Diagnostic and therapeutic challenges of treating opportunistic fungal cellulitis: a case series.

BACKGROUND: Cellulitis is an infection most commonly caused by bacteria and successfully treated with antibiotics. However, certain patient populations, especially the immunocompromised, are at risk for fungal cellulitis, which can be misidentified as bacterial cellulitis and contribute to significant morbidity and mortality. CASE PRESENTATIONS: We describe three cases of opportunistic fungal cellulitis in immunosuppressed patients that were initially mistaken for bacterial infections refractory to antibiotic therapy. However, atypical features of cellulitis ultimately prompted further diagnostics to identify fungal cellulitis and allow initiation of appropriate antifungals. We discuss: (1) a 52-year-old male immunosuppressed hematopoietic cell transplant recipient with Fusarium solani cellulitis on his right lower extremity that was treated with amphotericin B and voriconazole with full resolution of the cellulitis; (2) a 70-year-old male lung transplant recipient with Fusarium solani cellulitis on his left lower extremity that ultimately progressed despite antifungals; and (3) a 68-year-old male with a history of kidney transplantation with suspected Purpureocillium lilacinum cellulitis on his left lower extremity ultimately treated with posaconazole with resolution of the skin lesions. CONCLUSIONS: Fusarium solani and Purpureocillium lilacinum are important pathogens causing opportunistic fungal cellulitis. These cases remind providers to be vigilant for fungal cellulitis when skin and soft tissue infection does not adequately respond to antibiotics and atypical features of cellulitis are present.

The changing impact of cytomegalovirus among hematopoietic cell transplant recipients during the past decade: A single institutional cohort study.

BACKGROUND: With advancements in allogeneic hematopoietic cell transplantation (alloHCT), the need for cytomegalovirus (CMV) surveillance persists. METHODS: We present a retrospective analysis on the impact of CMV with preemptive therapy in 1065 alloHCT patients with donor and/or recipient CMV seropositivity from 2009 to 2019. RESULTS: Fifty-one percent developed clinically significant CMV infection (CMV-CSI); 6.5% had CMV disease. In multivariate analysis stratified by serostatus and preparative regimen, the use of anti-thymocyte globulin (hazard ratios 2.97, 95% confidence interval 2.00-4.42, p < .001) was associated with development of CMV-CSI. Median length of stay for index hospitalization was longer in patients with CMV-CSI (27 vs. 25 days, respectively; p = .002), as were rates (32.9% vs. 17.7%; p < .001) and duration (9 d vs. 6 d; p < .001) of rehospitalization, and median total inpatient days (28 d vs. 26 d; p < .001). Patients with CMV-CSI had higher rates of neutropenia (47% vs. 20%; p < .001) and transfusion support (packed red blood cell, median 5 vs. 3; p < .001; platelets, median 3 vs. 3; p < .001). CONCLUSION: Preemptive therapy does not negate the impact of CMV-CSI on peri-engraftment toxicity and healthcare utilization. This cohort represents a large single center study on the impact of CMV in the preletermovir era and serves as a real-world comparator for assessing the impact of future prophylaxis.

Discovery and evaluation of non-basic small molecule modulators of the atypical chemokine receptor CXCR7.

The atypical chemokine receptor C-X-C chemokine receptor type 7 (CXCR7) is an attractive therapeutic target for a variety of cardiac and immunological diseases. As a strategy to mitigate known risks associated with the development of higher molecular weight, basic compounds, a series of pyrrolidinyl-azolopyrazines were identified as promising small-molecule CXCR7 modulators. Using a highly enabled parallel medicinal chemistry strategy, structure-activity relationship studies geared towards a reduction in lipophilicity and incorporation of saturated heterocycles led to the identification of representative tool compound 20. Notably, compound 20 maintained good potency against CXCR7 with a suitable balance of physicochemical properties to support in vivo pharmacokinetic studies.

Letermovir Prophylaxis Decreases Burden of Cytomegalovirus (CMV) in Patients at High Risk for CMV Disease Following Hematopoietic Cell Transplant.

Despite effective therapies, cytomegalovirus (CMV) continues to have a significant impact on morbidity and mortality in hematopoietic cell transplant recipients. At particular risk are recipients of alternative grafts such as umbilical cord blood (UCB), haploidentical transplants (haplo), or patients conditioned with T-cell depleting regimens such as anti-thymocyte globulin (ATG). With the approval of letermovir, its impact on high-risk patients is of particular interest. To evaluate the impact of letermovir prophylaxis at our center, we performed a retrospective analysis of 114 high-risk patients who received letermovir as prophylaxis (LET PPX) between January 2018 through December 2019, including 30 UCB and 22 haplo recipients, compared with 637 historical controls with comparable risk between January 2013 and December 2019. By post-transplant day 100 (D+100), letermovir prophylaxis significantly decreased the incidence of both CMV DNAemia compared with controls (45.37% versus 74.1%; P < .001) and clinically significant CMV infection (12.04% versus 48.82%; P < .001). The impact of LET PPX was even more profound on the incidence of clinically significant CMV infection (CSI), defined as the administration of antiviral therapy as preemptive therapy for CMV DNAemia or treatment for CMV disease. CSI was significantly lower in haplo recipients on LET PPX compared with controls (13.64% versus 73.33%; P= .02) and UCB recipients on LET PPX compared with controls (3.45% versus 37.5%; P < .001). No patients on LET primary PPX developed CMV disease in any treatment group by D+100 compared with controls (0% versus 5.34%, respectively; P = .006). Patients on LET PPX had fewer hospitalizations involving initiation of anti-CMV therapy compared with controls (0.93% versus 15.23%, respectively). Our analysis of the largest cohort of patients at high risk for CMV reactivation published to date demonstrates that letermovir prophylaxis significantly reduces the number of patients who receive CMV-active antiviral therapy for either DNAemia or disease due to CMV.

Letermovir Prophylaxis for Cytomegalovirus in Hematopoietic-Cell Transplantation.

BACKGROUND: Cytomegalovirus (CMV) infection remains a common complication after allogeneic hematopoietic-cell transplantation. Letermovir is an antiviral drug that inhibits the CMV-terminase complex. METHODS: In this phase 3, double-blind trial, we randomly assigned CMV-seropositive transplant recipients, 18 years of age or older, in a 2:1 ratio to receive letermovir or placebo, administered orally or intravenously, through week 14 after transplantation; randomization was stratified according to trial site and CMV disease risk. Letermovir was administered at a dose of 480 mg per day (or 240 mg per day in patients taking cyclosporine). Patients in whom clinically significant CMV infection (CMV disease or CMV viremia leading to preemptive treatment) developed discontinued the trial regimen and received anti-CMV treatment. The primary end point was the proportion of patients, among patients without detectable CMV DNA at randomization, who had clinically significant CMV infection through week 24 after transplantation. Patients who discontinued the trial or had missing end-point data at week 24 were imputed as having a primary end-point event. Patients were followed through week 48 after transplantation. RESULTS: From June 2014 to March 2016, a total of 565 patients underwent randomization and received letermovir or placebo beginning a median of 9 days after transplantation. Among 495 patients with undetectable CMV DNA at randomization, fewer patients in the letermovir group than in the placebo group had clinically significant CMV infection or were imputed as having a primary end-point event by week 24 after transplantation (122 of 325 patients [37.5%] vs. 103 of 170 [60.6%], P<0.001). The frequency and severity of adverse events were similar in the two groups overall. Vomiting was reported in 18.5% of the patients who received letermovir and in 13.5% of those who received placebo; edema in 14.5% and 9.4%, respectively; and atrial fibrillation or flutter in 4.6% and 1.0%, respectively. The rates of myelotoxic and nephrotoxic events were similar in the letermovir group and the placebo group. All-cause mortality at week 48 after transplantation was 20.9% among letermovir recipients and 25.5% among placebo recipients. CONCLUSIONS: Letermovir prophylaxis resulted in a significantly lower risk of clinically significant CMV infection than placebo. Adverse events with letermovir were mainly of low grade. (Funded by Merck; ClinicalTrials.gov number, NCT02137772 ; EudraCT number, 2013-003831-31 .).

Inactivated varicella zoster vaccine in autologous haemopoietic stem-cell transplant recipients: an international, multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Recipients of autologous haemopoietic stem-cell transplants (auto-HSCT) have an increased risk of herpes zoster and herpes zoster-related complications. The aim of this study was to establish the efficacy and safety of an inactivated varicella zoster vaccine for the prevention of herpes zoster after auto-HSCT. METHODS: In this randomised, double-blind, placebo-controlled phase 3 trial, participants were recruited from 135 medical centres (ie, stem-cell transplant centres and hospitals) in North America, South America, Europe, and Asia. Patients were eligible if they were aged 18 years or older, scheduled to receive an auto-HSCT within 60 days of enrolment, and had a history of varicella infection or were seropositive for antibodies to varicella zoster virus, or both. Exclusion criteria included a history of herpes zoster within the previous year of enrolment, and intended antiviral prophylaxis for longer than 6 months after transplantation. Participants were randomly assigned according to a central randomisation schedule generated by the trial statistician, to receive either the inactivated-virus vaccine from one of three consistency lots, a high-antigen lot, or placebo, stratified by age (<50 vs ≥50 years) and intended duration of antiviral prophylaxis after transplantation (≤3 months vs >3 to ≤6 months). Participants, investigators, trial staff, and the funder's clinical and laboratory personnel were masked to group assignment. Participants were given four doses of inactivated vaccine or placebo, with the first dose 5-60 days before auto-HSCT, and the second, third, and fourth doses at about 30, 60, and 90 days after transplantation. The primary efficacy endpoint was the incidence of herpes zoster, confirmed by PCR or adjudication by a masked clinical committee, or both, assessed in all participants randomly assigned to the vaccine consistency lot group or placebo group who received at least one dose of vaccine and had auto-HSCT. Safety was assessed in all randomised participants who received at least one dose of vaccine and had follow-up data. A prespecified vaccine efficacy success criterion required the lower bound of the 95% CI be higher than 25% for the relative reduction of the hazard ratio of herpes zoster infection in participants given the vaccine from one of the consistency lots compared with those given placebo. This trial is registered on ClinicalTrials.gov (NCT01229267) and EudraCT (2010-020150-34). FINDINGS: Between Dec 7, 2010, and April 25, 2013, 560 participants were randomly assigned to the vaccine consistency lot group, 106 to the high-antigen lot group, and 564 to the placebo group. 249 (44%) of patients in the vaccine consistency lot group, 35 (33%) in the high-antigen lot group, and 220 (39%) in the placebo group discontinued before study end, mostly because of death or withdrawal. 51 participants were excluded from the primary efficacy endpoint analyses because they did not undergo auto-HSCT or were not vaccinated, or both (22 [4%] in the vaccine consistency lot group, and 29 [5%] in the placebo group). Mean follow-up for efficacy was 2·4 years (SD 1·3) in the vaccine consistency lot group and 2·3 years (SD 1·3) in the placebo group. 42 (8%) of 538 participants in the vaccine consistency lot group (32·9 per 1000 person-years) and 113 (21%) of 535 in the placebo group (91·9 per 1000 person-years) had a confirmed case of herpes zoster. The estimated vaccine efficacy was 63·8% (95% CI 48·4-74·6), meeting the pre-specified success criterion. For the combined vaccine groups versus the placebo group, the proportion of patients with serious adverse events (216 [33%] of 657 vs 181 [33%] of 554; risk difference 0·2%, 95% CI -5·1 to 5·5) and serious vaccine-related adverse events (five [1%] vs five [1%]; risk difference 0·1%, -1·4 to 1·1) were similar. Vaccine-related injection-site adverse events occurred more frequently in participants given vaccine than those given placebo (191 [29%] vs 36 [7%]; risk difference 22·6%, 95% CI 18·5-26·6; p<0·0001). INTERPRETATION: This study shows for the first time in a large phase 3 trial that early vaccination of auto-HSCT recipients during the peri-transplant period can be effective for the prevention of an opportunistic infection like herpes zoster and that the vaccine is well tolerated. FUNDING: Merck & Co., Inc.

Echinocandin prophylaxis in patients undergoing haematopoietic cell transplantation and other treatments for haematological malignancies.

Antifungal prophylaxis is the standard of care for patients undergoing intensive chemotherapy for haematological malignancy or haematopoietic cell transplantation (HCT). Prophylaxis with azoles reduces invasive fungal infections and may reduce mortality. However, breakthrough infections still occur, and the use of azoles is sometimes complicated by pharmacokinetic variability, drug interactions, adverse events and other issues. Echinocandins are highly active against Candida species, including some organisms resistant to azoles, and have some clinical activity against Aspergillus species as well. Although currently approved echinocandins require daily intravenous administration, the drugs have a favourable safety profile and more predictable pharmacokinetics than mould-active azoles. Clinical data support the efficacy and safety of echinocandins for antifungal prophylaxis in haematology and HCT patients, though data are less robust than for azoles. Notably, sparse evidence exists supporting the use of echinocandins as antifungal prophylaxis for patients with significant graft-versus-host disease (GvHD) after HCT. Two drugs that target (1,3)-ß-d-glucan are in development, including an oral glucan synthase inhibitor and an echinocandin with unique pharmacokinetics permitting subcutaneous and weekly administration. Echinocandins are a reasonable alternative to azoles and other agents for antifungal prophylaxis in patients undergoing intensive chemotherapy for haematological malignancy or those receiving HCT, excluding those with significant GvHD.

Letermovir for cytomegalovirus prophylaxis in hematopoietic-cell transplantation.

BACKGROUND: Cytomegalovirus (CMV) infection is a leading cause of illness and death in patients who have undergone allogeneic hematopoietic-cell transplantation. Available treatments are restricted by clinically significant toxic effects and drug resistance. METHODS: In this phase 2 study, we evaluated the effect of letermovir (also known as AIC246), a new anti-CMV drug with a novel mechanism of action, on the incidence and time to onset of prophylaxis failure in CMV-seropositive recipients of allogeneic hematopoietic-cell transplants from matched related or unrelated donors. From March 2010 through October 2011, we randomly assigned 131 transplant recipients in a 3:1 ratio to three sequential study cohorts according to a double-blind design. Patients received oral letermovir (at a dose of 60, 120, or 240 mg per day, or matching placebo) for 12 weeks after engraftment. The primary end point was all-cause prophylaxis failure, defined as discontinuation of the study drug because of CMV antigen or DNA detection, end-organ disease, or any other cause. Patients underwent weekly surveillance for CMV infection. RESULTS: The reduction in the incidence of all-cause prophylaxis failure was dose-dependent. The incidence of prophylaxis failure with letermovir, as compared with placebo, was 48% versus 64% at a daily letermovir dose of 60 mg (P=0.32), 32% at a dose of 120 mg (P=0.01), and 29% at a dose of 240 mg (P=0.007). Kaplan-Meier time-to-onset profiles for prophylaxis failure showed a significant difference in the comparison of letermovir at a dose of 240 mg per day with placebo (P=0.002). The safety profile of letermovir was similar to placebo, with no indication of hematologic toxicity or nephrotoxicity. CONCLUSIONS: Letermovir, as compared with placebo, was effective in reducing the incidence of CMV infection in recipients of allogeneic hematopoietic-cell transplants. The highest dose (240 mg per day) had the greatest anti-CMV activity, with an acceptable safety profile. (Funded by AiCuris; ClinicalTrials.gov number, NCT01063829.).

Infections after Transplantation of Bone Marrow or Peripheral Blood Stem Cells from Unrelated Donors.

Infection is a major complication of hematopoietic cell transplantation. Prolonged neutropenia and graft-versus-host disease are the 2 major complications with an associated risk for infection, and these complications differ according to the graft source. A phase 3, multicenter, randomized trial (Blood and Marrow Transplant Clinical Trials Network [BMT CTN] 0201) of transplantation of bone marrow (BM) versus peripheral blood stem cells (PBSC) from unrelated donors showed no significant differences in 2-year survival between these graft sources. In an effort to provide data regarding whether BM or PBSC could be used as a preferential graft source for transplantation, we report a detailed analysis of the infectious complications for 2 years after transplantation from the BMT CTN 0201 trial. A total of 499 patients in this study had full audits of infection data. A total of 1347 infection episodes of moderate or greater severity were documented in 384 (77%) patients; 201 of 249 (81%) of the evaluable patients had received a BM graft and 183 of 250 (73%) had received a PBSC graft. Of 1347 infection episodes, 373 were severe and 123 were life-threatening and/or fatal; 710 (53%) of these episodes occurred on the BM arm and 637 (47%) on the PBSC arm, resulting in a 2-year cumulative incidence 84.7% (95% confidence interval [CI], 79.6 to 89.8) for BM versus 79.7% (95% CI, 73.9 to 85.5) for PBSC, P = .013. The majority of these episodes, 810 (60%), were due to bacteria, with a 2-year cumulative incidence of 72.1% and 62.9% in BM versus PBSC recipients, respectively (P = .003). The cumulative incidence of bloodstream bacterial infections during the first 100 days was 44.8% (95% CI, 38.5 to 51.1) for BM versus 35.0% (95% CI, 28.9 to 41.1) for PBSC (P = .027). The total infection density (number of infection events/100 patient days at risk) was .67 for BM and .60 for PBSC. The overall infection density for bacterial infections was .4 in both arms; for viral infections, it was .2 in both arms; and for fungal/parasitic infections, it was .04 and .05 for BM and PBSC, respectively. The cumulative incidence of infection before engraftment was 47.9% (95% CI, 41.5 to 53.9) for BM versus 32.8% (95% CI, 27.1 to 38.7) for PBSC (P = .002), possibly related to quicker neutrophil engraftment using PBSC. Infections remain frequent after unrelated donor hematopoietic cell transplantation, particularly after BM grafts.

Determination of Unbound Partition Coefficient and in Vitro-in Vivo Extrapolation for SLC13A Transporter-Mediated Uptake.

Unbound partition coefficient (Kpuu) is important to an understanding of the asymmetric free drug distribution of a compound between cells and medium in vitro, as well as between tissue and plasma in vivo, especially for transporter-mediated processes. Kpuu was determined for a set of compounds from the SLC13A family that are inhibitors and substrates of transporters in hepatocytes and transporter-transfected cell lines. Enantioselectivity was observed, with (R)-enantiomers achieving much higher Kpuu (>4) than the (S)-enantiomers (<1) in human hepatocytes and SLC13A5-transfected human embryonic 293 cells. The intracellular free drug concentration correlated directly with in vitro pharmacological activity rather than the nominal concentration in the assay because of the high Kpuu mediated by SLC13A5 transporter uptake. Delivery of the diacid PF-06649298 directly or via hydrolysis of the ethyl ester prodrug PF-06757303 resulted in quite different Kpuu values in human hepatocytes (Kpuu of 3 for diacid versus 59 for prodrug), which was successfully modeled on the basis of passive diffusion, active uptake, and conversion rate from ester to diacid using a compartmental model. Kpuu values changed with drug concentrations; lower values were observed at higher concentrations possibly owing to a saturation of transporters. Michaelis-Menten constant (Km) of SLC13A5 was estimated to be 24 µM for PF-06649298 in human hepatocytes. In vitro Kpuu obtained from rat suspension hepatocytes supplemented with 4% fatty acid free bovine serum albumin showed good correlation with in vivo Kpuu of liver-to-plasma, illustrating the potential of this approach to predict in vivo Kpuu from in vitro systems.

Co-transplantation of pure blood stem cells with antigen-specific but not bulk T cells augments functional immunity.

Impaired immunity is a fundamental obstacle to successful allogeneic hematopoietic cell transplantation. Mature graft T cells are thought to provide protection from infections early after transplantation, but can cause life-threatening graft-vs.-host disease. Human CMV is a major pathogen after transplantation. We studied reactivity against the mouse homologue, murine CMV (MCMV), in lethally irradiated mice given allogeneic purified hematopoietic stem cells (HSCs) or HSCs supplemented with T cells or T-cell subsets. Unexpectedly, recipients of purified HSCs mounted superior antiviral responses compared with recipients of HSC plus unselected bulk T cells. Furthermore, supplementation of purified HSC grafts with CD8(+) memory or MCMV-specific T cells resulted in enhanced antiviral reactivity. Posttransplantation lymphopenia promoted massive expansion of MCMV-specific T cells when no competing donor T cells were present. In recipients of pure HSCs, naive and memory T cells and innate lymphoid cell populations developed. In contrast, the lymphoid pool in recipients of bulk T cells was dominated by effector memory cells. These studies show that pure HSC transplantations allow superior protective immunity against a viral pathogen compared with unselected mature T cells. This reductionist transplant model reveals the impact of graft composition on regeneration of host, newly generated, and mature transferred T cells, and underscores the deleterious effects of bulk donor T cells. Our findings lead us to conclude that grafts composed of purified HSCs provide an optimal platform for in vivo expansion of selected antigen-specific cells while allowing the reconstitution of a naive T-cell pool.

U.S. Food and Drug Administration approval summary: omacetaxine mepesuccinate as treatment for chronic myeloid leukemia.

On October 26, 2012, the U.S. Food and Drug Administration (FDA) granted accelerated approval to omacetaxine mepesuccinate (Synribo; Teva Pharmaceuticals USA, Inc., North Wales, PA, http://www.tevausa.com) for the treatment of adult patients with chronic phase (CP) or accelerated phase (AP) chronic myeloid leukemia (CML) with resistance and/or intolerance to two or more tyrosine kinase inhibitors (TKIs). The approval was based on the FDA review of data from 111 patients with CML in CP or in AP who had received two or more prior TKIs, including imatinib. Major cytogenetic response was achieved in 18% of patients with CP, with a median response duration of 12.5 months. Major hematologic response was achieved in 14% of patients with AP, with a median response duration of 4.7 months. The FDA safety evaluation was based on submitted data from 163 patients with CP or AP CML who had received at least one dose of omacetaxine mepesuccinate. The safety evaluation was limited by the single-arm design of the clinical trials as conducted in a small number of previously treated patients. The most common (≥20%) adverse reactions of any grade in enrolled patients included thrombocytopenia, anemia, neutropenia, diarrhea, nausea, fatigue, asthenia, injection site reaction, pyrexia, and infection. The FDA concluded that omacetaxine mepesuccinate has shown activity and a favorable benefit-to-risk profile for the studied population of adult patients with CML (CP or AP) with resistance and/or intolerance to two or more TKIs. Further evidence of response durability to verify clinical benefit is pending.

Prophylactic rituximab after allogeneic transplantation decreases B-cell alloimmunity with low chronic GVHD incidence.

B cells are involved in the pathogenesis of chronic GVHD (cGVHD). We hypothesized that prophylactic anti-B-cell therapy delivered 2 months after transplantation would decrease allogeneic donor B-cell immunity and possibly the incidence of cGVHD. Therefore, in the present study, patients with high-risk chronic lymphocytic leukemia (n = 22) and mantle-cell lymphoma (n = 13) received a total lymphoid irradiation of 80 cGy for 10 days and antithymocyte globulin 1.5 mg/kg/d for 5 days. Rituximab (375 mg/m(2)) was infused weekly on days 56, 63, 70, and 77 after transplantation. The incidence of acute GVHD was 6%. The cumulative incidence of cGVHD was 20%. Nonrelapse mortality was 3%. Rituximab treatment after allogeneic transplantation significantly reduced B-cell allogeneic immunity, with complete prevention of alloreactive H-Y Ab development in male patients with female donors (P = .01). Overall survival and freedom from progression at 4 years for chronic lymphocytic leukemia patients were 73% and 47%, respectively; for mantle-cell lymphoma patients, they were 69% and 53%, respectively.

Trends in mental health services utilization and stigma in US soldiers from 2002 to 2011.

OBJECTIVES: We characterized trends in mental health services utilization and stigma over the course of the Afghanistan and Iraq wars among active-component US soldiers. METHODS: We evaluated trends in mental health services utilization and stigma using US Army data from the Health-Related Behavior (HRB) surveys from 2002, 2005, and 2008 (n = 12,835) and the Land Combat Study (LCS) surveys administered to soldiers annually from 2003 to 2009 and again in 2011 (n = 22,627). RESULTS: HRB and LCS data suggested increased mental health services utilization and decreased stigma in US soldiers between 2002 and 2011. These trends were evident in soldiers with and without posttraumatic stress disorder (PTSD), major depressive disorder (MDD), or PTSD and MDD. Despite the improving trends, more than half of soldiers with mental health problems did not report seeking care. CONCLUSIONS: Mental health services utilization increased and stigma decreased over the course of the wars in Iraq and Afghanistan. Although promising, these findings indicate that a significant proportion of US soldiers meeting criteria for PTSD or MDD do not utilize mental health services, and stigma remains a pervasive problem requiring further attention.

Identification of a novel conformationally constrained glucagon receptor antagonist.

Identification of orally active, small molecule antagonists of the glucagon receptor represents a novel treatment paradigm for the management of type 2 diabetes mellitus. The present work discloses novel glucagon receptor antagonists, identified via conformational constraint of current existing literature antagonists. Optimization of lipophilic ligand efficiency (LLE or LipE) culminated in enantiomers (+)-trans-26 and (-)-trans-27 which exhibit good physicochemical and in vitro drug metabolism profiles. In vivo, significant pharmacokinetic differences were noted with the two enantiomers, which were primarily driven through differences in clearance rates. Enantioselective oxidation by cytochrome P450 was ruled out as a causative factor for pharmacokinetic differences.

Dying with motor neurone disease, what can we learn from family caregivers?

BACKGROUND: Increasingly, people with neurodegenerative illness are cared for at home until close to death. Yet, discussing the reality of dying remains a social taboo. OBJECTIVE: To examine the ways, family caregivers of people living with motor neurone disease (MND) experienced the dying of their relative and to identify how health practitioners can better prepare families for end-of-life care. DESIGN: Secondary analysis was undertaken on data sets generated from two longitudinal qualitative studies employing similar data collection and analysis methods. Combining data sets increased participant numbers in a low incidence disease group. SETTING AND PARTICIPANTS: Primary studies were undertaken with family caregivers in England and Australia. Interview and observational data were collected mostly in home. Participants who discussed dying and death formed the sample for secondary analysis. RESULTS: Combined data revealed four major themes: planning for end of life, unexpected dying, dignity in the dying body and positive end to MND. Despite short survival predictions, discussions among family members about dying were often sporadic and linked to loss of hope. Effective planning for death assisted caregivers to manage the final degenerative processes of dying. When plans were not effectively communicated or enacted, capacity to preserve personhood was reduced. DISCUSSION AND CONCLUSION: Returning death and dying to social discourse will raise the level of community awareness and normalize conversations about end-of-life care. Strategies for on-going, effective communication that facilitates advance care planning among patients, their families and practitioners are essential to improve dying and death for people with MND and their family caregivers.

The design and synthesis of a potent glucagon receptor antagonist with favorable physicochemical and pharmacokinetic properties as a candidate for the treatment of type 2 diabetes mellitus.

A novel and potent small molecule glucagon receptor antagonist for the treatment of diabetes mellitus is reported. This candidate, (S)-3-[4-(1-{3,5-dimethyl-4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenoxy}butyl)benzamido]propanoic acid, has lower molecular weight and lipophilicity than historical glucagon receptor antagonists, resulting in excellent selectivity in broad-panel screening, lower cytotoxicity, and excellent overall in vivo safety in early pre-clinical testing. Additionally, it displays low in vivo clearance and excellent oral bioavailability in both rats and dogs. In a rat glucagon challenge model, it was shown to reduce the glucagon-elicited glucose excursion in a dose-dependent manner and at a concentration consistent with its rat in vitro potency. Its properties make it an excellent candidate for further investigation.

Behavioral counseling after screening for alcohol misuse in primary care: a systematic review and meta-analysis for the U.S. Preventive Services Task Force.

BACKGROUND: Alcohol misuse, which includes the full spectrum from risky drinking to alcohol dependence, is a leading cause of preventable death in the United States. PURPOSE: To evaluate the benefits and harms of behavioral counseling interventions for adolescents and adults who misuse alcohol. DATA SOURCES: MEDLINE, EMBASE, the Cochrane Library, CINAHL, PsycINFO, International Pharmaceutical Abstracts, and reference lists of published literature (January 1985 through January 2012, limited to English-language articles). STUDY SELECTION: Controlled trials at least 6 months' duration that enrolled persons with alcohol misuse identified by screening in primary care settings and evaluated behavioral counseling interventions. DATA EXTRACTION: One reviewer extracted data and a second checked accuracy. Two independent reviewers assigned quality ratings and graded the strength of the evidence. DATA SYNTHESIS: The 23 included trials generally excluded persons with alcohol dependence. The best evidence was for brief (10- to 15-minute) multicontact interventions. Among adults receiving behavioral interventions, consumption decreased by 3.6 drinks per week from baseline (weighted mean difference, 3.6 drinks/wk [95% CI, 2.4 to 4.8 drinks/wk]; 10 trials; 4332 participants), 12% fewer adults reported heavy drinking episodes (risk difference, 0.12 [CI, 0.07 to 0.16]; 7 trials; 2737 participants), and 11% more adults reported drinking less than the recommended limits (risk difference, 0.11 [CI, 0.08 to 0.13]; 9 trials; 5973 participants) over 12 months compared with control participants (moderate strength of evidence). Evidence was insufficient to draw conclusions about accidents, injuries, or alcohol-related liver problems. Trials enrolling young adults or college students showed reduced consumption and fewer heavy drinking episodes (moderate strength of evidence). Little or no evidence of harms was found. LIMITATIONS: Results may be biased to the null because the behavior of control participants could have been affected by alcohol misuse assessments. In addition, evidence is probably inapplicable to persons with alcohol dependence and selective reporting may have occurred. CONCLUSION: Behavioral counseling interventions improve behavioral outcomes for adults with risky drinking. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality.

Trends in binge and heavy drinking, alcohol-related problems, and combat exposure in the U.S. military.

Population-based Department of Defense health behavior surveys were examined for binge and heavy drinking among U.S. active duty personnel. From 1998-2008, personnel showed significant increases in heavy drinking (15% to 20%) and binge drinking (35% to 47%). The rate of alcohol-related serious consequences was 4% for nonbinge drinkers, 9% for binge drinkers, and 19% for heavy drinkers. Personnel with high combat exposure had significantly higher rates of heavy (26.8%) and binge (54.8%) drinking than their counterparts (17% and 45%, respectively). Heavy and binge drinking put service members at high risk for problems that diminish force readiness and psychological fitness.

Randomized, double-blind trial of fluconazole versus voriconazole for prevention of invasive fungal infection after allogeneic hematopoietic cell transplantation.

Invasive fungal infection (IFI) is a serious threat after allogeneic hematopoietic cell transplant (HCT). This multicenter, randomized, double-blind trial compared fluconazole (N = 295) versus voriconazole (N = 305) for the prevention of IFI in the context of a structured fungal screening program. Patients undergoing myeloablative allogeneic HCT were randomized before HCT to receive study drugs for 100 days, or for 180 days in higher-risk patients. Serum galactomannan was assayed twice weekly for 60 days, then at least weekly until day 100. Positive galactomannan or suggestive signs triggered mandatory evaluation for IFI. The primary endpoint was freedom from IFI or death (fungal-free survival; FFS) at 180 days. Despite trends to fewer IFIs (7.3% vs 11.2%; P = .12), Aspergillus infections (9 vs 17; P = .09), and less frequent empiric antifungal therapy (24.1% vs 30.2%, P = .11) with voriconazole, FFS rates (75% vs 78%; P = .49) at 180 days were similar with fluconazole and voriconazole, respectively. Relapse-free and overall survival and the incidence of severe adverse events were also similar. This study demonstrates that in the context of intensive monitoring and structured empiric antifungal therapy, 6-month FFS and overall survival did not differ in allogeneic HCT recipients given prophylactic fluconazole or voriconazole. This trial was registered at www.clinicaltrials.gov as NCT00075803.