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BACKGROUND: Post-transplantation immunosuppressive therapy reduces the risk of graft rejection but raises the risk of infection and malignancy. A biomarker of the level of immunosuppression can be helpful in monitoring immunosuppressive therapy. Inverse correlation between Torque teno virus (TTV) from the Anelloviridae (AV) family load and immune competence was described in previous studies. The aim of this study was to analyze the association between AV family viruses' kinetics and the risk for graft rejection in the first year after kidney transplantation in children. METHODS: The titers of three genera (TTV, TTMDV, and TTMV) from the AV family were monitored by real-time PCR in consecutive samples from children before and after kidney transplantation. RESULTS: Twenty-one children who underwent kidney transplantation were enrolled. Five out of 21 patients experienced acute graft rejection within a year from transplantation. We found that in patients who experienced graft rejection, the median titers of TTV and total AV titers at 5-6 months post-transplantation were lower than in those who did not. Using a threshold determined by ROC analysis, significant differences in TTV and total AV load were found between patients who had or did not have graft rejection (p = 0.002 and 0.004, respectively). No association was found between the dominance of any AV genus titer and the likelihood of rejection. CONCLUSION: This pilot study suggests that children after kidney transplantation with low TTV and total AV titers 5-6 months post-transplantation are at increased risk for graft rejection within a year after transplantation. A higher resolution version of the Graphical abstract is available as Supplementary information.

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BACKGROUND: Different case finding approaches have been used to identify early COPD. The objective of this study was to assess the feasibility and the yield of opportunistic early COPD case finding in visitors to a large medical centre. PATIENTS AND METHODS: From May 2014 to June 2017, we consecutively recruited adults aged ≥ 18 years visiting the Shaare Zedek Medical Center, in Jerusalem. Our 3-step intervention included: a) pre-screening for symptoms with the 5-item "Could it be COPD?" questionnaire (score= 0-5 pts); b) pre-BD spirometry; and c) referral to a caregiver. Airflow obstruction was defined by a FEV1/FVC < 0.7. Spirometry results were used as an incentive to promote smoking cessation and quit rates were verified by phone survey 3 months after the intervention. RESULTS: A total of 1001 subjects (956 smokers; 45 ex-smokers) were recruited. Mean (SD) age was 48.3 years (13.5). Airflow obstruction was detected in 180 (18%) subjects of whom 142 (78.9%) were unaware of it, including 27 subjects with severe (50% ≥ FEV1 ≤ 30% predicted) (n=25) or very severe (FEV1 < 30% predicted) (n=2) obstruction. Multiple logistic regression analysis found that age, BMI, cigarette smoking (p.y.) and a "Could it be COPD?" questionnaire score ≥ 3 points correctly classified 83.3% of cases of airflow obstruction. At follow-up, 54.5% of participants reported smoking as usual, 30.9% reduced smoking [mean (SD) = 10.1 ± 7.8 cigarettes/day], 7.4% increased smoking [mean (SD) = 9.2 ± 6.3 cigarettes/day] and 7.2% claimed smoking cessation. Among obstructed subjects, 38.7% had visited a physician because of COPD, while 20.7% were taking a new respiratory medication. CONCLUSION: Early COPD case finding was feasible and effective in identifying undiagnosed airflow obstruction among visitors to a medical centre. Smoking cessation counselling based on spirometry promoted a small but clinically meaningful cessation rate.

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BACKGROUND: Initiating varenicline use 4 weeks before the target quit date (TQD) reduces smoking in the run-in phase and increases end-treatment cessation rates; however, the lack of a smoke intake plateau suggests longer preloading periods are required. This study assessed whether varenicline preloading for 6 weeks reduced pre-quit smoke intake and enhanced 6-month abstinence outcomes compared with the standard 1-week preloading. METHODS: In this randomised single-centre controlled trial, (ClinicalTrials.gov identifier: NCT02634281), conducted between February 2016 and July 2018 in Israel, daily smokers (n = 242) aged ≥ 18 years were randomly assigned (1:1) to receive varenicline preloading for 6 weeks (n = 121) or a placebo for 5 weeks followed by varenicline for 1 week (n = 121) before the TQD. Participants and researchers were masked to both group assignment and treatment allocation. Both groups received standard 12-week post-TQD varenicline treatment. The primary outcome was the 24-week biochemically verified continuous abstinence rate (CAR) from weeks 6 (TQD)-30. Secondary outcomes included the 23-week CAR from 1-week post-TQD (week 7) to week 30, and the 7-day point-prevalence (PP) abstinence at week 30. Other measures included pre- and post-quit rewards, smoking urges, nausea, aversion, and markers of cigarette consumption. FINDINGS: By intention-to-treat, the 24-week CAR, weeks 6-30 with extended preloading was significantly higher than with standard preloading (23·1% vs. 4·1%; risk reduction [RR]: -0·19 [95% confidence interval [CI]:-0·10-0·24]; p < 0·001). Extended preloading also showed better secondary outcomes. Extended preloading significantly decreased pre-quit rewards, urges, and smoke intake, including unsolicited smoking abstinence. Post-quit urges remained remarkably lower with extended preloading. Participants receiving extended preloading reported more nausea at week 4 (39.6% vs 11.5%) and abnormal dreams at week 6 (7.7% vs. 0%). Participants receiving standard preloading reported more constipation at week 7 (7.6% vs. 0%) and dizziness at weeks 7 (12.1% vs. 2.5%) and 12 (10.7% vs 1.4%). INTERPRETATION: Extended preloading reduced ad lib smoking, enhanced cessation rates at 3 and 6 months, and decreased pre- and post-quit rewards and smoking drive in a pattern compatible with a reinforcement-reduction mechanism. These data substantiate extending the standard pre-treatment period, and suggest that targeting pre-quit smoking sensations should be a treatment priority, although confirmatory evidence is needed from larger clinical trials. FUNDING: This study was funded by a 2013 Global Research Award for Nicotine Dependence (GRAND) supported by Pfizer, Inc. (#WI182915).

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BACKGROUND: Hyperuricemia is associated with the development, progression and outcome of several diseases. The purpose of this study is to evaluate the serum uric acid (UA) levels as a predictor of long-term mortality in an older population (age 60 years and above). MATERIALS AND METHODS: Patients older than 60 years who were hospitalized in the departments of geriatrics and internal medicine in Shaare Zedek Medical Center in Jerusalem during a period of 4 months (March-June 2014) were included in this observational study. Association between hyperuricemia and long-term mortality were analyzed using multiple logistic regression, Kaplan-Meier and Cox proportional hazards regressions analysis. RESULTS: A total of 624 patients were included in our study with mean age of 77.2 ± 14.6 years. Overall, 381 patients died during the follow-up period (61.1%). Mortality rate in the hyperuricemic group (> 7 mg/dL) was higher (69.1%) than in the normouricemic group 58.4%. (P = 0.004). The median survival for hyperuricemic patients was significantly shorter compared to normouricemic patients (606 and 1018 days, respectively, P < 0.0001). High levels of UA were significantly associated with higher long-term mortality in patients with cardiovascular disease at their admission (P < 0.000). CONCLUSIONS: Elevated levels of UA in older patients in acute settings is a predictor of long-term mortality.

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BACKGROUND: Acellular dermal matrices (ADMs) are commonly used to support implant-based breast reconstruction. However, there is little comparative data on the incorporation process of different ADMs, and the value of meshing or fenestration versus solid sheet has not been established, although early clinical data suggest seroma rates may be reduced. This was a preclinical assessment of the incorporation process at optimal conditions in a pig model. METHODS: SurgiMend and AlloDerm matrices were implanted in subcutaneous pockets on the backs of 15-week-old female pigs. Half of the samples were meshed 1:2.5; the remainder was grafted as a fenestrated (SurgiMend) or solid sheet (AlloDerm). Tissues were harvested at 3 months. Histological slides were prepared for hematoxylin and eosin staining, and Masson trichrome and immunostaining with anticollagen type I fluorescein isothiocyanate stain. Histological parameters (inflammation, giant cell reaction, neovascularization, fibroplasias, and scar tissue formation) were graded blindly on a scale of 0 (no reaction) to 3 (severe reaction). RESULTS: All explanted ADMs (SurgiMend, n = 23; AlloDerm, n = 20) were firmly incorporated within the host tissue. SurgiMend showed more fibroplasia (P = 0.029) compared with AlloDerm in meshed or solid sheet form. Meshed ADMs showed a trend toward increased inflammation (P = 0.074) and giant cell reaction (P = 0.053) compared with solid sheet/fenestrated ADM. CONCLUSIONS: Meshing ADM may allow cells to populate matrices more rapidly, promoting integration compared with solid sheet ADMs. This study sets the histological basis for further clinical investigations, with the aim of demonstrating lower complication rates (and particularly reduced seroma formation) with meshed ADMs.

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BACKGROUND: Intraocular injections of antivascular endothelial growth factor (VEGF) agents are currently the main therapy in age-related macular degeneration (AMD). The safety of bevacizumab, an anti-VEGF compound frequently delivered off label, is debated, particularly for high-group risks. We aim to analyze the mortality associated with intravitreal injections of bevacizumab for AMD in patients previously diagnosed with acute myocardial infarct (MI). METHODS: In a national database, we identified bevacizumab-treated AMD patients with a diagnosis of MI prior to their first bevacizumab injection, delivered between September 2008 and October 2014 (n = 2100). We then generated sub-groups of patients treated within 3 months (n = 11), 6 months (n = 24), 12 months (n = 52), and 24 months (n = 124) after MI. Those patients were compared to age- and gender-matched members that had a MI at the same time and had never been exposed to anti-VEGF. Survival analysis was performed using propensity score-adjusted Cox regression. RESULTS: Bevacizumab-treated patients were slightly and insignificantly older than controls (mean age 83.25 vs 83.19 year, P = .75). Gender distribution was similar. In a Cox regression adjusted with propensity score, the following differences in mortality were found: within 3 months between MI and initiation of bevacizumab treatment, OR = 6.22 (95% C.I 1.08-35.97, P < .05); within 6 months, OR = 2.37 (95% C.I 0.93-6.02, P = .071); within 12 months, OR = 3.00 (95% C.I 1.44-6.28, P < .01); within 24 months after MI, OR = 2.24 (95% C.I 1.35-3.70, P < .01); and MI any time prior to first bevacizumab injection, OR = 1.71 (95% C.I 1.53-1.92, P < .001). CONCLUSIONS: We report increased mortality associated with the use of intravitreal bevacizumab in AMD patients after MI, compared to age- and gender-matched post-MI patients with no exposure to any anti-VEGF agent. Caution should be taken while offering bevacizumab to AMD patients after MI.

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BACKGROUND: Congenital Cytomegalovirus (CMV) is a very common intrauterine infection which can cause severe developmental disabilities. Transmission of the virus to the fetus occurs in only 40% of primarily infected women. The probability of intrauterine transmission is higher when infection occurs during the second trimester of pregnancy than in the first trimester. The Toll-like receptors (TLRs) protein family plays a key role in both innate immune response to CMV infections and in normal pregnancy. Specific single nucleotide polymorphisms (SNPs) in TLRs can affect CMV infections and maternal-fetal interface expression. Therefore, TLR SNPs could be involved in intrauterine transmission determination. STUDY AIM: To establish a correlation between TLR2 (rs4696480, rs3804100, rs1898830), TLR3 (rs3775291) and TLR7(rs179008) SNPs with CMV intrauterine transmission during the first and second trimester. METHODS: SNPs of 83 pregnant women with primary CMV were analyzed by Real-Time PCR and PCR-RFLP assay and compared to intrauterine transmission state. RESULTS: Women bearing the GG genotype in the rs1898830 TLR2 SNP who were infected with CMV during the second trimester did not transmit the virus to the fetus. Likewise, in the co-dominant or recessive models of this SNP, a significant association was found between the genotypes and CMV intrauterine transmission. In all cohort women or in women infected during the first trimester, no such associations were found between the tested SNPs and intrauterine transmission of the virus. CONCLUSION: Women bearing the GG genotype in the rs1898830 SNP, who are infected with CMV during the second trimester of pregnancy, have a low likelihood of transmitting the virus to the fetus.

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BACKGROUND: The aim of this study is to analyze mortality in patients treated with bevacizumab for wet AMD. METHODS: We conducted a retrospective case-control study between patients who received intravitreal injections of bevacizumab as the sole treatment for exudative AMD between September 2008 and October 2014 (n = 5385) and age and gender matched controls (n = 10,756). All individuals included in the study were reviewed for sociodemographic data and comorbidities. Survival analysis was performed using adjusted Cox regression, using relevant adjusted variables. RESULTS: During follow-up (maximum: 73 months), 1063 (19.7%) individuals after bevacizumab died compared with 1298 (12.1%) in the control group (P < .001). After adjusted Cox survival regression, mortality differed significantly between the groups, Odds ratio = 1.69, (95% C.I. 1.54-1.84), P < .001. CONCLUSIONS: We found an increased long-term mortality in individuals with wet AMD treated with bevacizumab compared to a same age and gender group without wet AMD.

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BACKGROUND: Cigarette smoking is a widespread problem around the world. In Israel, the prevalence of smoking is 23%. Smokers who are Orthodox abstain from smoking during the Sabbath, i.e., from sundown Friday to sundown Saturday, due to a religious prohibition. The prevalence of smoking among Orthodox men is 13%. However, there are no data on patterns of smoking or on the addiction profiles in this population. OBJECTIVES: To explore the smoking patterns, motivation for smoking and nicotine addiction among Orthodox Jewish men, compared to non-Orthodox men, as well as the differences in the urge to smoke and withdrawal symptoms on Saturday versus weekdays in the Orthodox group. METHODS: The participants completed the Fagerstrom test for nicotine dependence, questionnaires on reasons for smoking and smoking patterns, as well as two brief questionnaires on the urge to smoke and withdrawal symptoms after overnight abstinence on a weekday and after the end of the Sabbath. RESULTS: Both groups were strongly addicted to nicotine and there were no differences in the reasons for smoking, withdrawal symptoms and nicotine craving after an overnight abstinence on weekdays. However, religious smokers had low levels of craving for nicotine and few withdrawal symptoms during Sabbath abstinence when compared to weekdays. CONCLUSIONS: Although we found no difference in the baseline characteristics with regard to nicotine addiction, smoking motivation, urge to smoke and withdrawal symptoms between religious and non-religious groups, the former are able to abstain from smoking during 25 hours of the Sabbath every week with significantly fewer withdrawal symptoms compared to week days.

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Research shows that the physician's personal attributes and social characteristics have a strong association with their end-of-life (EOL) decision making. Despite efforts to increase patient, family and surrogate input into EOL decision making, research shows the physician's input to be dominant. Our research finds that physician's social values, independent of religiosity, have a significant association with physician's tendency to withhold or withdraw life sustaining, EOL treatments. It is suggested that physicians employ personal social values in their EOL medical coping, because they have to cope with existential dilemmas posed by the mystery of death, and left unresolved by medical decision making mechanisms such as advanced directives and hospital ethics committees.

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BACKGROUND: To the best of our knowledge, there is no validated instrument for measuring knowledge of psychiatric aspects of alcohol use disorder (AUD) amongst medical students. Our aim was to develop an instrument for this purpose and to describe the instrument's psychometric properties. We also investigated whether the instrument could demonstrate a significant change in scores following an educational intervention consisting of a 60-minute PowerPoint lecture on AUD, associated handouts, and role-plays. METHODS: The Knowledge of Psychiatric Aspects of Alcohol Questionnaire (KPAAQ) was developed from the Kaplan and Saddock textbook synopsis chapter on alcohol related disorders. The questionnaire included 6 categories of clinically relevant material: metabolism of alcohol, short-term effects of alcohol, long-term effects of alcohol, AUD, alcohol withdrawal, and alcohol use in pregnancy. The KPAAQ was administered to 75 medical students in Years 4 and 5 from the Hebrew University in Jerusalem, Israel, during a relevant clinical rotation. Following the initial administration of the KPAAQ, the students attended a 60-minute lecture (in Hebrew) based on material from the University of Sydney's learning module on alcohol. The KPAAQ was readministered to the students immediately following the lecture. RESULTS: The KPAAQ demonstrated good reliability (Cronbach α =.92 for all questions) and validity r(209) =.674, P <.001. Knowledge of alcohol and alcoholism significantly increased after the educational intervention (F(2, 154) = 151.60, P <.001). Post hoc comparisons using the Scheffe test revealed a significant positive change in knowledge after students received the intervention (mean difference = 33, P <.001). CONCLUSIONS: These initial findings suggest that the KPAAQ is a reliable and valid instrument for assessing medical student knowledge of psychiatric aspects of AUD over 6 clinical categories.

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RATIONALE, AIMS AND OBJECTIVES: Off-hours medical care in hospitals is provided by residents, while attendings on call are available for assistance. This study evaluated the gap between residents' expectations and professional guidelines' requirements of attendings on call and what actually occurs during night shifts, while comparing surgical and medical specialties. METHODS: Two questionnaires based on professional guidelines were filled by residents. The first queried about residents' expectations of attendings on call, and the second asked about communication with the attendings during actual night shifts. RESULTS: While 91 (100%) of residents expected the attending on call to be available by phone during the shift, only 44 (48%) expected the attending to initiate contact, and only 17 (19%) expected the attending to visit the ward or emergency department (ED) without being requested to do so. In 127 shifts (84%), some form of communication occurred. Residents called their attendings during 105 shifts (70%). However, attendings initiated contact with residents at the beginning or during the shift in only 67 (44%) and 62 (41%) shifts, respectively, and initiated a visit to the ward/ED during the shift in only 41 cases (27%). Surgical attendings initiated contact in these three ways significantly more frequently than medical attendings [21 (28%) versus 46 (61%), 20 (26%) versus 42 (56%) and 4 (5%) versus 37 (50%), respectively; P < 0.001]. CONCLUSION: While communication during night shifts between residents and attendings occurs in most shifts, attendings initiate far less contact with residents than is required by the guidelines.

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BACKGROUND: We evaluated the clinical significance of urine cultures from patients with an indwelling urinary catheter (UC) from which 2 different pathogens were isolated. METHODS: Urine cultures from patients with a UC from which 2 different organisms were isolated were randomly divided into a control group (culture results were reported as usual) and a study group (culture results were reported as "mixed growth"). Endpoints included change in antibiotic treatment, use of broad spectrum agents, time for clinical improvement, and duration of admission. RESULTS: A total of 81 cultures met the inclusion criteria. Antibiotic treatment was changed after 72-96 h in 19 (48%) study patients and in 25 (61%) controls (NS). There was no difference regarding narrowing or broadening of antibiotic spectrum, and duration of hospitalization was similar. In each group, 15 (36%) patients died. CONCLUSION: Our findings imply that laboratory work-up of 2 pathogens from patients with an indwelling catheter may be discarded.

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