Isavuconazole-tacrolimus drug-drug interactions in HSCT patients.

OBJECTIVES: Because tacrolimus has a narrow therapeutic window and exhibits both intraindividual and interindividual variability, we attempted to establish the percentage of calcineurin inhibitor (CNI) dose reduction to prevent toxicity and ensure stem cell engraftment when using this immunosuppressant with the antifungal isavuconazole (ISA). By calculating the tacrolimus concentration/dose (C/D) ratio, we expected to demonstrate the magnitude of change in the C/D ratio from baseline after ISA administration. METHODS: We evaluated the interaction between ISA, a new triazole antifungal used in prophylaxis for invasive fungal infections, and the CNI class of immunosuppressive drugs, specifically tacrolimus, in 11 blood samples from HSCT recipients. RESULTS: The mean tacrolimus C/D ratio increased 1.44-fold from baseline 48 h after ISA administration (P = 0.001). CONCLUSIONS: Although further investigation is needed, the results of this study suggest that a reduction of 18% in tacrolimus may be recommended.

Direct observation of hand hygiene can show differences in staff compliance: Do we need to evaluate the accuracy for patient safety?

Background: Direct observation of hand hygiene is the standard practice recommended by the World Health Organization to monitor its compliance. Objective: To evaluate the accuracy of hand hygiene observation performed by units' observers. Methods: A descriptive study was carried out in seven patient care units in a 75-bed community hospital in Qatar. Four trained nurses performed hand hygiene observation in May 2016, any day of the week and in different shifts, following the same methodology as routine units' observers. Hand hygiene opportunities were registered, including hand hygiene moments, staff category, and actions (handrubs, hand washing, missed hand hygiene, and gloves without hand hygiene). Results: During January-May 2016, routine monitoring reported 25,319 opportunities with a compliance of 89.2%, and 91.6% for nurses, 89.6% for physicians, and 85.1% for ancillary staff. Trained external observers reported 815 opportunities and compliance of 54.7%, with the highest compliance observed after blood and body fluid exposure (80.0%) and after patient contact (85.5%), and the lowest figures before patient contact (34.2%) and before aseptic procedure (34.0%). Conclusion: This study provides essential information about the accuracy of the monitoring procedure and the compliance of hand hygiene that requires immediate action to protect patients and staff from healthcare-associated infections.

[Marfan syndrome associated with aortic dissection, venous thromboembolism and hyperhomocysteinemia]. / Síndrome de Marfan con disección aórtica asociada a tromboembolismo venoso e hiperhomocisteinemia.

Marfan syndrome is an infrequent genetic disorder of connective tissue whose clinical manifestations mainly affect the cardiovascular, ocular and musculoskeletal systems. Serious cardiovascular manifestations are generally the cause of mortality of Marfan patients. Thromboembolic venous disease is intimately related to different risk factors: inherited, acquired, mixed or unknown; hyperhomocysteinemia is a moderate risk factor for venous thromboembolism. We present the case of a 47-year-old woman with Marfan syndrome associated to a painless type A aortic dissection, who simultaneously suffered venous thromboembolism of left upper and lower limbs with pulmonary embolism. Hyperhomocysteinemia was found through thrombofilia screening. The patient's condition has evolved favorably.

Towards a synthetic cell cycle.

Recent developments in synthetic biology may bring the bottom-up generation of a synthetic cell within reach. A key feature of a living synthetic cell is a functional cell cycle, in which DNA replication and segregation as well as cell growth and division are well integrated. Here, we describe different approaches to recreate these processes in a synthetic cell, based on natural systems and/or synthetic alternatives. Although some individual machineries have recently been established, their integration and control in a synthetic cell cycle remain to be addressed. In this Perspective, we discuss potential paths towards an integrated synthetic cell cycle.

Citizen Science, a promising tool for detecting and monitoring outbreaks of the crown-of-thorns starfish Acanthaster spp.

Monitoring potentially devastating coral-eating crown-of-thorns starfish (COTS) populations at scales relevant to management is a challenging task. Here, we investigated a citizen science approach to detect COTS outbreaks and prioritize management responses. Between 2014 and 2018, 38 000 COTS were recorded through 641 online observation reports submitted across New Caledonia, Vanuatu and Fiji by private stakeholders (51%), NGOs (22%), business operator (11%), research/government agencies (16%). COTS were observed in multiple areas, including in remote/inhabited reefs where they had never been reported. A three-level classification was developed to discriminate risk areas and propose operational guidelines to streamline management actions. About two-thirds of reports had low abundances (<10 starfish sighted) and could be addressed with low priority. Verification surveys at 65 reef sites confirmed outbreaks in half of the cases, along with high peak densities (7 000 ind.ha-1). Combining professional and non-professional observers increased the detection range (+27%) and the number of COTS detections (+129%). Citizen reports were eventually followed by removal campaigns organized within diverse institutional frameworks. While citizen monitoring has intrinsic limitations, we advocate that it constitutes a complementary and promising approach to support the ongoing management efforts in all countries affected by COTS.

[Pheochromocytoma associated with von Recklinghausen neurofibromatosis]. / Feocromocitoma asociado a neurofibromatosis de von Recklinghausen.

A pheochromocytoma is an adrenal gland tumor that secretes epinephrine and norepinephrine hormones, and is responsible for regulating heart rate and blood pressure, among other functions. The condition can occur alone or in combination with other disorders, and genetic and environmental factors play a key role. Neurofibromatosis-1 (NF-1) an inherited "autosomal dominant" disorder is one of the most common genetic disorders, characterized by formation of neurofibromas (tumors involving nerve tissue) in the skin, subcutaneous tissue, cranial and spinal root nerves. NF1 generally is diagnosed by physical examination. There is no cure for NF1, but there are ways to treat some of its effects. Neurofibromatosis arterial hypertension caused by pheochromocytoma is extremely rare, less frecuent than 1% in childrens less than 10 years old, and young adults. We present a case of an extremely infrequent association between neurofibromatosis and a pheochromocytoma in a young woman with a newly diagnosed hypertension. We discuss the underlying pathophysiological mechanisms and clinical implications.

Incidence and Etiology of Surgical Site Infections in Appendectomies: A 3-Year Prospective Study.

OBJECTIVES: Surgical site infections (SSIs) constitute a threat, especially in complicated appendicitis, and are commonly due to gram-negative organisms. We sought to describe the incidence of SSIs in appendectomies performed during a three-year period (January 2013 to December 2015) in a community hospital in Qatar, and compare this with external benchmarks. METHODS: We conducted a longitudinal study at The Cuban Hospital, Qatar. We used the standardized surveillance criteria to define SSI developed by the Centers for Disease Control. Information about age, sex, smoking habits, diabetes mellitus status, body mass index, and the result of bacteriologic studies were collected. RESULTS: Of a total 603 patients, 22 (3.6%) cases of SSI were reported, with an infection rate of 13.6%, 4.5%, and 1.0% in 2013, 2014, and 2015, respectively. SSIs were observed more frequently in patients with contaminated/dirty wounds (6.6%). About 65% of isolates from the surgical site were multidrug-resistant organisms (Escherichia coli and Klebsiella spp.). CONCLUSIONS: This study describes the incidence of SSI in appendectomy, which could be used as a benchmark for the facility improvement program. The high frequency of multidrug-resistant organisms in SSIs requires additional studies focused on evaluating the effectiveness of the current preventive practices with a particular reference to antimicrobial prophylaxis.

Impact of a focused antimicrobial stewardship program in adherence to antibiotic prophylaxis and antimicrobial consumption in appendectomies.

Antibiotic use in appendectomy constitutes a fundamental practice to achieve the clinical outcomes and the prevention of surgical site infection. A prospective interventional study was performed in a community hospital from January 2013 to December 2015 with the aim of determining the effect of a focused antimicrobial stewardship program in the compliance with antibiotic prophylaxis and the antimicrobial consumption in appendectomies. The compliance with the antibiotic prophylaxis was monitored for the timing of administration, the selection and dose and the discontinuation. The monitoring of antimicrobial consumption was performed by a pharmacist using ATC/DDD methodology. The stewardship program includes the education of the staff and the monitoring of the quality of antibiotic prophylaxis and consumption, and feedback. Comparison of the variables over the years was performed using student's t-test or chi-square test as required. In 603 appendectomies performed the compliance with timely administration was achieved in 72.9%, 99.6% and 100% during 2013, 2014 and 2015 respectively and the compliance with the discontinuation had an increase from 86.4% (2013) to 96.7% in 2015. Consumption of antimicrobial was 355.1 DDD/100 procedures (DDD) in flemonous, 447.3 DDD in suppurative, 892.8 DDD in gangrenous and 1162.7 DDD in perforated appendectomies. Reduction in consumption for cefuroxime (26.2%), metronidazole (12.6%) and ceftriaxone (18.1%) was observed. The consumption of antimicrobials in flemonous and suppurated appendectomies achieved the lowest figure in 2015. The focused antimicrobial stewardship program was effective to improve the timely administration and the proper discontinuation of prophylactic antibiotic, with an important reduction of antimicrobial consumption.

Diagnostic role of new Doppler index in assessment of renal artery stenosis.

BACKGROUND: Renal artery stenosis (RAS) is one of the main causes of secondary systemic arterial hypertension. Several non-invasive diagnostic methods for RAS have been used in hypertensive patients, such as color Doppler ultrasound (US). The aim of this study was to assess the sensitivity and specificity of a new renal Doppler US direct-method parameter: the renal-renal ratio (RRR), and compare with the sensitivity and specificity of direct-method conventional parameters: renal peak systolic velocity (RPSV) and renal aortic ratio (RAR), for the diagnosis of severe RAS. METHODS: Our study group included 34 patients with severe arterial hypertension (21 males and 13 females), mean age 54 (+/- 8.92) years old consecutively evaluated by renal color Doppler ultrasound (US) for significant RAS diagnosis. All of them underwent digital subtraction arteriography (DSA). RAS was significant if a diameter reduction > 50% was found. The parameters measured were: RPSV, RAR and RRR. The RRR was defined as the ratio between RPSV at the proximal or mid segment of the renal artery and RPSV measured at the distal segment of the renal artery. The sensitivity and specificity cutoff for the new RRR was calculated and compared with the sensitivity and specificity of RPSV and RAR. RESULTS: The accuracy of the direct method parameters for significant RAS were: RPSV >200 cm/s with 97% sensitivity, 72% specificity, 81% positive predictive value and 95% negative predictive value; RAR >3 with 77% sensitivity, 90% specificity, 90% positive predictive value and 76% negative predictive value. The optimal sensitivity and specificity cutoff for the new RRR was >2.7 with 97% sensitivity (p < 0.004) and 96% specificity (p < 0.02), with 97% positive predictive value and 97% negative predictive value. CONCLUSION: The new RRR has improved specificity compared with the direct method conventional parameters (RPSV >200cm/s and RAR >3). Both RRR and RPSV show better sensitivity than RAR for the RAS diagnosis.

Antibiotic Consumption During a 4-year Period in a Community Hospital with an Antimicrobial Stewardship Program.

OBJECTIVES: We sought to evaluate the trend of antibiotic consumption in patients admitted to a community hospital in Qatar with an antimicrobial stewardship program. METHODS: This observational study was carried out in a 75-bed facility in Western Qatar over a 4-year period (2012-2015). The monitoring of antimicrobial consumption from inpatient wards was performed from the pharmacy records and presented as defined daily dose (DDD) divided by the patient days and expressed as 100 bed-days (DBD). RESULTS: The consumption of antimicrobials in 2012 was 171.3 DBD, and increased to 252.7 DBD in 2013, 229.1 DBD in 2014, and 184.7 DBD in 2015. Cephalosporins use reduced from 98.2 DBD in 2013 to 51.5 DBD in 2015 while the consumption of penicillins increased during the beginning of 2014 with a slight decrease in 2015. Carbapenems consumption during 2014-2015 was lower than previous years, and vice-versa for aminoglycosides. Fluoroquinolones had a sustained increase with 37.1% increased consumption in 2015 compared to the two previous years. There was an increase in the use of intravenous (IV) (108.5%) and oral azithromycin (55.1%) and the use of oral (152.8%) and IV moxifloxacin (22.9%). CONCLUSIONS: We observed a decrease in antibiotic use in patients admitted to a community hospital with an antimicrobial stewardship program, but the increase in fluoroquinolones consumption is a concern that requires focused strategies.

Outbreaks of brucellosis related to the consumption of unpasteurized camel milk.

Brucellosis is the most frequent zoonosis reported in Qatar, mainly related to exposure to infected camels. An outbreak of human brucellosis in 14 members of a family living in a rural area in Qatar is reported herein. Clinical, epidemiological and laboratory results from all 14 patients with Brucella and 12 non-confirmed family members were collected from files. All patients reported fever for a maximum of 14 days, associated with arthralgia (6 patients), weakness (4 patients), headache (4 patients), diarrhea (2 patients) and abdominal pain (2 patients). The median age of the patients was 10 years and that of non-cases was 16 years, with a predominance of males (92.9%). Elevated levels of transaminases were observed in patients. A mixed infection caused by Brucella abortus and Brucella melitensis was identified by blood culture and serology. The source of the infection was the milk of an infected camel. The outbreak of brucellosis melitensis/abortus related to the consumption of camel milk constitutes a gap in the prevention and control of the potential sources of brucellosis in animal farms. Proper control and education of the population are required.

[Prothrombotic state in early stages of chronic Chagas' disease. Its association with thrombotic risk factors]. / Estado protrombótico en estadios tempranos de la enfermedad de Chagas crónica. Su asociación con factores de riesgo trombótico.

OBJECTIVE: The aim of this study was to explore the presence of prothrombotic state in early stages of chronic Chagas' disease with serum markers of thrombosis and fibrinolysis, and to investigate it's association with thrombotic risk factors for venous thromboembolic disease. PATIENTS AND METHODS: Forty two patients with chronic Chagas' disease were compared with 21 healthy volunteers. Thrombotic markers used were fragment 1 + 2, ATM complex, fibrinogen/fibrin degradation products, D-dimer and beta-thromboglobulin. Fibrinolysis was evaluated with euglobulin lysis time, tissue plasminogen activator and it's inhibitor levels. A thrombophilic screening was performed. Antithrombin and protein C were determined by functional methods, as well as free fraction of protein S, resistance to activated protein C, factor V Leiden R506Q mutation, prothrombin G20210A mutation, homocysteine and antiphospholipid antibodies: lupus and anticardiolipin antibodies isoforms IgG and IgM. RESULTS: In chronic Chagas' disease patients, statistically significant differences were observed in thrombotic markers: fragment 1 + 2 (p < 0.0001), ATM complex (p < 0.0001), fibrinogen/fibrin degradation products (p < 0.05) and D-dimer (p < 0.05). beta-thromboglobulin did not reach statistically significant difference (p = 0.06). Statistically significant differences (p < 0.0001) were found only in euglobulin lysis time, a non specific fibrinolytic marker. Specific fibrinolytic markers tissue plasminogen activator and it's inhibitor, however, did not show statistically significant differences among studied groups. CONCLUSIONS: Eighty six percent of patients had positive thrombophilic screening for at least one thrombophilic risk factor. Thrombophilic risk factors were inherited in 39% and acquired in 83% of the patients.

Similarity between the in vitro activity and toxicity of two different Fungizone/Lipofundin admixtures.

PURPOSE: Amphotericin B (AmB), an antifungal agent that presents a broad spectrum of activity, remains the gold standard in the antifungal therapy. However, sometimes the high level of toxicity forbids its clinical use. The aim of this work was to evaluate and compare the efficacy and toxicity in vitro of Fungizon (AmB-D) and two new different AmB formulations. METHODS: three products were studied: Fungizon, and two Fungizon /Lipofundin admixtures, which were diluted through two methods: in the first one, Fungizon was previously diluted with water for injection and then, in Lipofundin (AmB-DAL); the second method consisted of a primary dilution of AmB-D as a powder in the referred emulsion (AmB-DL). For the in vitro assay, two cell models were used: Red Blood Cells (RBC) from human donors and Candida tropicallis (Ct). The in vitro evaluation (K+ leakage, hemoglobin leakage and cell survival rate-CSR) was performed at four AmB concentrations (from 50 to 0.05 mg x L(-1)). RESULTS: The results showed that the action of AmB was not only concentration dependent, but also cellular type and vehicle kind dependent. At AmB concentrations of 50 mg x L(-1), although the hemoglobin leakage for AmB-D was almost complete (99.51), for AmB-DAL and AmB-DL this value tended to zero. The p = 0.000 showed that AmB-D was significantly more hemolytic. CONCLUSION: The Fungizon-Lipofundin admixtures seem to be the more valuable AmB carrier systems due to their best therapeutic index presented.

The major acute phase serum protein in pigs is homologous to human plasma kallikrein sensitive PK-120.

A major acute phase protein (pig-MAP) has been isolated from the sera of pigs after turpentine injection. The protein is the pig counterpart of a recently cloned human serum protein denominated PK-120, which is a putative substrate for kallikrein [Nishimura et al., 1995 FEBS Lett. 357, 207-211]. The protein exists in other mammalian species and it is also an acute phase protein, at least in the rat. Pig-MAP shows homology, as PK-120, with the heavy chain 2 (HC-2) of the inter-alpha-trypsin inhibitor superfamily but does not possess trypsin inhibitory activity.

Differential effects of pentoxifylline on the hepatic inflammatory response in porcine liver cell cultures. Increase in inducible nitric oxide synthase expression.

Pentoxifylline (PTX) has been shown to exert hepatoprotective effects in various liver injury models. However, little information is available about the effect of PTX on the hepatic acute phase response. In the present study, the effect of PTX on a lipopolysaccharide (LPS)-induced acute phase response in primary porcine liver cell cultures was examined. During 72 hr of incubation with or without LPS, the ability of PTX to influence the secretion of tumour necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), acute phase proteins, and nitric oxide (NO) was assessed. PTX completely inhibited LPS-induced TNF-alpha production and attenuated IL-6 only after 48 hr of incubation. In contrast, PTX potentiated NO production and the expression of inducible nitric oxide synthase (iNOS) in hepatocytes after stimulation with LPS. The increased expression of iNOS and concurrent production of NO was also observed when liver cell cultures were incubated with dibutyryl cyclic adenosine monophosphate. No effect of PTX on acute phase protein secretion was observed during 72 hr of incubation. The present results show that PTX differentially affects the endotoxin-induced inflammatory response in primary porcine liver cell cultures by suppressing TNF-alpha and IL-6 while potentiating NO production.

Cathepsin D in breast cancer tissue.

The cathepsin D concentration in 18 women with benign breast pathology has a cut-off value of 43 pmol/mg of protein. High values have been detected in two cases of chronic mastitis. These high values of cathepsin D were found in a study of 62 patients suffering from breast cancer and are independent of the hormone dependent state of the tumour. The cathepsin D concentration may have a prognostic function in breast cancer determination, as high concentrations are found in combination with other prognostic factors such as clinical stage, size of the tumour, state of the axillary lymph nodes and in the histological differentiation grade, where from a statistical point of view, the combination is important.

The porcine acute phase response to infection with Actinobacillus pleuropneumoniae. Haptoglobin, C-reactive protein, major acute phase protein and serum amyloid A protein are sensitive indicators of infection.

In an experimental infection model mimicking acute Actinobacillus pleuropneumoniae (Ap) infection in swine (Sus scrofa) by aerosol inoculation, the development of a number of typical clinical signs was accompanied by a prototypic acute phase reaction encompassing fever and an acute phase protein response peaking at around 2 days after infection. Haptoglobin, C-reactive protein (CRP), and major acute phase protein (MAP) responded with large increases in serum levels, preceding the development of specific antibodies by 4-5 days. Serum amyloid A protein (SAA) was also strongly induced. The increase, kinetics of induction and normalization were different between these proteins. It is concluded that experimental Ap-infection by the aerosol route induces a typical acute phase reaction in the pig, and that pig Hp, CRP, MAP, and SAA are major acute phase reactants. These findings indicate the possibility of using one or more of these reactants for the nonspecific surveillance of pig health status.

[The prothrombotic state in early stages of chronic chagas' disease]. / Estado protrombótico en estadios tempranos de la enfermedad de Chagas crónica.

OBJECTIVE: This study was designed to explore the presence of a prothrombotic state in the early stages of chronic Chagas' disease by evaluating serum markers of thrombosis and fibrinolysis. PATIENTS AND METHOD: Forty-two patients with chronic Chagas' disease (12 men and 30 women, 32.5 6.7 years) were compared with 21 healthy volunteers (10 men and 11 women, 24.2 5.6 years). The markers of thrombotic activation used were fragment 1 + 2, ATM complex, PDF/pdf, D-dimer, and beta-thromboglobulin. Fibrinolysis was evaluated before and after venous occlusion, together with euglobulin lysis time, t-PA, and PAI-1 titers. RESULTS: The markers of thrombotic state were significantly higher in patients with chronic Chagas' disease than in controls: F1 + 2 (p < 0.0001), ATM (p < 0.0001), PDF/pdf (p < 0.05), and D dimer (p < 0.05). There was no significant difference in beta-thromboglobulin (p = 0.06). Euglobulin lysis time, a global fibrinolytic marker, differed significantly (p < 0.0001) between patients with Chagas' disease and healthy volunteers. However, the more specific fibrinolytic markers t-PA and PAI-1 did not differ significantly between the two study groups. CONCLUSIONS: Although there were no significant differences in fibrinolytic markers between patients with chronic Chagas' disease and healthy volunteers, the significant increase in thrombosis markers (F1 + 2, ATM complex, PDF/pdf, and D dimer) suggests the presence of a prothrombotic state in the early stages of chronic Chagas' disease.