H7N2) viruses detected in the United States during the early 2000s.

Neuraminidase Mutations Conferring Resistance to Oseltamivir in Influenza A(H7N9) Viruses.

UNLABELLED: Human infections by avian influenza A(H7N9) virus entail substantial morbidity and mortality. Treatment of infected patients with the neuraminidase (NA) inhibitor oseltamivir was associated with emergence of viruses carrying NA substitutions. In the NA inhibition (NI) assay, R292K conferred highly reduced inhibition by oseltamivir, while E119V and I222K each caused reduced inhibition. To facilitate establishment of laboratory correlates of clinically relevant resistance, experiments were conducted in ferrets infected with virus carrying wild-type or variant NA genes recovered from the A/Taiwan/1/2013 isolate. Oseltamivir treatment (5 or 25 mg/kg of body weight/dose) was given 4 h postinfection, followed by twice-daily treatment for 5 days. Treatment of ferrets infected with wild-type virus resulted in a modest dose-dependent reduction (0.7 to 1.5 log10 50% tissue culture infectious dose [TCID50]) in nasal wash viral titers and inflammation response. Conversely, treatment failed to significantly inhibit the replication of R292K or E119V virus. A small reduction of viral titers was detected on day 5 in ferrets infected with the I222K virus. The propensity for oseltamivir resistance emergence was assessed in oseltamivir-treated animals infected with wild-type virus; emergence of R292K virus was detected in 3 of 6 ferrets within 5 to 7 days postinfection. Collectively, we demonstrate that R292K, E119V, and I222K reduced the inhibitory activity of oseltamivir, not only in the NI assay, but also in infected ferrets, judged particularly by viral loads in nasal washes, and may signal the need for alternative therapeutics. Thus, these clinical outcomes measured in the ferret model may correlate with clinically relevant oseltamivir resistance in humans. IMPORTANCE: This report provides more evidence for using the ferret model to assess the susceptibility of influenza A(H7N9) viruses to oseltamivir, the most prescribed anti-influenza virus drug. The information gained can be used to assist in the establishment of laboratory correlates of human disease and drug therapy. The rapid emergence of viruses with R292K in treated ferrets correlates well with the multiple reports on this NA variant in treated human patients. Our findings highlight the importance of the discovery and characterization of new antiviral drugs with different mechanisms of action and the use of combination treatment strategies against emerging viruses with pandemic potential, such as avian H7N9 virus, particularly against those carrying drug resistance markers.

Bevacizumab and temozolomide versus temozolomide alone as neoadjuvant treatment in unresected glioblastoma: the GENOM 009 randomized phase II trial.

We sought to determine the impact of bevacizumab on reduction of tumor size prior to chemoradiotherapy in unresected glioblastoma patients. Patients were randomized 1:1 to receive temozolomide (TMZ arm) or temozolomide plus bevacizumab (TMZ + BEV arm). In both arms, neoadjuvant treatment was temozolomide (85 mg/m(2), days 1-21, two 28-day cycles), concurrent radiation plus temozolomide, and six cycles of adjuvant temozolomide. In the TMZ + BEV arm, bevacizumab (10 mg/kg) was added on days 1 and 15 of each neoadjuvant cycle and on days 1, 15 and 30 of concurrent treatment. The primary endpoint was investigator-assessed response to neoadjuvant treatment. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and the impact on outcome of MGMT methylation in tumor and serum. One hundred and two patients were included; 43 in the TMZ arm and 44 in the TMZ + BEV arm were evaluable for response. Results favored the TMZ + BEV arm in terms of objective response (3 [6.7 %] vs. 11 [22.9 %]; odds ratio 4.2; P = 0.04). PFS and OS were longer in the TMZ + BEV arm, though the difference did not reach statistical significance. MGMT methylation in tumor, but not in serum, was associated with outcome. More patients experienced toxicities in the TMZ + BEV than in the TMZ arm (P = 0.06). The combination of bevacizumab plus temozolomide is more active than temozolomide alone and may well confer benefit in terms of tumor shrinkage in unresected patients albeit at the expense of greater toxicity.

An oil-in-water nanoemulsion enhances immunogenicity of H5N1 vaccine in mice.

To enhance the immunogenicity of the Influenza H5N1 vaccine, we developed an oil-in-water nanoemulsion (NE) adjuvant. NE displayed good temperature stability and maintained particle size. More importantly, it significantly enhanced IL-6 and MCP-1 production to recruit innate cells, including neutrophils, monocytes/macrophages and dendritic cells to the local environment. Furthermore, NE enhanced dendritic cell function to induce robust antigen-specific T and B cell immune responses. NE-adjuvanted H5N1 vaccine not only elicited significantly higher and long-lasting antibody responses, but also conferred enhanced protection against homologous clade 1 as well as heterologous clade 2 H5N1 virus challenge in young as well as in aged mice. The pre-existing immunity to seasonal influenza did not affect the immunogenicity of NE-adjuvanted H5N1 vaccine.

Office and ambulatory blood pressure control in hypertensive patients treated with different two-drug and three-drug combinations.

There is scarce information regarding ambulatory blood pressure (BP) achieved in daily practice with a wide range of antihypertensive drug combinations. We looked for differences in office and ambulatory BP among major drug combinations of two and three antihypertensive agents from a different drugs class. A total of 17187 patients treated with six types of two-drug combinations and 9724 treated with six types of three-drug combinations from the Spanish ABPM Registry were analyzed. We compared achieved office and ambulatory BP, as well as office (< 140/90 mmHg) and ambulatory (24-hour BP < 130/80; day BP < 135/85, and night BP < 120/70 mmHg) BP control among groups. The combination of renin-angiotensin system (RAS) blockers with diuretics and the triple combination of RAS blockers with diuretics and calcium channel blockers (CCB) were associated with lower values of 24-hour, daytime and nighttime BP, as well as more pronounced nocturnal BP dip. Compared with such combinations (reference), other double combinations had lower rates of ambulatory BP control. Moreover, triple combinations containing alpha blockers also had lower rates of ambulatory BP control. We conclude that even with similar office BP control, differences exist among antihypertensive two-drug and three-drug combinations with respect to ambulatory BP control achieved during treatment, with RAS blockers/diuretics and RAS blockers/CCBs/diuretics obtaining better control rates. This can help physicians choose among drug combinations in order to obtain further ambulatory BP reductions.

A Newly Emerged Swine-Origin Influenza A(H3N2) Variant Dampens Host Antiviral Immunity but Induces Potent Inflammasome Activation.

We compared the innate immune response to a newly emerged swine-origin influenza A(H3N2) variant containing the M gene from 2009 pandemic influenza A(H1N1), termed "A(H3N2)vpM," to the immune responses to the 2010 swine-origin influenza A(H3N2) variant and seasonal influenza A(H3N2). Our results demonstrated that A(H3N2)vpM-induced myeloid dendritic cells secreted significantly lower levels of type I interferon (IFN) but produced significantly higher levels of proinflammatory cytokines and induced potent inflammasome activation. The reduction in antiviral immunity with increased inflammatory responses upon A(H3N2)vpM infection suggest that these viruses have the potential for increased disease severity in susceptible hosts.

Characterization of drug-resistant influenza A(H7N9) variants isolated from an oseltamivir-treated patient in Taiwan.

BACKGROUND: Patients contracting influenza A(H7N9) infection often developed severe disease causing respiratory failure. Neuraminidase (NA) inhibitors (NAIs) are the primary option for treatment, but information on drug-resistance markers for influenza A(H7N9) is limited. METHODS: Four NA variants of A/Taiwan/1/2013(H7N9) virus containing a single substitution (NA-E119V, NA-I222K, NA-I222R, or NA-R292K) recovered from an oseltamivir-treated patient were tested for NAI susceptibility in vitro; their replicative fitness was evaluated in cell culture, mice, and ferrets. RESULTS: NA-R292K led to highly reduced inhibition by oseltamivir and peramivir, while NA-E119V, NA-I222K, and NA-I222R caused reduced inhibition by oseltamivir. Mice infected with any virus showed severe clinical signs with high mortality rates. NA-I222K virus was the most virulent in mice, whereas virus lacking NA change (NA-WT) and NA-R292K virus seemed the least virulent. Sequence analysis suggests that PB2-S714N increased virulence of NA-I222K virus in mice; NS1-K126R, alone or in combination with PB2-V227M, produced contrasting effects in NA-WT and NA-R292K viruses. In ferrets, all viruses replicated to high titers in the upper respiratory tract but produced only mild illness. NA-R292K virus, showed reduced replicative fitness in this animal model. CONCLUSIONS: Our data highlight challenges in assessment of the replicative fitness of H7N9 NA variants that emerged in NAI-treated patients.

High prevalence of masked uncontrolled hypertension in people with treated hypertension.

AIM: There are limited data on the quality of treated blood pressure (BP) control during normal daily life, and in particular, the prevalence of 'masked uncontrolled hypertension' (MUCH) in people with treated and seemingly well-controlled BP is unknown. This is important because masked hypertension in 'treatment naïve' patients is associated with a high risk of cardiovascular events. We therefore conducted the first study to define the prevalence and characteristics of MUCH among a large sample of hypertensive patients in routine clinical practice in whom BP was treated and controlled to recommended clinic BP goals. METHODS AND RESULTS: We analysed data from the Spanish Society of Hypertension ambulatory blood pressure monitoring (ABPM) Registry and identified patients with treated and controlled BP according to current international guidelines (clinic BP <140/90 mmHg). Masked uncontrolled hypertension was diagnosed in these patients if despite controlled clinic BP, the mean 24-h ABPM average remained elevated (24-h systolic BP ≥130 mmHg and/or 24-h diastolic BP ≥80 mmHg). From 62 788 patients with treated BP in the Spanish registry, we identified 14 840 with treated and controlled clinic BP, of whom 4608 patients (31.1%) had MUCH according to 24-h ABPM criteria (mean age 59.4 years, 59.7% men). The prevalence of MUCH was significantly higher in males, patients with borderline clinic BP (130-9/80-9 mmHg), and patients at high cardiovascular risk (smokers, diabetes, obesity). Masked uncontrolled hypertension was most often because of poor control of nocturnal BP, with the proportion of patients in whom MUCH was solely attributable to an elevated nocturnal BP almost double that solely attributable to daytime BP elevation (24.3 vs. 12.9%, P < 0.001). CONCLUSION: The prevalence of masked suboptimal BP control in patients with treated and well-controlled clinic BP is high. Clinic BP monitoring alone is thus inadequate to optimize BP control because many patients have an elevated nocturnal BP. These findings suggest that ABPM should become more routine to confirm BP control, especially in higher risk groups and/or those with borderline control of clinic BP.