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The novel coronavirus SARS-CoV-2 and the associated infectious disease COVID-19 pose a significant challenge to healthcare systems worldwide. Patients with cancer have been identified as a high-risk population for severe infections, rendering prophylaxis and treatment strategies for these patients particularly important. Rapidly evolving clinical research, resulting in the recent advent of various vaccines and therapeutic agents against COVID-19, offers new options to improve care and protection of cancer patients. However, ongoing epidemiological changes and rise of new virus variants require repeated revisions and adaptations of prophylaxis and treatment strategies to meet these new challenges. Therefore, this guideline provides an update on evidence-based recommendations with regard to vaccination, pharmacological prophylaxis and treatment of COVID-19 in cancer patients in light of the currently dominant omicron variants. It was developed by an expert panel of the Infectious Diseases Working Party (AGIHO) of the German Society for Hematology and Medical Oncology (DGHO) based on a critical review of the most recent available data.

Purpose The association between CVD risk factors and mortality is well established, however, current tools for addressing subgroups have focused on the overall burden of disease. The identification of risky combinations of characteristics may lead to a better understanding of physiologic pathways that underlie morbidity and mortality in older adults. Methods Participants included 5067 older adults from the Cardiovascular Health Study, followed for up to 6 years. Using latent class analysis (LCA), we created CV damage phenotypes based on probabilities of abnormal brain infarctions, major echocardiogram abnormalities, N-terminal probrain natriuretic peptide, troponin T, interleukin-6, c reactive-protein, galectin-3, cystatin C. We assigned class descriptions based on the probability of having an abnormality among risk factors, such that a healthy phenotype would have low probabilities in all risk factors. Participants were assigned to phenotypes based on the maximum probability of membership. We used Cox-proportional hazards regression to evaluate the association between the categorical CV damage phenotype and all-cause and CVD-mortality. Results The analysis yielded 5 CV damage phenotypes consistent with the following descriptions: healthy (59%), cardio-renal (11%), cardiac (15%), multisystem morbidity (6%), and inflammatory (9%). All four phenotypes were statistically associated with a greater risk of all-cause mortality when compared with the healthy phenotype. The multisystem morbidity phenotype had the greatest risk of all-cause death (HR: 4.02; 95% CI: 3.44, 4.70), and CVD-mortality (HR: 4.90, 95% CI: 3.95, 6.06). Conclusions Five CV damage phenotypes emerged from CVD risk factor measures. CV damage across multiple systems confers a greater mortality risk compared to damage in any single domain.

Since its first detection in China in late 2019 the novel coronavirus SARS-CoV-2 and the associated infectious disease COVID-19 continue to have a major impact on global health care and clinical practice. Cancer patients, in particular those with haematological malignancies, seem to be at an increased risk for a severe course of infection. Deliberations to avoid or defer potentially immunosuppressive therapies in these patients need to be balanced against the overarching goal of providing optimal antineoplastic treatment. This poses a unique challenge to treating physicians. This guideline provides evidence-based recommendations regarding prevention, diagnostics and treatment of SARS-CoV-2 infection and COVID-19 as well as strategies towards safe antineoplastic care during the COVID-19 pandemic. It was prepared by the Infectious Diseases Working Party (AGIHO) of the German Society for Haematology and Medical Oncology (DGHO) by critically reviewing the currently available data on SARS-CoV-2 and COVID-19 in cancer patients applying evidence-based medicine criteria., Highlights • Cancer patients are vulnerable to SARS-CoV-2 infection and severe COVID-19. • Comprehensive management strategies are required in care for cancer patients. • Evidence-based recommendations help clinicians make informed treatment decisions. • Providing state-of-the-art cancer care is possible during COVID-19 pandemic.

Purpose Although social support has been shown to be associated with survival among persons with cardiovascular disease, little research has focused on whether social support, measured before the onset of heart failure, can enhance survival after diagnosis. The objective of this study was to assess the association between prediagnosis social support and postdiagnosis survival among older adults with heart failure. Methods We obtained the data from the Cardiovascular Health Study, which included noninstitutionalized adults aged 65 years or older from four sites in the United States with primary enrollment in 1989–1990. We used two measures of social support, the Lubben Social Network Scale and the Interpersonal Support Evaluation List. The analytic data set included 529 participants with a social support measure within two years before diagnosis of heart failure. Results After adjustment for demographic covariates, cardiovascular risk factors, and general health status, mortality rates were lower among participants in the highest tertile of social network scores (HR 0.74, 95% CI: 0.59, 0.93) and the middle tertile (HR 0.73 [0.58, 0.90]), compared with the lowest tertile. Results with interpersonal support were null. Conclusions These findings suggest that prediagnosis structural social support may modestly buffer heart failure patients from mortality.

Human 15-lipoxygenase-1 (15-LOX-1) is a mammalian lipoxygenase which plays an important regulatory role in several CNS and inflammatory lung diseases. To further explore the role of this enzyme in drug discovery, novel potent inhibitors with favorable physicochemical properties are required. In order to identify such new inhibitors, we established a combinatorial screening method based on acylhydrazone chemistry. This represents a novel application of combinatorial chemistry focusing on the improvement of physicochemical properties, rather than on potency. This strategy allowed us to efficiently screen 44 reaction mixtures of different hydrazides and our previously reported indole aldehyde core structure, without the need for individual synthesis of all possible combinations of building blocks. Our approach afforded three new inhibitors with IC50 values in the nanomolar range and improved lipophilic ligand efficiency.

The clinical and epidemiologic management of the SARS-CoV-2 pandemic is critically dependent on molecular assays with short turn-around time. We validated the novel Xpert Xpress SARS-CoV-2 assay using a commercial nucleic acid testing (Roche Cobas 6800). We found an excellent concordance over a range of SARS-CoV-2 loads and across established human coronaviruses.

Objectives Chronic hepatitis C virus (HCV) infection affects the immune system. Whether elimination of HCV with direct-acting antivirals (DAA) restores immunity is unclear. We used mass cytometry to get a broad and in-depth assessment of blood cell populations of patients with chronic HCV before and after DAA therapy. Methods Before and 12 weeks after sustained virological response (SVR12) to DAA therapy, 22 cell populations were analysed by mass cytometry in blood collected from ten healthy control individuals and 20 HCV-infected patients with (ten patients) or without (ten patients) human immunodeficiency virus (HIV) infection. Results HCV infection altered the frequency of 14/22 (64%) blood cell populations. At baseline, the frequencies (median, interquartile range (IQR); control, HCV, HCV/HIV) of intermediate monocytes (1.2, IQR 0.47–1.46; 1.76, IQR 0.83–2.66; 0.78, IQR 0.28–1.77), non-classical monocytes (1.11, IQR 0.49–1.26; 0.9, IQR 0.18–0.99; 0.54, IQR 0.28–1.77), conventional dendritic cells type 2 (0.55, IQR 0.35–0.59; 0.31, IQR 0.16–0.38; 0.19, IQR 0.11–0.36) and CD56dim natural killer cells (8.08, IQR 5.34–9.79; 4.72, IQR 2.59–6.05) 3.61, IQR 2.98–5.07) were reduced by 35% to 65%, particularly in HCV/HIV co-infected patients. In contrast, activated double-negative T cells (0.07, IQR 0.06–0.10; 0.10, IQR 0.09–0.19; 0.19, IQR 0.12–0.25), activated CD4 T cells (0.28, IQR 0.21–0.36; 0.56, IQR 0.33–0.77; 0.40, IQR 0.22–0.53) and activated CD8 T cells (0.23, IQR 0.14–0.42; 0.74, IQR 0.30–1.65; 0.80, IQR 0.58–1.16) were increased 1.4 to 3.5 times. Upon stimulation with Toll-like receptor ligands, the expression of cytokines was up-regulated in 7/9 (78%) and 17/19 (89%) of the conditions in HCV- and HCV/HIV-infected patients, respectively. Most alterations persisted at SVR12. Conclusions Chronic HCV and HCV/HIV infections induce profound and durable perturbations of innate and adaptive immune homeostasis.

This study aimed at assessing the specificity of the Elecsys® HIV combi PT in comparison to the ARCHITECT® HIV Ag/Ab Combo. With both of these assays, 3997 unselected sera from patients of a tertiary health care centre in Basel, Switzerland, were screened for HIV. Reactive sera were reanalysed on the VIDAS® HIV Duo Ultra to identify false-reactive specimens prior to confirmation by quantitative PCR and line immunoassay. The Elecsys® compared to the ARCHITECT® shows a similar specificity (99.7% versus 99.8%) but a slightly lower positive predictive value (71.8% versus 80%). Samples tested with a cut-off index (COI) between 0.91 and 4.85 (cut-off

BK polyomavirus (BKPyV) causes premature kidney transplant (KT) failure in 1-15% of patients. Because antivirals are lacking, most programs screen for BKPyV-viremia and, if positive, reduce immunosuppression. To evaluate the relationship of viremia and BKPyV-specific immunity, we examined prospectively cryopreserved plasma and peripheral blood mononuclear cells at the time of transplantation (T0) and at 6 mo (T6) and 12 mo (T12) after transplant from 28 viremic KT patients and 68 nonviremic controls matched for the transplantation period. BKPyV IgG seroprevalence was comparable between cases (89.3%) and controls (91.2%; p = 0.8635), but cases had lower antibody levels (p = 0.022) at T0. Antibody levels increased at T6 and T12 but were not correlated with viremia clearance. BKPyV-specific T cell responses to pools of overlapping 15mers (15mer peptide pool [15mP]) or immunodominant CD8 9mers (9mer peptide pool [9mP]) from the early viral gene region were not different between cases and controls at T0; however, clearance of viremia was associated with stronger 9mP responses at T6 (p = 0.042) and T12 (p = 0.048), whereas 15mP responses were not informative (T6 p = 0.359; T12 p = 0.856). BKPyV-specific T cells could be expanded in vitro from all patients after transplant, permitting identification of 78 immunodominant 9mer epitopes including 50 new ones across different HLA class I. Thus, 9mP-responses may be a novel marker of reconstituting CD8 T cell function that warrants further study as a complement of plasma BKPyV loads for guiding immunosuppression reduction.

The epidemiology of respiratory viruses (RVs) in lung transplant recipients (LTRs) and the relationship of RVs to lung function, acute rejection (AR) and opportunistic infections in these patients are not well known. We performed a prospective cohort study (2009–2014) by collecting nasopharyngeal swabs (NPSs) from asymptomatic LTRs during seasonal changes and from LTRs with upper respiratory tract infectious disease (URTID), lower respiratory tract infectious disease (LRTID) and AR. NPSs were analyzed by multiplex polymerase chain reaction. Overall, 1094 NPSs were collected from 98 patients with a 23.6% positivity rate and mean follow‐up of 3.4 years (interquartile range 2.5–4.0 years). Approximately half of URTIDs (47 of 97, 48.5%) and tracheobronchitis cases (22 of 56, 39.3%) were caused by picornavirus, whereas pneumonia was caused mainly by paramyxovirus (four of nine, 44.4%) and influenza (two of nine, 22.2%). In LTRs with LRTID, lung function changed significantly at 1 mo (p = 0.03) and 3 mo (p = 0.04). In a nested case–control analysis, AR was associated with RVs (hazard ratio [HR] 6.54), Pseudomonas aeruginosa was associated with LRTID (HR 8.54), and cytomegalovirus (CMV) replication or disease was associated with URTID (HR 2.53) in the previous 3 mo. There was no association between RVs and Aspergillus spp. colonization or infection (HR 0.71). In conclusion, we documented a high incidence of RV infections in LTRs. LRTID produced significant lung function abnormalities. Associations were observed between AR and RVs, between P. aeruginosa colonization or infection and LRTID, and between CMV replication or disease and URTID., A large prospective study of the epidemiology of respiratory viruses in lung transplant recipients using molecular assays demonstrates a very high incidence of respiratory viral infection and an association between respiratory virus infectious diseases, immediate allograft dysfunction, and the development of acute rejection and opportunistic infection.

Cartridge-based multiplex panels covering numerous pathogens offer an advantage of minimal hands-on-time and short time to result to commercial RT-PCR assays. In this study, we evaluated the performance of the ePlex respiratory pathogen panel (RPP) compared to the Fast Track Diagnostics Respiratory pathogens 21 multiplex RT-PCR assay (FTD21) using 400 clinical respiratory samples. Discrepant results were further analysed by a reference nucleic acid amplification testing (NAT) and a composite reference approach was used for final interpretation. Discordant results were observed in 56 targets corresponding to 54 samples. Sensitivities and specificities were 85.5% and 99.9% for the ePlex RPP and 95.8% and 99.7% for the FTD21 system, respectively. Altogether, the ePlex RPP is a valuable tool for the rapid detection of a number of different respiratory viruses with the exception of the coronavirus family (low sensitivity ranging from 50-80%) and samples with a low pathogen load (Ct values >33).

Transplant patients are at increased risk of viral complications due to impaired control of viral replication, resulting from HLA mismatching between graft and host and the immunosuppression needed to avert alloimmune reactions. In the past decade, quantitative viral load measurements have become widely available to identify patients at risk and to inform treatment decisions with respect to immunosuppressive drugs and antiviral therapies. Because viral loads are viewed as the result of viral replication and virus-specific immune control, virus-specific T cell monitoring has been explored to optimize management of adenovirus, BK polyomavirus and cytomegalovirus ("ABC") in transplant patients. Although most studies are descriptive using different technologies, the overall results show that the quantity and quality of virus-specific T cells inversely correlate with viral replication, whereby strong cellular immune responses are associated with containment of viral replication. The key obstacles to the introduction of assays for virus-specific T cells into clinical practice is the definition of reliable cutoffs for clinical decision making, the poor negative predictive value of some assays, and the absence of interventional trials justifying changes of antiviral treatment or immunosuppression. More clinical research is needed using optimized assays and targets before standardization and commutability can be envisaged as achieved for viral load testing.

BK polyomavirus (BKPyV) replication causes nephropathy and premature kidney transplant failure. Insufficient BKPyV‐specific T cell control is regarded as a key mechanism, but direct effects of immunosuppressive drugs on BKPyV replication might play an additional role. We compared the effects of mammalian target of rapamycin (mTOR)‐ and calcineurin‐inhibitors on BKPyV replication in primary human renal tubular epithelial cells. Sirolimus impaired BKPyV replication with a 90% inhibitory concentration of 4 ng/mL by interfering with mTOR–SP6‐kinase activation. Sirolimus inhibition was rapid and effective up to 24 h postinfection during viral early gene expression, but not thereafter, during viral late gene expression. The mTORC‐1 kinase inhibitor torin‐1 showed a similar inhibition profile, supporting the notion that early steps of BKPyV replication depend on mTOR activity. Cyclosporine A also inhibited BKPyV replication, while tacrolimus activated BKPyV replication and reversed sirolimus inhibition. FK binding protein 12kda (FKBP‐12) siRNA knockdown abrogated sirolimus inhibition and increased BKPyV replication similar to adding tacrolimus. Thus, sirolimus and tacrolimus exert opposite effects on BKPyV replication in renal tubular epithelial cells by a mechanism involving FKBP‐12 as common target. Immunosuppressive drugs may therefore contribute directly to the risk of BKPyV replication and nephropathy besides suppressing T cell functions. The data provide rationales for clinical trials aiming at reducing the risk of BKPyV replication and disease in kidney transplantation., Comparing direct effects of immunosuppressive drugs on BK polyomavirus replication in primary human renal proximal tubular epithelial cells, this study demonstrates that the virus is inhibited by sirolimus but activated by tacrolimus through a mechanism involving competitive binding to the small host cell protein FKBP‐12.

A 15-year-old boy with a posterior urethral valve received a deceased donor kidney transplant (KT) in March 2011. Basiliximab induction followed by tacrolimus-based triple medication was used as immunosuppression. Eleven months after KT, the graft function deteriorated and the biopsy demonstrated interstitial nephritis suggestive of acute rejection. BK polyomavirus (BKPyV) surveillance in urine and plasma was negative. The patient received methylprednisolone pulses and anti-thymocyte globulin. Immunohistochemistry was positive for simian virus 40 (SV40) large T-antigen (LTag) in the biopsies, and quantitative polymerase chain reaction for JC polyomavirus (JCPyV) indicated high viral loads in urine and borderline levels in plasma. Immunosuppression was reduced and follow-up biopsies showed tubular atrophy and interstitial fibrosis. Two years after KT, antibody-mediated rejection resulted in graft loss and return to hemodialysis. Retrospective serologic work-up indicated a primary JCPyV infection with seroconversion first for IgM, followed by IgG, but no indication of BKPyV infection. In the SV40 LTag positive biopsies, JCPyV deoxyribonucleic acid (DNA) with archetype noncoding control region was detected, while BKPyV DNA was undetectable. To the best of our knowledge, this is the first reported case of primary JCPyV infection as the cause of PyV-associated nephropathy in KT.

BK polyomavirus (BKPyV) infection is widespread and typically asymptomatic during childhood, but may cause nephropathy in kidney transplant recipients. However, there is only limited knowledge on BKPyV-specific immunity in children and adults, and its role in BKPyV-replication and disease posttransplant. We therefore characterized BKPyV-specific immunity from 122 immunocompetent individuals (1-84 years), 38 adult kidney recipients with (n = 14) and without BKPyV-associated complications (n = 24), and 25 hemodialysis (HD) patients. Blood samples were stimulated with overlapping peptides of BKPyV large-T antigen and VP1 followed by flow-cytometric analysis of activated CD4 T cells expressing interferon-γ, IL-2 and tumor necrosis factor-α. Antibody-levels were determined using enzyme-linked immunosorbent assay. Both BKPyV-IgG levels and BKPyV-specific CD4 T cell frequencies were age-dependent (p = 0.0059) with maximum levels between 20 and 30 years (0.042%, interquartile range 0.05%). Transplant recipients showed a significantly higher BKPyV-specific T cell prevalence (57.9%) compared to age-matched controls (21.7%) or HD patients (28%, p = 0.017). Clinically relevant BKPyV-replication was associated with elevated frequencies of BKPyV-specific T cells (p = 0.0002), but decreased percentage of cells expressing multiple cytokines (p = 0.009). In conclusion, BKPyV-specific cellular immunity reflects phases of active BKPyV-replication either after primary infection in childhood or during reactivation after transplantation. Combined analysis of BKPyV-specific T cell functionality and viral loads may improve individual risk assessment.

The non-mevalonate pathway constitutes a source of novel drug targets. This biosynthetic route is essential for pathogens but is absent in humans. Our systematic evaluation of the druggability of all enzymes provides a convenient way of selecting targets that should be most easily inhibited by small-molecule drugs. We found that not every target is equally druggable and we identified novel, druggable, potentially allosteric sites. These results should accelerate the development of anti-infective drugs with a novel mode of action, which are needed ever more urgently in light of the rapid emergence of drug-resistant strains.

The human BK polyomavirus (BKV) is the major cause of polyomavirus-associated nephropathy (PyVAN) putting 1-15% of kidney transplant patients at risk of premature allograft failure, but is less common in other solid organ transplants. Because effective antiviral therapies are lacking, screening kidney transplant patients for BKV replication in urine and blood has become the key recommendation to guide the reduction of immunosuppression in patients with BKV viremia. This intervention allows for expanding BKV-specific cellular immune responses, curtailing of BKV replication in the graft, and clearance of BKV viremia in 70-90% patients. Postintervention rejection episodes occur in 8-12%, most of which are corticosteroid responsive. Late diagnosis is faced with irreversible functional decline, poor treatment response, and graft loss. Adjunct therapies such as cidofovir, leflunomide and intravenous immunoglobulins have been used, but the benefit is not documented in trials. Retransplantation after PyVAN is largely successful, but requires close monitoring for recurrent BKV viremia.

Natalizumab, a highly specific α4-integrin antagonist, is approved for treatment of patients with active relapsing-remitting multiple sclerosis (RRMS). It is generally recommended for individuals who have not responded to a currently available first-line disease-modifying therapy or who have very active disease. The expected benefits of natalizumab treatment have to be weighed against risks, especially the rare but serious adverse event of progressive multifocal leukoencephalopathy. In this Review, we revisit and update previous recommendations on natalizumab for treatment of patients with RRMS, based on additional long-term follow-up of clinical studies and post-marketing observations, including appropriate patient selection and management recommendations.

J. Gavald a, J. M. Aguado, O. Manuel, P. Grossi, H. H. Hirsch on behalf of the ESCMID Study Group of Infection in Compromised Hosts (ESGICH) 1) Infectious Diseases Department, Hospital Vall d’Hebron, Vall d’Hebron Research Institute VHIR, Barcelona, 2) Hospital Universitario 12 de Octubre, Madrid, Spain, 3) Infectious Diseases Service and Transplantation Center, University Hospital and University of Lausanne, Lausanne, Switzerland, 4) Infectious Diseases Section, Department of Surgical and Morphological Sciences, University of Insubria, Varese, Italy and 5) Transplantation & Clinical Virology, Department Biomedicine (Haus Petersplatz), University of Basel, Basel, Switzerland E-mail: joan.gavalda@vhir.org Article published online: 8 May 2014 Clin Microbiol Infect 2014; 20 (Suppl. 7): 1–3

Polyomavirus-associated nephropathy (PyVAN) is rare in nonrenal solid organ transplantation and only limited information is available from single cases. We describe a 67-year-old female presenting with hypertension and progressive kidney failure due to PyVAN 60 months after lung transplantation. Plasma BK virus (BKV) loads were 4.85 log¹⁰ copies/mL at diagnosis and cleared slowly over 14 months after switching from tacrolimus, mycophenolate and prednisone to low-dose tacrolimus, sirolimus and leflunomide, the latter being discontinued for anemia and diarrhea. BKV- and JC virus-specific immunoglobulins were detectable prior to transplantation. Only BKV-specific IgG and IgM increased during follow-up. BKV-specific T cells were detectable in blood following in vitro expansion, but cleared with reincreased sirolimus, yet BKV viremia remained undetectable. We identified eight other cases of PyVAN in nonrenal solid organ transplantation including lung (n = 1), heart (n = 6) and pancreas (n = 1). Overall, diagnosis was later than commonly seen in kidney transplants (median 18 months, interquartile range 10-29). Seven patients were male, five received triple immunosuppression consisting of tacrolimus, mycophenolate, prednisone. Immunosuppression was reduced in four cases and cidofovir and/or leflunomide administered in five and two cases, respectively. Renal function deteriorated in five requiring hemodialysis in four. We discuss mTOR inhibitors versus cidofovir and leflunomide as potential PyVAN rescue therapy.

Cytomegalovirus (CMV) infection and graft-versus-host disease (GVHD) are important complications after allogeneic hematopoietic stem cell transplantation (HSCT) with a clear link. Multiple studies show that GVHD and its treatment put patients at risk for CMV replication. Data on CMV replication as a cause of GVHD, in contrast, are controversial. We analyzed the reciprocal association of CMV replication with acute GVHD (aGVHD) in 515 patients treated with allogeneic HSCT between 1993 and 2008. Cumulative incidences at day 100 were 17% for CMV replication, 68% for aGVHD grade I-IV, and 48% for GVHD grade II-IV. Multivariate time-dependent analyses revealed that the presence of GVHD increased the risk of CMV replication in a dose-dependent manner: hazard ratio (HR) for CMV replication for patients with aGVHD grade I was 1.35 (95% confidence interval [CI] 0.82-2.21); HR for patients with aGVHD grade II-IV was 1.61 (95% CI 1.11-2.36, P-value for trend = .01). During phases of CMV replication, patients were at increased risk of developing aGVHD (HR 2.18, 95% CI 1.30-3.65, P < .01). These data confirm that GVHD and its therapy can induce CMV replication. They further demonstrate the reciprocal novel finding that patients are at significantly increased risk of developing aGVHD during CMV replication.

High-level replication of polyomavirus BK (BKV) in kidney transplant recipients is associated with the emergence of BKV variants with rearranged (rr) non-coding control region (NCCR) increasing viral early gene expression and cytopathology. Cloning and sequencing revealed the presence of a BKV quasispecies which included non-functional variants when assayed in a recombinant virus assay. Here we report that the rr-NCCR of BKV variants RH-3 and RH-12, both bearing a NCCR deletion including the 5′ end of the agnoprotein coding sequence, mediated early and late viral reporter gene expression in kidney cells. However, in a recombinant virus they failed to produce infectious progeny despite large T-antigen and VP1 expression and the formation of nuclear virus-like particles. Infectious progeny was generated when the agnogene was reconstructed in cis or agnoprotein provided in trans from a co-existing BKV rr-NCCR variant. We conclude that complementation can rescue non-functional BKV variants in vitro and possibly in vivo.

The human polyomavirus BK (BKV) is linked to two ma-jor complications in transplant recipients, polyomavirus-associated nephropathy (PyVAN) (1–4) and polyomavirus-associated hemorrhagic cystitis (PyVHC) (5,6). PyVAN andPyVHC have been encountered in a variety of immunod-eficient patients (7,8), but most cases of PyVAN arise inkidney transplant patients at rates of 1–10%, while PyVHCpreferentially affects allogeneic hematopoietic stem celltransplant patients at rates of 5–15% (7,9). BKV hasbeen less frequently associated with other pathologies,such as ureteric stenosis, pneumonitis, hemophagocyticsyndrome, encephalitis, retinitis, multiorgan failure andpolyomavirus-associated multifocal leukoencephalopathy(PyVML) (10–12), a complication of the central nervoussystem mostly caused by the closely related polyomavirusJC (JCV) (13). The objective of this section is to updateprevious recommendations (14) regarding diagnosis andmanagement of BKV replication and PyVAN in solid organtransplantation (SOT) using the grading proposed by Grosset al. (15).BKV belongs to the family Polyomaviridaetogether withfive other polyomaviruses detected in human specimens,that is JCV, KI virus, WU virus, Merkel cell carcinoma virusand Simian virus 40 (16,17). The virions are nonenvelopedparticles of 42 nm diameter and fairly resistant to envi-ronmental inactivation (18). The circular double-strandedDNA genome of

Fast BK virus (BKV) replication in renal tubular epithelial cells drives polyomavirus-BK-associated nephropathy (PVAN) to premature kidney transplant (KT) failure. BKV also replicates in urothelial cells, but remains asymptomatic in two-thirds of affected KT patients. Comparing 518 day-matched plasma-urine samples from 223 KT patients, BKV loads were approximately 3000-fold higher in urine than in plasma (p0.000001). Molecular and quantitative parameters indicated that95% of urine BKV loads resulted from urothelial replication and5% from tubular epithelial replication. Fast BKV replication dynamics in plasma and urine with half-lives of12 h accounted for daily urothelial and tubular epithelial cell loss of 4 x 10(7) and 6 x 10(7), respectively. BKV dynamics in both sites were only partly linked, with full and partial discordance in 36% and 32%, respectively. Viral expansion was best explained by models where BKV replication started in the kidney followed by urothelial amplification and tubular epithelial cell cross-feeding reaching a dynamic equilibrium after approximately 10 weeks. Curtailing intrarenal replication by 50% was ineffective and80% was required for clearing viremia within 7 weeks, but viruria persisted for14 weeks. Reductions90% cleared viremia and viruria by 3 and 10 weeks, respectively. The model was clinically validated in prospectively monitored KT patients supporting80% curtailing for optimal interventions.

New classes of agents have sequentially increased the specificity of post-transplant immunosuppression, leading to profound improvements in success rates after renal transplantation. The next era will focus on increased long-term survival rates through optimal use of existing agents and the rational development of drugs based on prior identification of specific immunologic targets. Conventionally, long-term outcomes after kidney transplantation have been assessed by surrogate markers, notably acute rejection, but graft-threatening complications such as development of new-onset diabetes mellitus and polyomavirus nephropathy must be addressed if long-term survival rates are to be improved. Mycophenolic acid therapy must be administered optimally to ensure that adequate exposure is achieved in the immediate post-transplant period and, subsequently, by avoiding underdosing due to gastrointestinal events. Chronic allograft nephropathy remains a major concern, and protocol-led, reliable monitoring strategies are essential to enable early intervention, for example, through introduction of proliferation signal inhibitor therapy with concomitant calcineurin inhibitor reduction or withdrawal. The range of immunosuppressive regimens now available and in development, together with improved assessment of patients' risk profiles for immunologic events and comorbid disease, offers the opportunity for further individualization of immunosuppression after renal transplantation.

The human polyomavirus BK (BKV) causes nephropathy and hemorrhagic cystitis in kidney and bone marrow transplant patients, respectively. The anti-viral cidofovir (CDV) has been used in small case series but the effects on BKV replication are unclear, since polyomaviruses do not encode viral DNA polymerases. We investigated the effects of CDV on BKV(Dunlop) replication in primary human renal proximal tubule epithelial cells (RPTECs). CDV inhibited the generation of viral progeny in a dose-dependent manner yielding a 90% reduction at 40 microg/mL. Early steps such as receptor binding and entry seemed unaffected. Initial large T-antigen transcription and expression were also unaffected, but subsequent intra-cellular BKV DNA replication was reduced by90%. Late viral mRNA and corresponding protein levels were also 90% reduced. In uninfected RPTECs, CDV 40 microg/mL reduced cellular DNA replication and metabolic activity by 7% and 11% in BrdU and WST-1 assays, respectively. BKV infection increased DNA replication to 142% and metabolic activity to 116%, respectively, which were reduced by CDV 40 microg/mL to levels of uninfected untreated RPTECs. Our results show that CDV inhibits BKV DNA replication downstream of large T-antigen expression and involves significant host cell toxicity. This should be considered in current treatment and drug development.

Purpose Frailty, which has been conceptualized as a state of decreased physiologic reserve contributing to functional decline, has a prevalence among older African Americans that is twice that in older whites. This study assesses the independent contribution of race to frailty. Methods We evaluated 786 African-American and 4491 white participants of the Cardiovascular Health Study (CHS). Frailty is defined as meeting three or more of five criteria derived from CHS measures: lowest quintile for grip strength, self-reported exhaustion, unintentional weight loss of 10 lbs or greater in 1 year, slowest quintile for gait speed, and lowest quintile for physical activity. Controlling for age, sex, comorbidity, socioeconomic factors, and race, multinomial logistic regression estimated the odds ratio (OR) of prefrail (one or two criteria) to not frail and frail to not frail. Results Among African Americans, 8.7% of men and 15.0% of women were frail compared with 4.6% and 6.8% of white men and women, respectively. In adjusted models, nonobese African Americans had a fourfold greater odds of frailty compared with whites. The increased OR of frailty associated with African-American race was less pronounced among those who were obese or disabled. Conclusion African-American race is associated independently with frailty.

The Isidis Plantita region on Mars is a landing site favored by engineers for its inherent safety. The landing site of Beagle 2 was in this area, as was one of the prime backup landing sites for the Mars Exploration Rover Spirit. Therefore, it seems likely that for future lander missions to Mars this area will be on the shortlist. Within its first orbits Mars Express has passed over Isidis Planitia and the Beagle 2 landing site. From these passes we have derived first estimates of the surface temperature for a region covering the planned landing site of Beagle 2 using in the long wavelength channel (5–45 μm) of the Planetary Fourier Spectrometer (PFS) next term on Mars Express. We have compared these temperatures with a map of surface temperatures for this area derived from a modeling with the Berlin Mars near Surface Thermal model (Helbert, J., Benkhoff, J. A new approach to assessing the burial depth of ground ice deposits and its application to proposed MER landing sites in Isidis Planitia. Journal of Geophysical Research 108(E12), ROV 28-1, 2003).

The Planetary Fourier Spectrometer (PFS) experiment on board the Mars Express mission has two channels coveringthe 1.2–5mm (SWC) and the 5–50mm (LWC). The LongWavelength Channel (LWC) measures the thermal emission spectrum of Mars between 200 and 2000 cm � 1 with a spectral resolution of 1.4 cm � 1 , in absence of apodisation. We present here the calibration of this channel and its performance. The instrument calibration has been performed on ground, before launch, in space during Near Earth Verification (NEV) measurements, and at Mars. Special attention has been given to the problem of microvibrations on board the spacecraft. In order to obtain correct results, the source-instrument–detector interaction is studied very accurately. The instrument variations duringa pericentre pass impose a complex procedure for the LW channel calibration, but fortunately the procedure adopted seems to work well. Samples of the calibrated data are given (as single spectrum and as an average over a few spectra) to show the performance of the experiment and its scientific potentialities. r 2005 Elsevier Ltd. All rights reserved.

We report the case of a 47-year-old man who developed progressive multifocal leukoencephalopathy (PML) after receiving immuno-suppressive therapy for renal transplantation. The patient presented with a focal seizure and cognitive changes 5 months post-transplantation. He was found to have enhancing lesions in the parietal lobe and typical findings of PML in a brain biopsy. Immunosuppression was discontinued and the neurological symptoms gradually resolved over a period of 4 weeks. The patient is free of any neurological symptoms 36 months after the diagnosis of PML and imaging studies demonstrate resolution of the PML lesions. The patient returned to hemodialysis 3 months after immunosuppression was discontinued. We also present a review of the literature on PML in renal transplant recipients.

Evaluation of urine cytology (UC) for decoy cells and quantitative determinations of viruria (urine viral load [UPCR])and viremia (viral load in blood [VLB]) have been proposed as surrogate markers of polyomavirus allograft nephropathy (PVAN). In this study, we present the experience with the concurrent evaluation of UC, UPCR, and VLB in 349 patients (940 sets of samples). Results were correlated with each other and with a previous, concurrent, or subsequent biopsy diagnosis of PVAN. Patients were followed up for a mean of 27 months posttransplantation. We conclude that both UC and UPCR are useful for screening of renal transplant recipients. Simultaneous performance of both UC and UPCR does not add useful clinical information. In patients with positive UC, performance of UPCR, however, can allow for the distinction between BK and JC polyoma viruses. Quantitative measurement of viremia is not indicated in patients lacking viruria because no patients with PVAN present with this combination of findings. In patients with viruria, a positive viremia strongly correlates with PVAN. Rationale selection of screening protocols based on the current knowledge of the infection and tailored to the available laboratory capabilities in each transplantation center can optimize the use of resources.

Polyomavirus hominis 1, better known as BK virus (BKV), infects up to 90% of the general population. However, significant clinical manifestations are rare and limited to individuals with impaired immune functions. BKV has been associated with diverse entities such as haemorrhagic cystitis, ureteric stenosis, vasculopathy, pneumonitis, encephalitis, retinitis, and even multi-organ failure. In addition, BKV has been implicated in autoimmune disease and possibly cancer. Due to high prevalence and frequent reactivation, the role of BKV in some of these pathologies has been difficult to define. Development of BKV diseases is likely to require complementing determinants in the host, the target organ, and possibly the virus, that are subject to modulators such as immunosuppression. These complex aspects are highlighted in polyomavirus-associated nephropathy (PAN), an emerging disease in renal allograft recipients that may jeopardise the progress in renal transplantation accomplished in the past 10 years. Intervention is difficult due to the lack of specific antivirals and relies mostly on improving immune control. Diagnostic strategies using urine cytology and BKV load measurements in plasma have led to earlier diagnosis of PAN, which increased the success rate of intervention. Case series suggest that cidofovir might be effective, especially when combined with reduced immunosuppression.

Depression is associated with increased cardiovascular disease, but the underlying mechanisms are not well understood. This study examines associations of depressive symptoms with inflammation and coagulation factors in persons aged > 65 years. Blood samples were obtained from 4,268 subjects free of cardiovascular disease (age 72.4 +/- 5.5 years, 2,623 women). Inflammation markers were C-reactive protein (CRP), white blood cell (WBC) count, total platelet count, and albumin; coagulation factors included factors VIIc and VIIIc and fibrinogen. Depression was assessed with the Center for Epidemiologic Studies Depression scale, and states of energy depletion with a validated exhaustion index. Statistical adjustments were made for risk factors (age, sex, race, systolic blood pressure, smoking status, diabetes mellitus) and physical measures of frailty (isometric handgrip, timed 15-feet walk test, activity level). Depression was associated with elevated CRP (3.31 +/- 0.10 vs 3.51 +/- 0.21 mg/L), WBC (6.14 +/- 0.03 vs 6.43 +/- 0.11 10(6)/L), fibrinogen (319 +/- 1 vs 326 +/- 3 mg/dl), and factor VIIc (124.6 +/- 0.6% vs 127.2 +/- 1.3%; all p 65 years.

Objective: To document objectively, improvements in sperm motion parameters in subfertile men after varicocele ligation with the use of computer-aided sperm analysis. Design: Retrospective chart review. Setting: An academic clinical environment. Patient(s): Thirty-four men with varicocele as the primary cause of infertility who underwent a physical examination, hormonal profile, and Doppler ultrasound evaluation. Intervention(s): Computer-aided sperm analysis was performed before and after either subinguinal or laparoscopic varicocele ligation. Main Outcome Measure(s): Patients were followed up for 3–18 months after operation, and average computer-aided sperm analysis values were obtained before and after operation. Computer-aided sperm analysis values were analyzed by paired Student's t -test, with special reference to motility and sperm motion parameters. Result(s): After varicocele ligation, patients demonstrated increases in mean sperm density and in the overall distribution of sperm with rapid velocity, although the increases were not statistically significant. Mean measures of straightness, linearity, and track speed also were increased after operation, but only progressive sperm velocity was increased to a statistically significant level. Conclusion(s): Because progressive velocity has been a primary computer-aided sperm analysis parameter predictive of male fertility and the success of assisted reproductive techniques, we conclude that varicocele ligation results in improvements in semen parameters, especially the key parameter of progressive sperm velocity.

Objective: To evaluate nested PCR for Toxoplasma gondii (TOX), JC virus (JCV) and Epstein-Barr virus (EBV) for diagnosis of toxoplasmic encephalitis (TE), progressive multifocal leukencephalopathy (PML) and primary central nervous system lymphoma (PCL). Methods: A prospective study encompassed 26 HIV-I-infected individuals presenting with focal neurologic signs and symptoms. Nested PCR was performed on both supernatants and pellets of centrifuged cerebrospinal fluid (CSF), on plasma and on white blood cells (WBCs). For a retrospective study, stored CSF supernatants were available from an additional 27 HIV-1-infected patients with TE, PML, and PCL. Results: TE, PML or PCL was diagnosed in 13 of 26 patients in the prospective group. Plasma and WBC analysis by PCR was not informative except in one case of TE. TOX and JCV were detected by PCR in the CSF pellets of four of five patients with TE, and of four of five patients with PML, respectively, but in no other cases. EBV was detected not only in three of three cases of PCL, but also in six patients suffering from other conditions. PCR on the CSF supernatants was less sensitive for all three etiologies. These results correlated with those of the retrospective PCR analysis, for which only stored CSF supernatants were available, revealing sensitivities of 33%, 50% and 66% for TE, PML and PCL, respectively, but specificities of 100%. Conclusions: In the clinical routine, TOX and JCV PCR on centrifuged CSF pellets can be recommended to obtain an early diagnosis of TE and PML. Under these conditions, EBV PCR helps to exclude PCL as a cause of FBLs, as it is highly sensitive, but not specific, for PCI- in HIV-I-infected individuals.