text:
Checking in on the Class Clown
The social mood evolution is upon us.
The European dog has wagged our tail during this sovereign sequel to the first phase of our financial crisis.
It is, in many ways, the mirror image or the 2008 financial scrimmage.
The pebble causing ripples across the pond?
Euro-Bonds, also known as Germany V. Other.
Closer to home, it's Red, Blue, Blah... with a massive opportunity evolving.
I shared some vibes on social mood in 2006 that suddenly seem apropos. At the risk of being the guy who quotes himself -- yes, I'm aware and no, I don't like it -- the dynamic is cumulative, as most elements of our financial condition are.
To that end, some thoughts on the landscape, as first shared in the summer of 2006:
We've spent countless hours chewing through the fundamental backdrop, technical landscape, structural underpinnings, and psychological crosscurrents. We apply our craft each day with great pride and determined enthusiasm, challenging ourselves to climb an endless ladder of financial acumen.
But this column isn't about the next best trade or the contextual implications of a secular shift, it's about our societal state and simple coexistence as we subtly shift into a new era of American lifestyle. It's easy to ignore this evolution while staring at our screens, but a step outside our comfort zone -- and a step into the world around us -- unveils a disturbing yet unavoidable truth.
The 2004 election brought the dichotomy between blue states and red states to the forefront of the mainstream mindset, but a more disturbing conundrum has evolved that had little to do with party lines or political affiliations.
As we edge through the post-bubble world, the growing chasm between the "haves" and "have not's" has become readily apparent. Indeed, while the names have changed to protect the affluent, the middle class has quietly eroded to forge a wedge between the lifestyles of the rich and a struggle to exist. Welcome to Serf City, USA, a place where we're entirely more comfortable not discussing the rigors of everyday life or the struggles that so many currently endure.
Those of us who grew up on Wall Street wore CAPITALISM across our chest like a badge of honor. Meritocracy and intellectual agility differentiated our existence and afforded us status in a white shoe world. The dot.com frenzy bridged those Benjamin's to the digital age, and migrated wealth to Silicon Valley and beyond.
Once that ship sailed, fiscal and monetary agendas were implemented to prolong the modern day Jazz Age with hopes of avoiding the other side of that joyous ride. And in what many believe was the last hurrah at the Bubble Spa, home equity became the enabler of paper trades and happy trails. Yes, for some, life, or the perception thereof, has been very good indeed.
Meanwhile, on the other side of the tracks, a different breed of reality has emerged. Wage growth is stagnant, energy costs are on the rise, education expenses are escalating and our once proud manufacturing sector has been outsourced abroad.
When the going gets tough, as the counter-parties of our government obligations have recently shown us, the tough tend to take care of themselves. That manifestation wears many faces, be it nationalization of natural resources or a debasement of the dollar as the world currency reserve. We can pretend it doesn't exist but denial has never been a viable investment strategy.
As we digest the ramifications of eminent domain, understand the motivation of the bankruptcy laws and accept that social security and pension programs are inherently flawed, the growing societal chasm has become increasingly apparent.
Indeed, almost 40% of all US wealth is in the hands of the top 1% of the population, compared to 13% 25 years ago. As this dichotomy manifests, the implications for consumer spending, real-estate investment and long-term savings will be profoundly impacted. We've discussed the "dollar devaluation vs. asset class deflation" thesis for quite some time but it will become entirely more meaningful when words become reality and these dynamics arrive at our front door.
I often opine that the stock market is the world's largest thermometer and the truest reflection of our collective health. The good doctors at our central bank know this, of course, and have taken great strides to supplement our organic ecosystem with artificial stimuli.
The imbalances have been building under a seemingly calm surface but they're starting to percolate in the socioeconomic arena. This will have profound implications in a delicate global balance and will continue the seismic shift until it reaches critical mass deemed to "matter" by the financial markets and those absorbed by them.
What can we do?
- Be aware and alert of the evolution that surrounds us rather than hope that it will quietly dissipate.
- Save when we can and stay out of debt, particularly as it pertains to the adjustable rate mortgages that our former Fed deity so readily proclaimed to be a solution.
- Diversify holdings and explore alternative currency vehicles, understanding that cash may be king but our kingdom itself is shrinking.
- Know that capital preservation is the first step towards prolonged profitability and understand that it will be a long, hard road.
- And be mindful of our blessings rather than stressing about petty differences or unnecessary acrimony. These words may sound trite, but society is simply the sum of its parts.
If I've learned anything during my short time on earth, it's that net worth and self-worth aren't mutually exclusive endeavors. I hope that I'm mistaken about what I foresee to be the inevitable consequences of our societal addictions as we all stand to benefit from a rising tide.
Wisdom has taught me that I know very little and perhaps my trepidation will serve as the grist of sustainable economic success. I will simply ask that you see all sides of the probability spectrum and take steps to ensure that you're in a position to sell hope and buy despair.
For if the chasm between perception and reality closes, opportunities will abound for those in a position to capture them.
I will end this column by repeating an oft-mentioned mantra; we gotta go through it to get through it. We're going through it now and that's one step closer to where we want -- and need -- to be. That, on the margin, is constructive.
This is not the time to beat yourself up or wallow in the why.
It's time to look within, summon strength and seize opportunity; for mark my words, this too shall pass.
Twitter: @todd_harrison
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Todd Harrison is the founder and Chief Executive Officer of Minyanville. Prior to his current role, Mr. Harrison was President and head trader at a $400 million dollar New York-based hedge fund. Todd welcomes your comments and/or feedback at email@example.com.
The information on this website solely reflects the analysis of or opinion about the performance of securities and financial markets by the writers whose articles appear on the site. The views expressed by the writers are not necessarily the views of Minyanville Media, Inc. or members of its management. Nothing contained on the website is intended to constitute a recommendation or advice addressed to an individual investor or category of investors to purchase, sell or hold any security, or to take any action with respect to the prospective movement of the securities markets or to solicit the purchase or sale of any security. Any investment decisions must be made by the reader either individually or in consultation with his or her investment professional. Minyanville writers and staff may trade or hold positions in securities that are discussed in articles appearing on the website. Writers of articles are required to disclose whether they have a position in any stock or fund discussed in an article, but are not permitted to disclose the size or direction of the position. Nothing on this website is intended to solicit business of any kind for a writer's business or fund. Minyanville management and staff as well as contributing writers will not respond to emails or other communications requesting investment advice.
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Lortholary, Oliviera,b; Poizat, Gwendolinec; Zeller, Valéried; Neuville, Ségolènee; Boibieux, Andréf; Alvarez, Murielg; Dellamonica, Pierreh; Botterel, Françoisei; Dromer, Françoisea; Chêne, Genevièvec; The French Cryptococcosis Study Group
From the aCentre National de Référence Mycologie et Antifongiques, Unité de Mycologie Moléculaire, Institut Pasteur, Paris, France
bUniversité René Descartes, Hôpital Necker-Enfants malades, Centre d'Infectiologie Necker-Pasteur, Paris, France
cINSERM, Université Victor Segalen, Bordeaux, France
dPitié Salpétrière hospital, Paris, France
eSaint Louis hospital Paris, France
fLa Croix Rousse, Lyon, France
gPurpan hospital, Toulouse, France
hl'Archet hospital, Nice, France
iService de Parasitologie-Mycologie, Hôpital Henri Mondor, Créteil, France.
Received 18 May, 2006
Accepted 11 July, 2006
Correspondence to Olivier Lortholary, Center National de Référence Mycologie et Antifongiques, Institute Pasteur, Paris, France. Tel: +331 4568 8355; fax: +33 1 4565430; e-mail: email@example.com
This work was presented in part at the 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago, September 2003 [abstract M-1752].
Note: The study databasis was approved by the 'Commission Nationale Informatique et Libertés'.
Background: Immune restoration following combination antiretroviral therapy (cART) questions the maintenance of prophylaxis among HIV-infected patients with cryptococcosis.
Objective: To describe the long-term outcome after the diagnosis of cryptococcosis at the cART era.
Design: Multicentre cohort of patients with a diagnosis of cryptococcosis between 1996 and 2000, follow-up until December 2002. Comparison with a historical cohort (1990–1994) for survival.
Setting: Eighty-four French AIDS clinical centres.
Patients: Two-hundred and forty HIV-infected adult patients at the cART era and 149 at the pre-cART era experiencing a first episode of culture-confirmed cryptococcosis.
Results: In the cART era, 82/189 patients surviving more than 3 months after initiation of antifungal therapy had their maintenance therapy interrupted with a subsequent median follow-up of 19 months. Their relapse rate per 100 person-years was 0.9 [95%confidence interval (CI),0.0–2.0]. When considering the whole cART cohort, probability of reaching negative serum cryptococcal antigen was 71% after 48 months of follow-up. A CD4 cell count < 100/μl [relative risk (RR), 5.5; 95% CI, 1.3–22.2], antifungal therapy < 3 months over the past 6 months [RR, 5.0; 95% CI, 1.1–22.3] and serum cryptococcal antigen titre ≥ 1/512 [RR, 3.5; 95% CI, 1.1–10.8] were associated with a higher rate of cryptococcosis relapse. The mortality rate per 100 person-years was 15.3 [95% CI,12.2–18.4] in the cART era versus 63.8 [95% CI,53.0–74.9] in the pre-cART era although early mortality did not differ between the two periods.
Conclusion: Overall survival after cryptococcosis has dramatically improved at the cART era. Immune restoration and low serum cryptococcal antigen titres are associated with lower cryptococcosis relapse rates.
Extra-pulmonary cryptococcosis is a potentially life-threatening infection in severely immunocompromised HIV-infected individuals [1,2]. Therapeutic guidelines for this AIDS-defining illness are based on the results of major randomized trials [3]. After 3 months of acute phase therapy, life-long maintenance therapy with fluconazole was classically recommended to prevent relapses [4,5]. However, prolonged maintenance therapy may be responsible for pharmacokinetic interactions [6] and selection of Candida sp. strains with reduced susceptibility to azoles [7]. Furthermore, it may be limited by its cost, especially in developing countries where the disease is highly prevalent [8,9]. In countries with a large access to antiretrovirals, overall mortality and incidence of AIDS-defining opportunistic infections have been reduced dramatically [10], in particular the incidence of cryptococcosis [11–13]. In addition, the risk of cryptococcosis relapse decreased from 50–60% to 2–4% due to the introduction of maintenance antifungal therapy [4,5,14].
Reports based on limited samples have suggested that maintenance therapy could be safely withdrawn in HIV-infected patients treated by combination antiretroviral therapy (cART) presenting with stable immune restoration [15–20]. However, no study has documented the relapse rate, long-term survival and clearance of serum cryptococcal antigen since the introduction of cART. We thus took advantage of the nationwide surveillance of cryptococcosis in France [13,21] to describe the long-term outcome after a first episode of cryptococcosis at the cART era through a historical comparison with patients notified in the pre-cART era. We also estimated the incidence of cryptococcosis relapse and its determinants, and described the relationship between immune restoration, virological outcome and clearance of serum cryptococcal antigen overtime.
Using the ongoing nationwide surveillance of cryptococcosis managed by the French National Reference Center for Mycoses (NRCM) [13,21], a retrospective multicenter cohort called CryptoStop was designed including HIV-infected adults who developed a first episode of culture-confirmed cryptococcosis between April 1996 and June 2000. Standardized questionnaires were used to collect information on epidemiological, clinical, microbiological and therapeutic characteristics at baseline (i.e., initiation of antifungal induction therapy) and after 3, 6 and 12 months of antifungal therapy, then annually until December 2002. Laboratory procedures for cryptococcosis diagnosis and follow-up (cultures condition, kit for the detection of cryptococcal antigen) as well as management of HIV and C. neoformans infections followed local guidelines.
Cases diagnosed between January 1990 and December 1994 ('pre-cART era') among HIV-infected patients were matched for clinical centre to build up a 'historical cohort' for survival comparison. Cases diagnosed between January 1995 and March 1996 were excluded because of potential access to cART in this transitional period. The detailed information requested by the protocol was collected for 389 patients, i.e., 240/252 patients of the cART period and 149/380 patients of the historical period. All the questionnaires were reviewed by two of us to minimize missing data.
Clinical severity of cryptococcal meningitis was defined as the presence of altered mental status and/or seizures and/or cranial nerve palsy at the time of diagnosis [1,22]. cART consisted in the initial association of two nucleoside reverse transcriptase inhibitors plus at least one protease inhibitor or one non-nucleoside reverse transcriptase inhibitor. Time elapsed between cryptococcosis diagnosis and cART initiation was categorized as: < 8 days, within 7 days and ≥ 8 days.
Maintenance therapy was considered as started when the daily dosage of fluconazole was reduced to 200 mg/day before the third month of therapy and at month 3 in other cases. Relapses were defined as a new isolation of C. neoformans in culture, whatever the anatomic site, in a patient for whom initial fungal culture(s) had become negative. The underlying cause of death was considered to be cryptococcosis in the presence of clinical symptoms related to cryptococcosis together with a positive fungal culture within one month before death.
We used Chi2 tests to compare the distribution of categorical variables and Wilcoxon tests to compare the distribution of continuous variables. Survival time was calculated from the date of diagnosis of cryptococcosis (baseline) to death or the last available follow-up before December 2002. Time to a negative serum cryptococcal antigen was calculated from the date of diagnosis of cryptococcosis to the date of the first negative serum antigen result (when the result remained persistently negative after a positive one) or to the date of the last available serum antigen detection. Among the 189 patients who survived at least 3 months after diagnosis, time to relapse was calculated from the date of diagnosis of cryptococcosis to the date of diagnosis of relapse or death or the last available follow-up visit before December 2002. Incidence density of all three events was calculated as the ratio of the number of events in different patients over the total number of person-years at risk. Survival, probability of reaching a negative serum cryptococcal antigen and probability of occurrence of a relapse were all estimated using the Kaplan–Meier method. Cox proportional hazards models were used to study the association between patients' characteristics and either death, or cryptococcosis relapse.
Regarding cryptococcosis relapse analysis, variables associated with relapse in the univariate analysis with P < 0.25 were retained in the initial multivariate analysis. CD4 cell count, HIV-1 RNA plasma level, duration of antifungal therapy and serum cryptococcal antigen titre were considered as dichotomous time-dependent variables. For each variable, we chose a clinically relevant threshold.
Survival analysis included 240 patients at the cART era. Variables associated with survival in the univariate analysis with P < 0.25 were retained in the initial multivariate analysis. In addition, this model retained major known prognostic factors of survival, i.e., AIDS stage, injecting drug use, age, CD4 cell count and HIV RNA levels [23,24] as well as specific factors of cryptococcosis (severity, meningitis or dissemination at baseline). Information on meningitis or dissemination was considered missing when cerebrospinal fluid analysis (direct examination, antigen detection and culture) or culture was not performed in at least two non-contiguous body sites, respectively. SAS software (version 8.0, SAS Institute) was used for statistical analysis.
Among the 240 patients studied in the recent years, 41 died within the first 3 months, 10 were lost to follow-up and 189 survived beyond 3 months of antifungal therapy and had access to maintenance therapy. Among the 189 patients, 40/189 (21%) had received cART at least 8 days before cryptococcosis diagnosis, 26/189 (14%) within 7 days of diagnosis and 109/189 (58%) at least 8 days after. Finally, 14/189 (7%) never received cART. Baseline median CD4 cell count did not differ whether patients were receiving cART or not: 24 cells/μl [interquartile range (IQR), 12–52 cells/μl) and 18 cells/μl (IQR, 7–48 cells/μl), respectively, but HIV-1 RNA was slightly lower in the former group: 4.9 log10/ml (IQR, 3.4–5.2 log10/ml) and 5.1 log10/ml (IQR, 4.6–5.6 log10/ml), respectively (P < 0.01).
Eighty-two patients (43%) had their maintenance therapy interrupted – even if only transiently – and 107 patients (57%) never discontinued antifungal therapy. At baseline, the former group had a significantly higher proportion of cryptococcosis cases revealing AIDS, a reduced duration of antiretroviral treatment and cART intakes before cryptococcosis diagnosis and a trend towards higher CD4 cell count and lower frequency of meningitis (Table 1). These groups did not differ in terms of age (median, 38 years), sex (86% male), HIV transmission category (39% homosexual men, 42% heterosexual, 9% injecting drug users) and, among antiretroviral-naive patients, in terms of time to cART initiation (median, 1 month). In the 82 patients interrupting antifungal therapy, the median follow-up period was 53 months (IQR, 38–62 months). In the other 107 patients, the median follow-up duration was 27 months (IQR, 15–47 months). The median follow-up period after withdrawal of antifungal maintenance therapy was 19 months (IQR, 8–34 months). Median time between cryptococcosis diagnosis and withdrawal was 26 months (IQR, 13–37 months) and median time between cART and withdrawal was 26 months (IQR, 13–37 months). According to the physician in charge of the patient, maintenance antifungal therapy was stopped because of stable immune restoration (≥ 100 CD4 cells/μl, ≥ 6 months) in 65%, difficulties in taking long-term fluconazole in 16%, adverse events related to antifungal therapy in 5% and other reasons in 14%. At the time of withdrawal, all 82 patients were clinically well, their median reciprocal cryptococcal serum antigen titre was 82 (IQR, 8–400), their median CD4 cell count was 291 cells/μl (IQR, 165–418 cells/μl) and their median HIV-1 RNA was 2.3 log10 copies/ml (IQR, 1.7–3.9 log10 copies/ml). There was a non-significant trend towards higher median CD4 cells count 3, 6 and 12 months after diagnosis of cryptococcosis in patients who interrupted maintenance therapy (data not shown). The median time between cryptococcosis diagnosis and first negative serum cryptococcal antigen was 23 months (IQR, 13–40 months) in patients whose maintenance therapy was subsequently interrupted and it was 22 months (IQR, 12–38 months) in those with sustained maintenance therapy.
Antifungal therapy was resumed for 14 patients, leaving 68/82 patients for whom it was definitively interrupted. Among the 68 patients who experienced prolonged interruption as compared to those 14, median time between diagnosis of cryptococcosis and withdrawal of maintenance therapy was 27 months (range, 0–65 months) and 9 months (range, 2–44 months), respectively (P < 0.01). Characteristics differed significantly between the two groups with more severe fungal and HIV infections in the latter: baseline median CD4 cell count was 304 cells/μl (range, 8–972 cells/μl) and 109 cells/μl (range, 12–345 cells/μl), median HIV-1 RNA was 2.3 log10 copies/ml (range, 1.3–5.6log10 copies/ml) and 4.5 log10 copies/ml (range, 1.5–5.7 log10 copies/ml) and median serum cryptococcal reciprocal antigen titre was 10 (range, 0–8000) and 1000 (range, 8–16 000), respectively. At the time maintenance therapy had to be resumed in the 14 patients (after a median of 8 months), median CD4 cell count was 84 cells/μl (range, 3–142 cells/μl) and median HIV-1 RNA was 4.9 log10 copies/ml (range, 2.1–6.5 log10 copies/ml).
Among the 189 patients followed at the cART era, 15 culture-confirmed relapses were diagnosed, by positive cerebrospinal fluid samples in 13 cases. These patients differed from non-relapsing patients only in terms of baseline CD4 cell count. It was lower in those with subsequent relapse: 7 cells/μl (range, 0–40 cells/μl) than in other patients: 21 cells/μl (range, 0–480 cells/μl) (P < 0.001). Among the 68 patients whose maintenance therapy was definitely stopped, no relapse was recorded, while three relapses were observed at 15, 46 and 15 months after the initial diagnosis of cryptococcosis among the 14 patients with a transient interruption of maintenance therapy, and 12 relapses were diagnosed among the 107 patients for whom prolonged antifungal maintenance therapy was prescribed. Inconstant compliance to cART was notified by 7/12 patients (58%) and to fluconazole in 8/12 patients (67%). Overall, for the 15 patients experiencing relapse, the median time between diagnosis of the first episode of cryptococcosis and relapse was 12 months (range, 3–46 months). At the time of relapse, median CD4 cell count was 11 cells/μl (range, 1–169 cells/μl) and median HIV-1 RNA 4.6 log10 copies/ml (range, 1.3–5.3 log10 copies/ml).
Thus, the average relapse rate was 4.6 per 100 person-years [95%confidenceinterval(CI),2.0–7.2] for patients who continued maintenance therapy and 0.9 per 100 person-years (95% CI, 0.0–2.0) in those for whom antifungal therapy was interrupted. Of note, the relapse rate in our pre-cART cohort was 7.6 per 100 person-years (95% CI, 3.7–11.4).
The mean increase in CD4 cell count (cells/μl; 95% CI) between baseline and 6 months was significantly higher in patients without subsequent relapse than in the 15 patients experiencing relapse: +78 (+63 to +93) versus 21 (−21 to +64), respectively (P = 0.01). This difference remained true after 24 months of follow-up +187 (+156 to +219) versus +74 (+8 to +140) (P = 0.004). In the multivariate analysis (n = 189), a latest CD4 cell count (time-dependent variable) < 100 cells/μl was associated with a higher rate of cryptococcosis relapse: hazard ratio (HR), 5.5 (95% CI, 1.3–22.2; P = 0.02), as was a duration of antifungal therapy < 3 months over the past 6 months: HR, 5.0 (95% CI, 1.1–22.3; P = 0.03) and a latest serum cryptococcal antigen titre ≥ 1/512 (time-dependent variable): HR, 3.5 (95% CI, 1.1–10.8; P = 0.03).
The probability of reaching a negative serum cryptococcal antigen was 4.9% at 6 months of antifungal therapy, 12.4% at 12 months, 35.4% at 24 months and 70.5% at 48 months of antifungal therapy (Fig. 1). The evolution of CD4 cell count paralleled the probability of negative serum cryptococcal antigen curve while the curve of HIV-1 RNA followed an inverse shape. Among the 107 patients with sustained prescription of antifungal maintenance therapy, serum cryptococcal antigen became negative in 34% as compared to 50% in the group for which maintenance therapy was interrupted (P = 0.04). The probability of reaching a negative serum cryptococcal antigen according to baseline CD4 cell count, baseline HIV-1 RNA and initiation of cART is shown in Fig. 2. The lower the initial CD4 cell count, the lower the probability that the serum cryptococcal antigen will become negative during follow-up (Fig. 2a). The negativation of serum cryptococcal antigen occurred faster in antiretroviral-naive patients at baseline for whom HIV-1 RNA was the highest (Fig. 2b). Of note, CD4 cell count was the highest in the group of patients with baseline viral load > 5.5 log10 copies/ml.
Patients studied in the cART era were older and had higher CD4 cell counts compared with those diagnosed during the historical period (data not shown). Of 240 patients 147 (61%) presented cryptococcosis revealing AIDS including 120 with cryptococcosis alone, 22 with an associated AIDS classifying disease and five with at least two other associated AIDS classifying diseases, while in the pre-cART era cryptococcosis revealed AIDS in 71/149 (48%). In recent years, cryptococcosis was more often disseminated (53% versus 30%; P < 0.0001) and meningitis more severe (33% versus 13%; P < 0.001) while the number of patients treated by antiretroviral agents was lower (36% versus 52%; P = 0.002) as compared to the historical group. When considering antifungal therapy administered in both periods, among 195 patients with meningitis at baseline, 31 (16%) received fluconazole alone and 56 patients (29%) received amphotericin B alone at the cART era. When considering pre-cART era, among the 120 patients with meningitis at baseline, 47 (39%) received fluconazole alone and 50 (42%) received amphotericin B alone.
The median duration of follow-up was 30 months (range, < 1–74 months) versus 11 months (range, < 1–101 months) in the cART and pre-cART periods, respectively. The average mortality rate per 100 person-years was 15.3 (95% CI, 12.2–18.4 per 100 person-years) in the cART era versus 63.8 (95% CI, 53.0–74.9 per 100 person-years) in the pre-cART era. The probability of death at 3 months was 18% (95% CI, 13–23%) and 21% (95% CI, 14–27%) in the cART and pre-cART periods, respectively (Fig. 3). Mortality curves diverged from 6 months onwards, probability of death at 6, 12, 24 and 48 months being 22%, 25%, 34% and 41% in the cART and 32%, 54%, 76% and 92% in the pre-cART periods, respectively. Deaths related to cryptococcosis were 43/131 (33%) in the pre-cART period and 36/94 (38%) in the cART period. Of 82 patients patients with interruption of maintenance therapy 69 (84%) were alive without relapse compared to 57/107 (53%) in the other group (P < 0.0001). In the multivariate analysis, prescription of cART was significantly associated with a longer survival (HR, 0.13; 95% CI, 0.06–0.25), after adjustment for CD4 cell count, age, HIV transmission category, AIDS stage, and baseline HIV RNA.
Basing our observations on a large number of HIV-infected patients followed long term, we first confirm that withdrawing maintenance antifungal therapy can be safely considered in patients with stable immune restoration. Secondly, we document determinants of cryptococcosis relapse and describe the evolution towards negative cryptococcal antigen during the cART era. Thirdly, we report dramatic changes in the long-term outcome, although short-term survival after the diagnosis of cryptococcosis in the cART era remained as high as in the pre-cART period [16].
The safety of interrupting chemoprophylaxis against various opportunistic infections in patients presenting stable immune restoration over time has frequently been documented [18,25–30]. Recommendations for HIV management have suggested similar conclusions for cryptococcosis when a sustained increase of CD4 lymphocyte count (i.e., > 100–200 cells/μl for ≥ 6 months) is reached [31,32] as documented by studies of limited sizes [15–17]. Kirk et al. showed no relapse among 39 patients with cryptococcosis whose maintenance therapy was stopped providing their CD4 cell counts were > 50 cells/μl [18]. It was further confirmed in a randomized study including 42 patients who received 48 weeks of cART [19]. Finally, an international observational study including patients with a CD4 cell count > 100 cells/μl reported four cryptococcosis relapses in patients with stable immune restoration [20]. However, the alternative diagnosis of immune reconstitution inflammatory syndrome that can occur up to several months after cryptococcosis diagnosis was not excluded in three of four patients [33,34]. It is unlikely that a randomized trial will be designed given the very low rate of relapse. Thus, our report from a very large observational cohort represents the best current available data on the safety of stopping maintenance antifungal therapy.
No previous study at the cART era questioned the incidence and factors potentially associated with cryptococcal relapse. Here, we show that the relapse rate was very low, i.e., 0.9 per 100 person-years in those for whom antifungal therapy was interrupted. Based on extended follow-up of these patients, it is unlikely that this incidence of relapse is underestimated. Before the availability of cART, the estimated risk of cryptococcosis relapse in the absence of maintenance therapy was high, varying between 37% in a trial [14] and 50–60% in early retrospective studies [1,2]. In patients receiving daily fluconazole (100–200 mg/day) therapy, the risk varied between 2 and 4% in the literature [4,5,14] and 7.6 per 100 person-years in the present cohort. Thus, we observe here a lower risk of relapse than in the period when the best maintenance antifungal therapy was available but cART was not.
The influence of CD4 cell count on the subsequent risk of cryptococcosis relapse had not been previously documented [18–20]. Here, not only do we show that patients presenting subsequent microbiologically-confirmed relapse had a lower CD4 cell count at baseline but also that they experienced a less pronounced increase of CD4 cells during the first weeks of cART compared to patients who will not relapse. Thus, the nadir of CD4 cell count and the ability to obtain an early immune restoration significantly influence the risk of cryptococcosis relapse. Moreover, a CD4 cell count remaining < 100 cells/μl during follow-up was associated with a 5.5-fold rate of cryptococcosis relapse. We acknowledge that the cut-off for CD4 cell count was empirically estimated; nevertheless since our observation was retrospective and physicians based their decisions on no available recommendation, we believe that this might be an appropriate CD4 threshold for the decision to stop maintenance therapy. In addition, our data also suggest that clinicians should resume antifungal prophylaxis when the CD4 cell count is declining below 100 cells/μl. This emphasizes the need for careful clinical and immunological follow-up of patients for whom maintenance therapy is interrupted. Of particular importance, a serum cryptococcal antigen titre ≥ 1/512 at any time during follow-up was associated with a 3.5-fold rate of cryptococcosis relapse. In the pre-cART period, a lower initial serum cryptococcal antigen titre has been associated with a significantly lower risk of relapse [14]. However, sequential monitoring was not classically recommended as there was no relationship with outcome [35,36]. Based on our results, monitoring cryptococcal antigen titres together with CD4 T-cell counts should help determine when to stop or to resume antifungal maintenance therapy.
Finally, another major finding disclosed here is the still high early mortality related to cryptococcosis in the period of cART as compared to an historical period despite published guidelines [3]. Several factors might explain this observation. First, the population developing AIDS-associated cryptococcosis in Western countries has changed over time [12,13] and is diagnosed with more severe cryptococcosis as evidenced here. Second, all patients did not receive optimal therapy for cryptococcal meningitis, i.e., a combination of flucytosine and amphotericin B and management of elevated intracranial pressure-which are known to be a determinant of mycological success in patients with meningitis [37,38]. However, adjunctive therapy such as recombinant interferon-γ1b might contribute to improve the early outcome [39].
The dramatically improved long-term outcome and unchanged short-term evolution described here for cryptococcosis are in accordance with results reported for AIDS-associated tuberculosis [40] or severe Pneumocystis jiroveci pneumonia [41].
In conclusion, cART is associated with longer overall survival after AIDS-associated cryptococcosis. CD4 cell-count and serum cryptococcal antigen titre together with an antifungal therapy regimen should be recorded carefully during follow-up to identify patients at risk of cryptococcosis relapse.
We thank Dr Karine Sitbon and Cécile Droz for their excellent collaboration to the study; Ensemble contre le SIDA for their grant for the CryptoStop study and the fellowship for Dr Karine Sitbon and the excellent collaboration of the French Cryptococcosis Study Group including 84 clinical centers in France.
The following members of the French Cryptococcosis Study Group enrolled patients in the present study and collected clinical data (by alphabetical order of the cities):
C. de Roux Serratrice, T. Bensaid: Aix en Provence; J.L. Schmitt, C. Raccurt: Amiens; E. Pichard, J.P. Bouchara: Angers; C. Michon, S. Blanc: Annecy; J.F. Dor, V. Blanc: Antibes; A. de la Blanchardière, H. Lefranc: Avignon; X. Lionet, F. Leturdu: Argenteuil; M. Ferrand, X. Larrouy: Bayonne; C. Drobacheff, L. Million: Besançon; O. Lortholary, C. Bouges Michel: Bobigny; J.F. Viallard, Bernard Couprie: Hôpital Haut Leveque, J.M. Ragnaud, B. Couprie, Hôpital Pellegrin, J. Beylot, B. Couprie, Hôpital St André – Bordeaux; E. Rouveix, M.E. Bougnoux: Boulogne; N. Canu, F. Laurent: Bourg en Bresse; J. Julien, M. Gavignet: Bourges; L. de St Martin, E. Moalic: Brest; S. Lefort, Brive; J.M. Korach, D. Toubas: Chalon en Champagne; B. Salles, C. Sire: Chalon sur Saone; C. Jacomet, M. Cambon: Clermont Ferrand; E. Mortier, M.L. Joly Guillou: Colombes; V. Garait, X. Fauchet, Centre hospitalier intercommunal, A.S. Lascaut, Stéphane Bretagne: Hôpital Henri Mondor – Creteil; R. Verdon: Caen; M. Duong, A. Bonnin: Dijon; A. Devidas, C. Malbrunot: Corbeil; P. de Truchis, J.L. Gaillard: Garches; J.P. Stahl, B. Lebeau, Grenoble; Y. Quertainmont, F. Botterel: Kremlin Bicêtre; I. Rivoal, M.A. de Sailly: La Roche sur Yon; J.P. Bedos, O. Eloy: Le Chesnay; P. Weinbreck, M.L. Darde: Limoges; A. Boibieux, M.A. Piens: Hôpital de la Croix Rousse, P. Mialhes, M.A. Piens: Hôpital Hôtel Dieu, C. Jourdan, M.A. Piens: Hôpital Wertheimer, M. Bret, M.A. Piens: Hôpital Edouard Herriot – Lyon; H. Tissot Dupont, A. Blancard: Hôpital de la Conception, N. Petit, A. Michel Nguyen: Hôpital Ste Marguerite – Marseille; M. Nezri, M. Bietrix: Martigues; Y. la Torre, C. Chandesris: Montargis; X. Kabbani, Montfermeil; V. le Moing, P. Rispail: Montpellier; C. Rabaud, M. Biava: Nancy; E. Billaud, O. Morin: Nantes; P. Del Giudice, M. Gari Toussaint: Fréjus; P. Dellamonica, E. Rosenthal, M. Garit Toussaint: Nice; T. Prazuck, D.M. Poisson: Orléans; J.L. Vildé, P. Yéni, O. Bouchaud, V. Descamps, C. Chochillon: Hôpital Bichat, C. Piketty, V. Lavarde: Hôpital Georges Pompidou, D. Salmon, N. Franck, A. Paugam: Hôpital Cochin, A. Compagnucci, M. Cornet: Hôtel Dieu, L. Bodard, Y. Péan: Institut Mutualiste Monsouris, C. le Maignan, V. Lavarde: Hôpital Laennec, J.P. Viard, L. Roudière, S. Challier: Hôpital Necker-Enfants malades, B. Dupont, F. Dromer: Hôpital de l'Institut Pasteur, V. Zeller, A. Datry: Hôpital Pitié Salpétrière, G. Pialoux, J.L. Poirot: Hôpital Rothschild, M.C. Meyohas, E. Frajdenrach, P. Roux: Hôpital St Antoine, J. Gilquin, A. Marmorat: Hôpital St Joseph, S. Neuville, C. Lacroix: Hôpital St Louis, I. Lecomte, P. Roux: Hôpital Tenon – Paris; G. Le Moal, C. Kaufman-Lacroix: Poitiers; C. Arvieux, S. Chevrier: Rennes; P. Aboud, L. Favennec, Hôpital Charles Nicolle, D. Benhamou, L. Favennec: Hôpital Bois Guillaume – Rouen; M.A. Khuong, N. Godineau: St Denis; T. Debord: St Mandé; B. Héry, O. Morin: St Nazaire; X. Line, X. Fiacre, Soissons; X. Martinot, J.M. Lang, J. Waller: Strasbourg; S. Chadapaud, A. Blancard: Hôpital Chalucet, J.P de Jaureguyberry, A. Blancard: Hôpital St Anne – Toulon; M. Alvarez, M.D. Linas: Toulouse; Y. Yazdanpanah, X. de Keyser: Tourcoing; D. Vittecoq, F. Botterel: Villejuif; S. Dellion, J. Breuil: Villeneuve St Georges, France.
cryptococcosis; c-ART; immune restoration; outcome; survival; polysaccharide
© 2006 Lippincott Williams & Wilkins, Inc.
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NEW YORK -- Point-of-purchase advertising is not something to be taken lightly, particularly in view of the fact that 70% of all supermarket purchases are in some way influenced by such promotion. Throw in the statistics from a recent study that showed 96% of supermarket shoppers make at least one purchase that is in some way affected by POP material and 93% of shoppers make at least one totally unplanned purchase per trip to the store, and its importance is highlighted even more. That was ...
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FRESNO -- Mayor Ashley Swearengin has proclaimed May 3 – 10 "Historic Preservation Week" as part of the celebratory activities around the United States during the National Trust's Historic Preservation Month. The National Trust theme this year is a "New Age of Preservation: Embark, Inspire, Engage."
The City of Fresno adopted a Historic Preservation Ordinance in 1979 which established a Local Register of Historic Resources as well as a Historic Preservation Commission. Through the Ordinance the City Council recognized that a region's historical resources help to define a sense of place, connect us to our past, impart pride in its citizens, and are also important in economic revitalization and in heritage tourism.
Locally there will be numerous opportunities to engage and hopefully be inspired at a series of activities and events celebrating the region's diverse history. Participating with the City in the week-long festivities are The Fresno Historical Society, the Fresno Housing Authority, Fresno State University's Humanics Program, Heritage Fresno, Warnors Center for the Performing Arts and several property owners in the South Van Ness Industrial District.
All activities are free unless otherwise noted:
Saturday, May 3: Walking Tour of the South Van Ness Industrial District. 10 am to noon, meet at 175 Fulton Street. The area south of Fresno's downtown was the heart of Armenian Town and the region's fruit packing industry. Some of the sites on this walking tour include the J.M. Menend/Murray Ice Cream Company Building, the San Joaquin Grocery Warehouse and Sham's Rio Grande Service Station, which was recently restored following a devastating fire. Tour led by Karana Hattersley-Drayton, the City's Historic Preservation Project Manager. Event co-sponsored by Alena Foods and Baskin Mechanical Engineers.
Friday, May 9: The Great Architects of Historic Fresno Scavenger Hunt, 5:30 pm registration, hunt begins at 6 PM, Warnor's Theater, 1400 Fulton Street. Grab your friends, your smart phone and your running shoes for this updated twist on the traditional scavenger hunt. How many historic resources can you and your team find? Yes, this is a competition. Group teams are encouraged! All ticket sales benefit the Students4Giving Philanthropy Project of Humanics at Fresno State. To register: http://www.eventbrite.com/e/fresnos-great-architects-scavenger-hunt-tickets-11226820723?aff=efblike. Co-sponsored by the Fresno State Humanics Program and the Warnors Center for the Performing Arts.
Saturday, May 10: "The New Deal": Walking Tour of Fresno's Depression-era Architecture with Historic Displays, 10-noon, Veteran's Memorial Auditorium Foyer, 2425 Fresno Street. Join Karana Hattersley-Drayton, Historic Preservation Project Manager and members of the Historic Preservation Commission for a walking tour of New Deal buildings and infrastructure in and around the City's 1936 Memorial Auditorium. The walk will be about a mile in length on city streets. Heritage Fresno will provide refreshments and authors Janice Stevens and Pat Hunter will be on hand to sell and autograph their books on Fresno's architecture and history. Fresno Historical Society staff will display historic photos depicting the era when Franklin D. Roosevelt's "alphabet soup" of federal agencies put people back to work through a variety of agencies and projects.
Saturday, May 10: Helm Home Open House, noon-2 pm, 1749 L Street. The 1902 Mission Revival style "Alamo House" has been transformed from a pile of code violations and cracking plaster into a whitewashed gem. Join Fresno Housing Authority staff for this personal tour of the restored and refurbished interior. Refreshments will be served.
Saturday, May 10th: Meux Home Museum Celebrates Mother's Day with a Victorian Garden Tea. Gates open at 11:00 am seating begins at 11:30 am. $35.00 per person includes luncheon and tour of historic Meux family home. Reservations: (559) 291-4520.For general information about all the Preservation Week events please contact Karana Hattersley-Drayton, City of Fresno Historic Preservation Project Manager, (559) 621-8520 or email@example.com.


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Our Commitment to the Environment
All of the components that we recycle are processed down to the basic commodities right here in North America at an environmentally-friendly electronics e-cycling facility. These facilities are specifically designed to efficiently break down electronic components into resources that can then be reused or redistributed with little or no impact on the environment.
According to the EPA:
- More than 50 million computers are abandoned every year
- More than 3,000 tons of electronics are discarded every day
- 80% of discarded electronics end up in a landfill
- Only 5% of U.S. electronics recyclers refuse to export e-waste
Computers, monitors, and cell phones contain toxins, including lead and arsenic. Every day Americans dispose of 130,000 computers. Today, 23 cell phones are produced every second and Americans discard more than 100 million cell phones per year. MHD is committed to helping improve the environment and preventing these electronics from ending up in landfills.
Product Disassembly
All end-of-life products processed by MHD Enterprises are disassembled in a state of the art local e-cycling facility. We separate any unusable materials from the recyclable resources during the disassembly process to reduce the risk of cross contamination. MHD does not employ the use of electronic shredders (grinders) to dismantle electronic products. We believe that whole unit granulation can be the cause of cross contamination of material and may actually reduce the amount of raw materials that can be recycled.
Materials Disposal Policy
We are committed to preventing the unauthorized dumping of electronic waste in developing countries by implementing our Materials Disposal Policy. This policy requires that all of our certified partners pledge to this same commitment. Along with our Materials Disposal Policy, every certified recycling partner must pass through a strenuous approval process and be held to the highest industry standards. Continual monitoring and third party audits ensure that our e-cycling partners are in full compliance with our policies and that they are doing everything possible to mitigate any possible risk to the environment.
Zero Landfill Policy
We oppose the waste of reusable resources and the unnecessary disposal of excess, obsolete, and scrap electronics because oftentimes, these electronics end up in landfills. This is why we have developed an environmentally-friendly system that monitors the e-cycling process from start to finish and helps to minimize the impact on our environment.
Third Party Auditing
MHD has a complete and comprehensive independent third party audit of its e-cycling facilities to not only ensure total environmental compliance with State and Federal regulations, but also to evaluate our processes and procedures to make sure we are doing everything possible to reduce the impact on the environment.
Environmental Impact Monitoring
We monitor all of our downstream vendors to confirm that they are in compliance with our environmental policies. We have committed to the tracking of hazardous and non-hazardous materials throughout the entire recycling chain to ensure that the downstream intermediaries and recovery operations are meeting all applicable environmental and health regulations.


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Gorgeous 2013 Lala Textile Lawn For Women
Lala textile is a finest and popular textile in Pakistan fashion industry. Lala textile is newly launch there dresses in lawn prints. It's elegant and unique designs are available now on markets.
They use dark and light color with a good mixture. This collection is consisting on three piece soot. These three pieces are Printed shirt; simple dye shalwar and digital print chiffon silk dopata.
These dresses are stitched in the different style like; long shirt, frock, yoke with sleeve and sleeveless. The colors of the dresses are natural and attractive. Pippin and patch in other colors very neat and good stitched.
Trouser and pajama match with these dresses. Black, golden and brown print with beautiful neckline and skin printed chiffon dopata is awesome. Black border and neck line print shirt is gorgeous with different back print.
Panel style with a chunnated yoke is stunning in stitching style. Sleeves are in also print chiffon stuff in this collection. This collection is complete with so many styles like printed back, flower on back, printed neckline and border.
Brand: Lala textile
Stuff: lawn and chiffon
Color: bright
Design: long shirt and pajama
Perfect for: summer party wear
Category: Brands Collection


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The Alec Baldwin Full Employment Act.
Media Trackers bills itself as a "conservative nonprofit, nonpartisan investigative watchdog dedicated to promoting accountability in the media and government across Wisconsin through cutting-edge research and communications initiatives."
It is the website that on Oct. 29 ran a long blog post entitled "Mark Pocan's Husband Told Beaten GOP Operative 'You're a Marked Man,' Threatened and Harassed Via Text Message."
By that afternoon Isthmus and others were reporting that the alleged texts between Phil Frank, state Rep. Pocan's husband, and Kyle Wood, then a campaign worker for Republican congressional candidate Chad Lee, were made up. Pocan, a Democrat, and Lee are running for the 2nd Congressional District seat being vacated by Tammy Baldwin, who is running for U.S. Senate.
Madison police also updated an earlier incident report indicating that Wood, who is gay, had recanted previous statements about being beaten in his home.
The headline chosen by Media Trackers stated as fact that harassing texts were sent by Frank to Wood. Yet author Brian Sikma provided no evidence he had investigated the veracity of the texts. He nevertheless ran the alleged full transcript of the text exchange, which, when printed, ran three pages.
A reader using the handle "Badgerlvr" commented: "Thank you for doing the job that other 'reporters' fail to do."
In fact, Sikma failed to do what professional reporters do: namely, confirm allegations before publication.
For the rest of Davidoff's excellent story, please go to
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Trump's politics are not the problem.
The fiery Milwaukee Sheriff is on the shortlist to head the Department of Homeland Security.
By Wendell Berry
Manifesto: The Mad Farmer Liberation Front
Love the quick profit, the annual raise, vacation with pay. Want more of everything ready made. Be afraid to know your neighbors and to die. And you will have a window in your head. Not even your future will be a mystery any more. Your mind will be punched in a card and shut away in a little drawer. When they want you to buy something they will call you. When they want you to die for profit they will let you know. So, friends, every day do something that won't compute. Love the Lord. Love the world. Work for nothing. Take all that you have and be poor. Love someone who does not deserve it. Denounce the government and embrace the flag. Hope to live in that free republic for which it stands. Give your approval to all you cannot understand. Praise ignorance, for what man has not encountered he has not destroyed. Ask the questions that have no answers. Invest in the millennium. Plant sequoias. Say that your main crop is the forest that you did not plant, that you will not live to harvest. Say that the leaves are harvested when they have rotted into the mold. Call that profit. Prophesy such returns. Put your faith in the two inches of humus that will build under the trees every thousand years. Listen to carrion—put your ear close, and hear the faint chattering of the songs that are to come. Expect the end of the world. Laugh. Laughter is immeasurable. Be joyful though you have considered all the facts. So long as women do not go cheap for power, please women more than men. Ask yourself: Will this satisfy a woman satisfied to bear a child? Will this disturb the sleep of a woman near to giving birth? Go with your love to the fields. Lie easy in the shade. Rest your head in her lap. Swear allegiance to what is nighest your thoughts. As soon as the generals and the politicos can predict the motions of your mind, lose it. Leave it as a sign to mark the false trail, the way you didn't go. Be like the fox who makes more tracks than necessary, some in the wrong direction. Practice resurrection.
Wendell Berry is a poet, farmer, and environmentalist in Kentucky. This poem, first published in 1973, is reprinted by permission of the author and appears in his "New Collected Poems" (Counterpoint).


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The Interdisciplinary Telecom Program (ITP) includes the study of Internet, telecom, and energy communication networks. The program was specifically designed to provide a cross-disciplinary curriculum of electrical engineering, computer science, business, economics, policy, and law that prepares graduates to design, plan, analyze, and manage information networks and telecommunication systems.
Students can enter the program from a wide variety of technical, information technology, and liberal arts undergraduate studies. After selecting and completing two areas of emphasis for their master's program, such as wireless networks, network architecture, cyber security, smart grids, and regulatory policy, graduates will be able to apply their learning to careers at telecommunications, utilities, financial services, healthcare, e-commerce, and Internet-based organizations.
As the oldest and one of the most prestigious graduate telecom programs in the nation, the ITP continuously enhances its curriculum to lead the way in communications and technology. For more than 40 years, our cross-disciplinary focus has educated students from a variety of backgrounds such as engineering, business, economics, policy, and the legal professions who thrive on this intense and rapidly changing technology environment.
This is a field that is no longer a matter of technology alone; it has matured to link complicated technology, business, and management problems with legal, political, and regulatory challenges. It is essential that today's managers and future leaders understand both the technology and complex multidisciplinary environments that characterize the modern information network.
Through coursework, research, and laboratory studies, ITP students obtain an understanding of the latest thinking and best practices relating to networking, wireless systems, cyber security, 21st century telecom technology, as well as business and regulatory policy frameworks. A new digital energy lab is being launched to provide hands-on experience for students focusing on energy communications networks, integrating digital communications with our century-old electric power grid.
The Boulder-Denver area is home to a large number of high-tech companies dedicated to networking and the Internet, which offer internship opportunities for students. Boulder also is one of the top cities in the country for start-ups, and the area hosts several national labs, including the National Renewable Energy Laboratory, the U.S. government lab focused exclusively on energy which has a close affiliation with CU-Boulder.
The PhD in telecom enables students to address the key challenges of our global society's communications and networking infrastructure. For example, researchers at CU-Boulder are helping develop WiMAX, the next generation of the Internet — a more mobile version — and ITP is employing the new technology in a laboratory setting to allow students first-hand experience with this technology. For students interested in an energy focus, the Graduate Digital Energy Program represents ITP's commitment to and expansion into the energy sector — leveraging the study of Internet technology, wireless, network design, security, and other areas to integrate two-way telecommunications technology into the electric power grid.
ITP graduates receive job offers from a variety of start-ups as well as medium-sized and Fortune 1000 companies that rely on networks and the integration of two-way telecom technology into existing and newly created information infrastructures. Graduates of the program have received job offers from eBay, Yahoo, Facebook, Level 3 Communications, Intrado, Teletech, Qwest, and Comcast, among others.
Employment of computer network, systems, and database administrators is expected to grow much faster than average, with an increase of 30 percent by 2018. (U.S. Bureau of Labor Statistics)
Starting annual salary will vary depending on the size of a company, location and the telecom graduate's previous years of work experience. Median annual wages of network and computer systems administrators in the U.S. were $66,310 in 2008.
CUEngineering: A publication for alumni and friends. Read the 2016 edition of CUEngineering magazine here.


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PITTSBURGH — Giant Eagle here celebrated Earth Day on Monday with a special Facebook donation drive that will result in up to $10,000 being provided to Allegheny County Parks in the Pittsburgh region and the Cleveland and Columbus Metro Parks. "Giant Eagle will donate $1 each time our Facebook Earth Day post is 'Shared' on Monday," said Giant Eagle spokesperson Dan Donovan, in a statement. "With the simple push of a button our customers can promote ...
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