Efficacy of induction regimens for cryptococcal meningitis in HIV-infected adults: a systematic review and network meta-analysis.

Cryptococcal meningitis (CM) is the most fatal adult meningitis in patients with human immunodeficiency virus (HIV). There is no conclusive evidence for the superiority of 1-week amphotericin B deoxycholate (AmphB) + flucytosine (5-FC) regimen over other antifungals in the management of HIV patients with CM (HIV-CM patients). We aimed to evaluate the differences in efficacy and tolerability of different antifungal agents in HIV-CM patients by conducting a current network meta-analysis NMA. Overall, 19 randomized controlled trials were included with 2642 participants. A regimen indicated a possibly lower early mortality rate, namely, AmphB + 5-FC + Azole (OR = 1.1E-12, 95% CIs = 1.3E-41 to 0.06) comparing to AmphB + 5-FC. The current NMA provides evidence that AmphB + 5-FC + Azole are superior to all the investigated treatments for induction regimen in HIV-CM patients.

Exploring Potential Proteomic Biomarkers for Prognosis of Infective Endocarditis through Profiled Autoantibodies by an Immunomics Protein Array Technique.

Though infective endocarditis (IE) is a life-threatening cardiac infection with a high mortality rate, the effective diagnostic and prognostic biomarkers for IE are still lacking. The aim of this study was to explore the potential applicable proteomic biomarkers for IE through the Immunome™ Protein Array system. The system was employed to profile those autoantibodies in IE patients and control subjects. Our results showed that interleukin-1 alpha (IL1A), nucleolar protein 4 (NOL4), tudor and KH domain-containing protein (TDRKH), G antigen 2B/2C (GAGE2), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and X antigen family member 2 (XAGE2) are highly differentially-expressed among IE and non-IE control. Furthermore, bactericidal permeability-increasing protein (BPI), drebrin-like protein (DBNL), signal transducing adapter molecule 2 (STAM2), cyclin-dependent kinase 16 (CDK16), BAG family molecular chaperone regulator 4 (BAG4), and nuclear receptor-interacting protein 3 (NRIP3) are differentially-expressed among IE and healthy controls. On the other hand, those previously identified biomarkers for IE, including erythrocyte sedimentation rate, C-reactive protein, rheumatoid factor, procalcitonin, and N-terminal-pro-B-type natriuretic peptide demonstrated only minor significance. With scientific rationalities for those highly differentially-expressed proteins, they could serve as potential candidates for diagnostic biomarkers of IE for further analysis.

An early endosome-derived retrograde trafficking pathway promotes secretory granule maturation.

Regulated secretion is a fundamental cellular process in which biologically active molecules stored in long-lasting secretory granules (SGs) are secreted in response to external stimuli. Many studies have described mechanisms responsible for biogenesis and secretion of SGs, but how SGs mature remains poorly understood. In a genetic screen, we discovered a large number of endolysosomal trafficking genes required for proper SG maturation, indicating that maturation of SGs might occur in a manner similar to lysosome-related organelles (LROs). CD63, a tetraspanin known to decorate LROs, also decorates SG membranes and facilitates SG maturation. Moreover, CD63-mediated SG maturation requires type II phosphatidylinositol 4 kinase (PI4KII)-dependent early endosomal sorting and accumulation of phosphatidylinositol 4-phosphate (PI4P) on SG membranes. In addition, the PI4P effector Past1 is needed for formation of stable PI4KII-containing endosomal tubules associated with this process. Our results reveal that maturation of post-Golgi-derived SGs requires trafficking via the endosomal system, similar to mechanisms employed by LROs.

Vaccination coverage and associated factors for receipt of the 23-valent pneumococcal polysaccharide vaccine in Taiwan: A nation-wide community-based study.

Older adults, particularly those with chronic obstructive pulmonary disease, are advised to receive 23-valent pneumococcal polysaccharide vaccine (PPV23). However, the PPV23 vaccination rate in Taiwan and the determinants of receipt remain unclear.We analyzed the data of 1475 community-dwelling older adults aged ≥75 years who participated in the Healthy Aging Longitudinal Study in Taiwan. Each participant received assessments of PPV23 status, sociodemographic factors (age, sex, education level, marital status, living alone, and occupation), and health-related factors (chronic diseases, smoking status, alcohol intake, physical activities, cognitive status, and physical performance). PPV23 rate was defined as the number of participants who reported receiving free PPV23 divided by the total number of candidates for free PPV23. Multinomial logistic regression analysis was applied to investigate the sociodemographic and health-related determinants of PPV23 status.A PPV23 vaccination rate of 20.7% (305/1475) was observed. Participants who were female, current smokers, and had a low peak expiratory flow were associated with PPV23 nonreceipt (all P <.05). Of the participants who had a low peak expiratory flow, low education status, and physical inactivity were associated with PPV23 nonreceipt (all P <.05).The PPV23 vaccination rate among adults aged ≥75 years was low. Older adults who were women, current smokers, or who had a low PEF were less likely to receive the PPV23. These findings support continual efforts to improve the PPV23 coverage rate in vulnerable populations.

A Case Report of Penicillin-Tolerant Streptococcus mitis Endocarditis Chang-Hua Chen, MD, MSc, PhD.

There is no clear relationship between the serum inhibition test and clinical outcome for Streptococcus mitis (S. mitis) endocarditis. We report an 84-year-old male with endocarditis caused by penicillin-tolerant S. mitis. The results for the serum inhibitory test (SIT) and serum bactericidal test (SBT) showed a trough level of SIT = 1:256 and SBT = 1:4 and a peak level of SIT ≥ 1:1024 and SBT = 1:16. In addition, the SIT/SBT ratio was 64 at peak level and more than 64 at trough level, which is compatible with penicillin-tolerant S. mitis. Following a 42-day high-dose penicillin treatment (24 M IU/day, via a continuous drip), the patient made a good recovery. In vitro inhibitory and bactericidal test results were not a valid predictor of medical treatment failure. Physicians need to continue to evaluate the surgical indications when treating patients with S. mitis endocarditis.

Determinants of influenza vaccination in older adults: A nationwide community-based study in Taiwan.

AIMS: Influenza vaccination (InVa) is an effective measure for preventing influenza infection, which is a major cause of morbidity and mortality in older adults. However, the determinants of InVa remain unclear. METHODS: The present study included 4756 adults aged 55 years and older who completed the baseline examination of the Healthy Aging Longitudinal Study in Taiwan. During the examination, each participant received assessments of InVa status. Comprehensive assessments of sociodemographic (age, sex, education level, marital status, living alone and occupation) and health-related factors (chronic diseases, smoking status, alcohol intake, physical activities, cognitive status and physical performance) were also carried out. The InVa rate was defined as the number of participants who reported receiving free InVa divided by the total number of candidates for free InVa. Multinomial logistic regression analysis was applied to investigate the sociodemographic and health-related determinants of InVa status. RESULTS: The coverage rate of InVa was 44.8% (2130/4756). Older age (adjusted odds ratio [OR; >75 years vs <65 years] 7.72, 95% CI 6.26-9.52), multiple chronic diseases (OR [≥2 vs 0)] 1.31, 95% CI 1.10-1.65) and physical activity (OR [yes vs no] 1.43, 95% CI 1.23-1.64) were positively associated with receiving InVa. A current smoking status (OR 0.67, 95% CI 0.55-0.82) was negatively associated with receiving InVa. CONCLUSIONS: Older adults who received InVa differed from non-receivers in multiple sociodemographic and health-related characteristics. These findings support continual efforts to improve the InVa coverage rate in vulnerable populations. Geriatr Gerontol Int 2017; 17: 2396-2402.

Loss of the Arp2/3 complex component ARPC1B causes platelet abnormalities and predisposes to inflammatory disease.

Human actin-related protein 2/3 complex (Arp2/3), required for actin filament branching, has two ARPC1 component isoforms, with ARPC1B prominently expressed in blood cells. Here we show in a child with microthrombocytopenia, eosinophilia and inflammatory disease, a homozygous frameshift mutation in ARPC1B (p.Val91Trpfs*30). Platelet lysates reveal no ARPC1B protein and greatly reduced Arp2/3 complex. Missense ARPC1B mutations are identified in an unrelated patient with similar symptoms and ARPC1B deficiency. ARPC1B-deficient platelets are microthrombocytes similar to those seen in Wiskott-Aldrich syndrome that show aberrant spreading consistent with loss of Arp2/3 function. Knockout of ARPC1B in megakaryocytic cells results in decreased proplatelet formation, and as observed in platelets from patients, increased ARPC1A expression. Thus loss of ARPC1B produces a unique set of platelet abnormalities, and is associated with haematopoietic/immune symptoms affecting cell lineages where this isoform predominates. In agreement with recent experimental studies, our findings suggest that ARPC1 isoforms are not functionally interchangeable.

α-granule biogenesis: from disease to discovery.

Platelets are critical to hemostasis and thrombosis. Upon detecting injury, platelets show a range of responses including the release of protein cargo from α-granules. This cargo is synthesized by platelet precursor megakaryocytes or endocytosed by megakaryocytes and/or platelets. Insights into α-granule biogenesis have come from studies of hereditary conditions where these granules are immature, deficient or absent. Studies of Arthrogryposis, Renal dysfunction, and Cholestasis (ARC) syndrome identified the first proteins essential to α-granule biogenesis: VPS33B and VPS16B. VPS33B and VPS16B form a complex, and in the absence of either, platelets lack α-granules and the granule-specific membrane protein P-selectin. Gray Platelet Syndrome (GPS) platelets also lack conventionally recognizable α-granules, although P-selectin containing structures are present. GPS arises from mutations affecting NBEAL2. The GPS phenotype is more benign than ARC syndrome, but it can cause life-threatening bleeding, progressive thrombocytopenia, and myelofibrosis. We review the essential roles of VPS33B, VPS16B, and NBEAL2 in α-granule development. We also examine the existing data on their mechanisms of action, where many details remain poorly understood. VPS33B and VPS16B are ubiquitously expressed and ARC syndrome is a multisystem disorder that causes lethality early in life. Thus, VPS33B and VPS16B are clearly involved in other processes besides α-granule biogenesis. Studies of their involvement in vesicular trafficking and protein interactions are reviewed to gain insights into their roles in α-granule formation. NBEAL2 mutations primarily affect megakaryocytes and platelets, and while little is known about NBEAL2 function some insights can be gained from studies of related proteins, such as LYST.

The experience of intramuscular benzathine penicillin for prophylaxis of recurrent cellulitis: A cohort study.

BACKGROUND/PURPOSE: Recurrent cellulitis is an important clinical issue but the optimal strategy for prophylaxis is not determined. Intramuscular benzathine penicillin at a 4-week interval had been adopted in our hospital and the study was conducted to evaluate the efficacy. METHODS: From January 1, 2009 to May 31, 2013, all patients aged ≥ 18 year, with a history of recurrent cellulitis and having received at least three shots of intramuscular benzathine penicillin for prophylaxis were retrospectively recruited for analysis. Two treatment periods (prophylaxis period and nonprophylaxis period) were defined. The effects of benzathine penicillin prophylaxis and patient characteristics on the incidence rate of recurrent cellulitis were analyzed using Poisson regression model. RESULTS: A total of 72 patients were enrolled, including 26 (36.1%) men. The most common underlying conditions were past surgery at the proximal side of the affected limb (38, 52.8%), malignancy (31, 43.1%), and diabetes mellitus (24, 33.3%). The incidence rate of recurrent cellulitis in the prophylaxis period was 0.73 episode/patient-year, significantly lower than that of 1.25 episodes/patient-year in the nonprophylaxis period (p < 0.001). Tinea pedis was a significant factor associated with increasing incidence of recurrent cellulitis in our cohort. CONCLUSION: Intramuscular benzathine penicillin at a 4-week interval may be an effective prophylactic strategy to reduce the incidence of cellulitis. Further studies are necessary to determine the factors associated with failure of prophylaxis as well as optimal individualized dosage and dosing interval of the prophylactic agent.

Risk factors associated with postcraniotomy meningitis: A retrospective study.

Postcraniotomy meningitis (PCM) is a major challenge in neurosurgery, and changing patterns of infectious agents in PCM have been noted. The limited epidemiological data and urgent clinical needs motivated this research. We conducted this study to determine a risk assessment for PCM and the current pattern of infectious agents.We performed a retrospective case-control study of significant cases of postcraniotomy meningitis in the Changhua Christian Hospital System between January 1, 2008, and December 31, 2012. Postcraniotomy meningitis was diagnosed in 22 out of 4392 surgical patients; this data was reviewed for risk assessment.This study assessed the risk factors for postcraniotomy meningitis and found that it was more frequently seen in patients who were elderly (OR = 1.57, 95% CI = 1.32-2.98, P = 0.013), underwent emergency procedures (OR = 4.82, 95% CI = 1.50-14.53, P = 0.008), had leak of cerebrospinal fluid (OR = 4.62, 95% CI = 2.03-10.50, P = 0.012), had external ventricular drainage (OR = 4.68, 95% CI = 2.46-8.87, P = 0.006), were admitted to the intensive care unit (OR = 2.41, 95% CI = 1.53-8.08, P = 0.012), had used drain placement >72 hours (OR = 2.66, 95% CI = 1.04-4.29, P = 0.007), had surgery >4.5 hours (OR = 2.38, 95% CI = 1.39-4.05, P = 0.005), had repeat operations (OR = 2.74, 95% CI = 1.31-5.73, P = 0.018), endured trauma (OR = 5.97, 95% CI = 1.57-17.61, P = 0.007), or had 30-days mortality (OR = 5.07, 95% CI = 2.20-11.48, P = 0.001). The predominant pathogens isolated from cerebrospinal fluid were Staphylococcus aureus in 8 patients (36.7%) and Acinetobacter baumannii in 7 patients (31.8%). In our study, the mortality rate was 5.1% among all postcraniotomy patients.Accurate risk assessment, early diagnosis, and choice of appropriate antibiotics in accordance with epidemiologic information are the cornerstones of reducing mortality and morbidity in PCM. The changing pattern of infectious agents in PCM over time suggests the necessity of further studies to provide the most up-to-date insight to physicians.

Risk of cancer among HIV-infected patients from a population-based nested case-control study: implications for cancer prevention.

BACKGROUND: The burden of cancer is likely to increase among the human immunodeficiency virus (HIV)-positive population as it ages due to successful antiretroviral therapy (ART). The purpose of this study was to determine the risk of cancer in HIV-infected patients. METHODS: This study was a matched nested case-control study. It was performed using the National Health Insurance Research Database of Taiwan. The control group included non-HIV-infected patients matched by sex, age, and year of enrollment. Logistic regression analyses were performed and simultaneously adjusted for potential confounders (income, urbanization, and Charslon index of comorbidity to evaluate HIV infection as an independent risk of cancer. We calculated the overall and sex-specific standardized incidence ratios (SIR) to investigate the pattern of cancer risk and overall cancer risk in the patients with HIV infection. RESULTS: Of the 1,115 HIV-infected patients, 104 (9.33%) developed cancer during the 11-year follow-up period. The risk of cancer for patients with HIV infection was significant (adjusted odds ratio = 3.89, 95% confidence interval [CI] = 2.92-5.19) after adjustment for potential confounders. There was a significantly increased risk of developing non-Hodgkin lymphoma (SIR = 25.73, 95% CI = 6.83-90.85), cervical cancer (SIR = 4.01, 95% CI = 1.0-16.06), lymphoma (SIR = 20.26, 95% CI = 5.86-70.10), and respiratory and intrathoracic cancer (SIR = 20.09, 95% CI = 2.34-172.09) compared with the control group. In addition, HIV-infected patients were at significant risk for renal, oral, breast, liver, skin, and colorectal cancer. CONCLUSIONS: Patients with HIV infection are at increased risk for several specific cancers. Our results support the implementation of an active and accelerated cancer screening schedule for patients with HIV infection to increase their life span.

Changing epidemiology of candidemia in a medical center in middle Taiwan.

BACKGROUND: Candidemia remains a major cause of morbidity and mortality in the health care setting, and the epidemiology of Candida infection is changing. METHODS: Clinical and laboratory data from patients with candidemia were collected retrospectively at a tertiary medical center in Taiwan from July 1, 2009 to June 30, 2012 (a 36-month period). Demographics, clinical characteristics, and drug susceptibility of the invading Candida species of patients at the onset of candidemia were analyzed and compared with previous study from January 1, 2001 to June 30, 2003 (a 30-month period). RESULTS: A total of 209 episodes of candidemia in 205 patients were identified in this study period. When compared with the previous study period, more patients were admitted for medical conditions at percentages ranging from 49.5% to 69.8%; the incidence rate of health care-associated candidemia increased from 0.76 to 1.14 per 1000 discharges; the proportion of Candida albicans in patients with candidemia decreased from 64.8% to 43.6% whereas the proportion of Candida glabrata increased greatly from 1.1% to 21.6% and the proportions of Candida tropicalis and Candida parapsilosis were slightly elevated (19.8-22.0% and 2.2-7.3%, respectively). All of the C. albicans isolates remained susceptible to fluconazole, whereas 66.7% of C. glabrata isolates were dose-dependent susceptible, and 4.4% of C. glabrata isolates and 11.6% C. tropicalis isolates were resistant. There was one C. glabrata and one Candida guilliermondii resistant to echinocandin. The predictors for 30-day mortality included the high Acute Physiology and Chronic Health Evaluation II (APACHE II) score, use of parenteral nutrition, underlying malignancy, liver cirrhosis, and neutropenia whereas candidemia by C. parapsilosis or C. glabrata is a favorable predictor when compared with C. albicans. CONCLUSION: The distribution of Candida species in candidemia was changed. Although C. albicans remained the major species, the isolation of non-C. albicans spp., especially C. glabrata, increased. Patients with candidemia still had high mortalities due to severity of illness and underlying conditions.

Epidemiological characterization and prognostic factors in patients with confirmed cerebral cryptococcosis in central Taiwan

Background Cryptococcal meningitis is a deadly fungal infection. This study aimed to characterize the epidemiology of cerebral cryptococcosis and to define its prognostic factors. Methods This cross-sectional study collected clinical information from cryptococcal meningitis patients with confirmed cerebral cryptococcosis from 2006 to 2012 at the Changhua Christian Healthcare System to access prognostic factors. Result Fifty-nine adult cryptococcal meningitis patients were studied. The incidence at Changhua Christian Healthcare System was approximately 170 episodes per 100,000 patients within the studied period. Forty-one of 59 cryptococcal meningitis patients developed complications. Overall, 12 of 59 patients died, for a three-month mortality rate of 20.3 %. Prognostic factors positively associated with the three-month mortality included age (>55 years), patient delay, prolonged delay by the doctor in administering antifungal agent therapy, duration of intensive care unit stay, chronic lung disease, cryptococcemia, headache, altered mental status, positive blood cultures, and high cerebrospinal fluid opening pressure (>250 mm H2O). Conclusions We strongly recommend early administration of an antifungal agent to each suspected cryptococcal meningitis patient to decrease both the delay by doctors in administering therapy and the mortality risk. Aggressive and supportive care for severe cryptococcal meningitis patients is critical to decrease overall mortality from this infection.

Epidemiological characterization and prognostic factors in patients with confirmed cerebral cryptococcosis in central Taiwan

BackgroundCryptococcal meningitis is a deadly fungal infection. This study aimed to characterize the epidemiology of cerebral cryptococcosis and to define its prognostic factors.MethodsThis cross-sectional study collected clinical information from cryptococcal meningitis patients with confirmed cerebral cryptococcosis from 2006 to 2012 at the Changhua Christian Healthcare System to access prognostic factors.ResultsFifty-nine adult cryptococcal meningitis patients were studied. The incidence at Changhua Christian Healthcare System was approximately 170 episodes per 100,000 patients within the studied period. Forty-one of 59 cryptococcal meningitis patients developed complications. Overall, 12 of 59 patients died, for a three-month mortality rate of 20.3 %. Prognostic factors positively associated with the three-month mortality included age (>55 years), patient delay, prolonged delay by the doctor in administering antifungal agent therapy, duration of intensive care unit stay, chronic lung disease, cryptococcemia, headache, altered mental status, positive blood cultures, and high cerebrospinal fluid opening pressure (>250 mm H2O).ConclusionsWe strongly recommend early administration of an antifungal agent to each suspected cryptococcal meningitis patient to decrease both the delay by doctors in administering therapy and the mortality risk. Aggressive and supportive care for severe cryptococcal meningitis patients is critical to decrease overall mortality from this infection.(AU)

Initial presentations and final outcomes of primary pyogenic liver abscess: a cross-sectional study.

BACKGROUND: Although pyogenic liver abscess (PPLA) fatalities are decreasing owing to early diagnosis and effective treatments, PPLA-associated complications still exist. The purpose of this study was to analyze the characteristic features of initial presentations and final outcomes of PPLA caused by different pathogens. METHODS: This retrospective study collected and analyzed information regarding initial presentations and final outcomes in patients diagnosed with PPLA at admitted at Changhua Christian Hospital from January 1 to December 31, 2010. RESULTS: During the study period, we analyzed the records of a total of 134 patients with documented PPLA. There were no significant causative pathogen-related differences in symptoms at initial presentation. Compared with the survivor group, patients in the mortality group were characterized by male gender (p < 0.001), malignancy (p < 0.001), respiratory distress (p =0.007), low blood pressure (p = 0.024), jaundice (p = < 0.001), rupture of liver abscess (p < 0.001), endophthalmitis (p = 0.003), and multiple organ failure (p < 0.001). No patients received liver transplantation or were diagnosed with HIV during the study period. According to univariate logistic regression analysis, gender (OR = 1.185, 95% CI: 0.284-11.130, p = 0.006), malignancy (OR = 2.067, 95% CI: 1.174-13.130, p = 0.004), respiratory distress (OR = 1.667, 95% CI: 1.164-14.210, p = 0.006), low blood pressure (OR = 2.167, 95% CI: 2.104-13.150, p = 0.003), jaundice (OR = 1.9, 95% CI: 1.246-3.297, p = 0.008), rupture of liver abscess (OR = 5.167, 95% CI: 2.194-23.150, p = 0.003), endophthalmitis (OR = 2.167, 95% CI: 1.234-13.140, p = 0.005), and multiple organ failure (OR = 3.067, 95% CI: 1.184-15.150, p = 0.001) differed significantly between the mortality and survivor groups. CONCLUSION: Although the initial presentations of PPLA caused by different pathogens were similar, there were significant differences in mortality in cases involving: (1) male patients, (2) malignancy, (3) initial respiratory distress, (4) initial low blood pressure, (5) jaundice, (6) rupture of liver abscess, (7) endophthalmitis, , and (8) multiple organ failure. We strongly recommend using a severity score of the disease to determine the risk of mortality for each patient with PPLA. In order to prevent complications and reduce mortality, more attention must be paid to high-risk PPLA patients.