Highly drug-resistant pathogens implicated in burn-associated bacteremia in an Iraqi burn care unit.

OBJECTIVE: In low- and middle-income countries, bloodstream infections are an important cause of mortality in patients with burns. Increasingly implicated in burn-associated infections are highly drug-resistant pathogens with limited treatment options. We describe the epidemiology of bloodstream infections in patients with burns in a humanitarian surgery project in Iraq. METHODS: We performed a retrospective, descriptive study of blood culture isolates identified between July 2008 and September 2009 among patients with burns in a single hospital in Iraq who developed sepsis. RESULTS: In 1169 inpatients admitted to the burn unit during the study period, 212 (18%) had suspected sepsis, and 65 (6%) had confirmed bacteremia. Sepsis was considered the primary cause of death in 198 patients (65%; 95% CI 65-70) of the 304 patients that died. The most commonly isolated organisms were Pseudomonas aeruginosa (22 isolates [34%]), Staphylococcus aureus (17 [26%]), Klebsiella pneumoniae (8 [12%]), Staphylococcus epidermidis (7 [11%]), Acinetobacter baumannii (6 [9%]), and Enterobacter cloacae (5 [8%]). A high proportion of Enterobacteriaceae strains produced extended-spectrum beta-lactamase and S. aureus isolates were uniformly methicillin-resistant. For gram-negative bacteria, the most reliably active antibiotics were imipenen and amikacin. CONCLUSIONS: Burn patients with sepsis in Iraq were commonly found to have bloodstream pathogens resistant to most antibiotics available locally. Effective empirical therapy of burn sepsis in this region of Iraq would consist of vancomycin or teicoplanin and a carbapenem-class antibiotic with antipseudomonal activity.

Mid-upper arm circumference based nutrition programming: evidence for a new approach in regions with high burden of acute malnutrition.

BACKGROUND: In therapeutic feeding programs (TFP), mid-upper arm circumference (MUAC) shows advantages over weight-for-height Z score (WHZ) and is recommended by the World Health Organization (WHO) as an independent criterion for screening children 6-59 months old. Here we report outcomes and treatment response from a TFP using MUAC ≤118 mm or oedema as sole admission criteria for severe acute malnutrition (SAM). METHODS: Patient data from September 2007 to March 2009 for children admitted by MUAC ≤118 mm or oedema to a Médecins Sans Frontières (MSF) TFP in Burkina Faso were retrospectively analyzed. Analysis included anthropometric measurements at admission and discharge, program outcomes and treatment response. RESULTS: Of 24,792 patient outcomes analyzed, nearly half (48.8%; n = 12,090) were admitted with MUAC 116-118 mm. Most patients (88.7%; n = 21,983) were 6-24 months old. At admission, 52.7% (n = 5,041) of those with MUAC 116-118 mm had a WHZ <-3 SD. At discharge, 89.1% (n = 22,094) recovered (15% weight gain or oedema resolution), 7.9% (n = 1,961) defaulted, 1.5% (n = 384) failed to respond to treatment, and 1.0% (n = 260) died. Average weight gain was 5.4 g/kg/day, and average MUAC gain was 0.42 mm/day. Patients with MUAC ≤114 mm at admission had higher average daily weight and MUAC gains at discharge compared to those admitted with MUAC 116-118 mm, but those in the latter category required longer lengths of stay to achieve recovery (P<0.001). CONCLUSION: This analysis suggests that MUAC ≤118 mm as TFP admission criterion is a useful alternative to WHZ. Regarding treatment response, rates of weight and MUAC gain were acceptable. Applying 15% weight gain as discharge criterion resulted in longer lengths of stay for less malnourished children. Since MUAC gain parallels weight gain, it may be feasible to use MUAC as both an admission and discharge criterion.

Evaluation of clinical and immunological markers for predicting virological failure in a HIV/AIDS treatment cohort in Busia, Kenya.

BACKGROUND: In resource-limited settings where viral load (VL) monitoring is scarce or unavailable, clinicians must use immunological and clinical criteria to define HIV virological treatment failure. This study examined the performance of World Health Organization (WHO) clinical and immunological failure criteria in predicting virological failure in HIV patients receiving antiretroviral therapy (ART). METHODS: In a HIV/AIDS program in Busia District Hospital, Kenya, a retrospective, cross-sectional cohort analysis was performed in April 2008 for all adult patients (>18 years old) on ART for ≥12 months, treatment-naive at ART start, attending the clinic at least once in last 6 months, and who had given informed consent. Treatment failure was assessed per WHO clinical (disease stage 3 or 4) and immunological (CD4 cell count) criteria, and compared with virological failure (VL >5,000 copies/mL). RESULTS: Of 926 patients, 123 (13.3%) had clinically defined treatment failure, 53 (5.7%) immunologically defined failure, and 55 (6.0%) virological failure. Sensitivity, specificity, positive predictive value, and negative predictive value of both clinical and immunological criteria (combined) in predicting virological failure were 36.4%, 83.5%, 12.3%, and 95.4%, respectively. CONCLUSIONS: In this analysis, clinical and immunological criteria were found to perform relatively poorly in predicting virological failure of ART. VL monitoring and new algorithms for assessing clinical or immunological treatment failure, as well as improved adherence strategies, are required in ART programs in resource-limited settings.

Exposure to violence and PTSD symptoms among Somali women.

Posttraumatic stress disorder (PTSD) symptoms, exposure to traumatic stressors, and health care utilization were examined in 84 women attending a primary health care clinic in Mogadishu, Somalia. The Somalia-Posttraumatic Diagnostic Scale was used in this active warzone to measure symptoms. Nearly all women reported high levels of confrontations with violence; half described being exposed to a potentially traumatizing event. Nearly one third had significant PTSD symptoms. Compared to those who did not, women who reported exposure to a traumatic stressor reported more confrontations with violence (7.1 vs. 3.3; p < . 001), health complaints (3.8 vs. 2.9; p = .03), and nearly 3 times as much (p = .03) health service utilization. A potentially traumatizing event was found to be a simplified proxy for assessing mental health distress in women attending a primary health care facility in highly insecure, unpredictable, resource-limited settings.

Challenges of controlling sleeping sickness in areas of violent conflict: experience in the Democratic Republic of Congo.

BACKGROUND: Human African trypanosomiasis (HAT), or sleeping sickness, is a fatal neglected tropical disease if left untreated. HAT primarily affects people living in rural sub-Saharan Africa, often in regions afflicted by violent conflict. Screening and treatment of HAT is complex and resource-intensive, and especially difficult in insecure, resource-constrained settings. The country with the highest endemicity of HAT is the Democratic Republic of Congo (DRC), which has a number of foci of high disease prevalence. We present here the challenges of carrying out HAT control programmes in general and in a conflict-affected region of DRC. We discuss the difficulties of measuring disease burden, medical care complexities, waning international support, and research and development barriers for HAT. DISCUSSION: In 2007, Médecins Sans Frontières (MSF) began screening for HAT in the Haut-Uélé and Bas-Uélé districts of Orientale Province in northeastern DRC, an area of high prevalence affected by armed conflict. Through early 2009, HAT prevalence rate of 3.4% was found, reaching 10% in some villages. More than 46,000 patients were screened and 1,570 treated for HAT during this time. In March 2009, two treatment centres were forced to close due to insecurity, disrupting patient treatment, follow-up, and transmission-control efforts. One project was reopened in December 2009 when the security situation improved, and another in late 2010 based on concerns that population displacement might reactivate historic foci. In all of 2010, 770 patients were treated at these sites, despite a limited geographical range of action for the mobile teams. SUMMARY: In conflict settings where HAT is prevalent, targeted medical interventions are needed to provide care to the patients caught in these areas. Strategies of integrating care into existing health systems may be unfeasible since such infrastructure is often absent in resource-poor contexts. HAT care in conflict areas must balance logistical and medical capacity with security considerations, and community networks and international-response coordination should be maintained. Research and development for less complicated, field-adapted tools for diagnosis and treatment, and international support for funding and program implementation, are urgently needed to facilitate HAT control in these remote and insecure areas.

Trauma-related psychological disorders among Palestinian children and adults in Gaza and West Bank, 2005-2008.

BACKGROUND: Trauma from war and violence has led to psychological disorders in individuals living in the Gaza strip and West Bank. Few reports are available on the psychiatric disorders seen in children and adolescents or the treatment of affected populations. This study was conducted in order to describe the occurrence and treatment of psychiatric disorders in the Palestinian populations of the Gaza strip and Nablus district in the West Bank. METHODS: From 2005 to 2008, 1369 patients aged more than 1 year were identified through a local mental health and counseling health network. All were clinically assessed using a semi-structured interview based on the DSM-IV-TR criteria. RESULTS: Among 1254 patients, 23.2% reported post-traumatic stress disorder [PTSD], 17.3% anxiety disorder (other than PTSD or acute stress disorder), and 15.3% depression. PTSD was more frequently identified in children < or = 15 years old, while depression was the main symptom observed in adults. Among children < or = 15 years old, factors significantly associated with PTSD included being witness to murder or physical abuse, receiving threats, and property destruction or loss (p < 0.03). Psychological care, primarily in the form of individual, short-term psychotherapy, was provided to 65.1% of patients, with about 30.6% required psychotropic medication. Duration of therapy sessions was higher for children < or = 15 years old compared with adults (p = 0.05). Following psychotherapy, 79.0% had improved symptoms, and this improvement was significantly higher in children < or = 15 years old (82.8%) compared with adults (75.3%; p = 0.001). CONCLUSION: These observations suggest that short-term psychotherapy could be an effective treatment for specific psychiatric disorders occurring in vulnerable populations, including children, living in violent conflict zones, such as in Gaza strip and the West Bank.

Feasibility, drug safety, and effectiveness of etiological treatment programs for Chagas disease in Honduras, Guatemala, and Bolivia: 10-year experience of Médecins Sans Frontières.

BACKGROUND: Chagas disease (American trypanosomiasis) is a zoonotic or anthropozoonotic disease caused by the parasite Trypanosoma cruzi. Predominantly affecting populations in poor areas of Latin America, medical care for this neglected disease is often lacking. Médecins Sans Frontières/Doctors Without Borders (MSF) has provided diagnostic and treatment services for Chagas disease since 1999. This report describes 10 years of field experience in four MSF programs in Honduras, Guatemala, and Bolivia, focusing on feasibility protocols, safety of drug therapy, and treatment effectiveness. METHODOLOGY: From 1999 to 2008, MSF provided free diagnosis, etiological treatment, and follow-up care for patients <18 years of age seropositive for T. cruzi in Yoro, Honduras (1999-2002); Olopa, Guatemala (2003-2006); Entre Ríos, Bolivia (2002-2006); and Sucre, Bolivia (2005-2008). Essential program components guaranteeing feasibility of implementation were information, education, and communication (IEC) at the community and family level; vector control; health staff training; screening and diagnosis; treatment and compliance, including family-based strategies for early detection of adverse events; and logistics. Chagas disease diagnosis was confirmed by testing blood samples using two different diagnostic tests. T. cruzi-positive patients were treated with benznidazole as first-line treatment, with appropriate counseling, consent, and active participation from parents or guardians for daily administration of the drug, early detection of adverse events, and treatment withdrawal, when necessary. Weekly follow-up was conducted, with adverse events recorded to assess drug safety. Evaluations of serological conversion were carried out to measure treatment effectiveness. Vector control, entomological surveillance, and health education activities were carried out in all projects with close interaction with national and regional programs. RESULTS: Total numbers of children and adolescents tested for T. cruzi in Yoro, Olopa, Entre Ríos, and Sucre were 24,471, 8,927, 7,613, and 19,400, respectively. Of these, 232 (0.9%), 124 (1.4%), 1,475 (19.4%), and 1,145 (5.9%) patients, respectively, were diagnosed as seropositive. Patients were treated with benznidazole, and early findings of seroconversion varied widely between the Central and South American programs: 87.1% and 58.1% at 18 months post-treatment in Yoro and Olopa, respectively; 5.4% by up to 60 months in Entre Ríos; and 0% at an average of 18 months in Sucre. Benznidazole-related adverse events were observed in 50.2% and 50.8% of all patients treated in Yoro and Olopa, respectively, and 25.6% and 37.9% of patients in Entre Ríos and Sucre, respectively. Most adverse events were mild and manageable. No deaths occurred in the treatment population. CONCLUSIONS: These results demonstrate the feasibility of implementing Chagas disease diagnosis and treatment programs in resource-limited settings, including remote rural areas, while addressing the limitations associated with drug-related adverse events. The variability in apparent treatment effectiveness may reflect differences in patient and parasite populations, and illustrates the limitations of current treatments and measures of efficacy. New treatments with improved safety profiles, pediatric formulations of existing and new drugs, and a faster, reliable test of cure are all urgently needed.

Outcomes of a remote, decentralized health center-based HIV/AIDS antiretroviral program in Zambia, 2003 to 2007.

A cross-sectional study of patients living with HIV/ AIDS treated during 2003 to 2007 in decentralized, rural health centers in Zambia was performed to measure virological outcomes after 12 months of antiretroviral therapy and identify factors associated with virological failure. Data from 228 patients who started antiretroviral therapy >12 months prior were analyzed. In all, 93% received stavudine + lamivudine + nevirapine regimens, and median antiretroviral therapy duration was 23.5 months (interquartile range 20-28). Of the 205 patients tested for viral load, 177 (86%) had viral load <1000 copies/mL. Probability of developing virological failure (viral load >1000 copies/mL) was 8.9% at 24 months and 19.6% at 32 months. Predictors for virological failure were <100% adherence, body mass index <18.5 kg/m(2), and women <40 years old. Of those with virological failure who underwent 3 to 6 months of intensive adherence counseling, 45% obtained virological success. In a remote, resource-limited setting in decentralized health centers, virological and immunological assessments of patients on antiretroviral therapy >12 months showed that positive health outcomes are achievable.

Selective androgen receptor modulators based on a series of 7H-[1,4]oxazino[3,2-g]quinolin-7-ones with improved in vivo activity.

Modification on a lead series of [1,4]oxazino[3,2-g]quinolin-7-ones at the 2-position led to selective androgen receptor modulators with improved in vivo activity. The most potent analog (-)-33a exhibited full maintenance of levator ani muscle at 3mg/kg and reduced activity on ventral prostate weight in a 2-week orally-dosed and orchidectomized rat maintenance assay.

Substituted 6-(1-pyrrolidine)quinolin-2(1H)-ones as novel selective androgen receptor modulators.

The androgen receptor is a ligand inducible transcription factor that is involved in a broad range of physiological functions. Here we describe the discovery of a new class of orally available selective androgen receptor modulators. The lead compound, 6-[(2R,5R)-2-methyl-5-((R)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl]-4-trifluoromethylquinolin-2(1H)-one (6a), showed excellent anabolic activity in muscle with reduced effect on the prostate in a rat model of hypogonadism. The compound also improved bone strength in a rat model of post-menopausal osteoporosis.

Novel series of potent, nonsteroidal, selective androgen receptor modulators based on 7H-[1,4]oxazino[3,2-g]quinolin-7-ones.

Recent interest in orally available androgens has fueled the search for new androgens for use in hormone replacement therapy and as anabolic agents. In pursuit of this, we have discovered a series of novel androgen receptor modulators derived from 7H-[1,4]oxazino[3,2-g]quinolin-7-ones. These compounds were synthesized and evaluated in competitive binding assays and an androgen receptor transcriptional activation assay. A number of compounds from the series demonstrated single-digit nanomolar agonist activity in vitro. In addition, lead compound (R)-16e was orally active in established rodent models that measure androgenic and anabolic properties of these agents. In this assay, (R)-16e demonstrated full efficacy in muscle and only partially stimulated the prostate at 100 mg/kg. These data suggest that these compounds may be utilized as selective androgen receptor modulators or SARMs. This series represents a novel class of compounds for use in androgen replacement therapy.

Concise total syntheses of the bioactive mesotricyclic diterpenoids jatrophatrione and citlalitrione.

The highly functionalized [5.9.5] tricyclic framework resident in jatrophatrione (1) and citlalitrione (2) has been synthesized. The route begins with the tandem anionic oxy-Cope rearrangement/methylation/transannular ene cyclization of 21 and subsequent introduction of a conjugated enone double bond. Hydroxyl-directed 1,4-reduction of this functionality in 25 with LiAlH(4)/CuI/hexamethylphosphoramide/tetrahydrofuran sets the stage for the implementation of a Grob fragmentation and expedited generation of 27. Stereocontrolled intramolecular hydrosilylation allows for the subsequent introduction of a cyclic carbonate as in 53. This intermediate undergoes remarkably efficient, fully regiocontrolled Treibs reaction to generate 54, with this maneuver serving as a pivotal step for making 1 available five steps later. Treatment of 1 with m-chloroperbenzoic acid leads to 2, with attack occurring preferentially on a alpha-face of the double bond more remote to the carbonyl.

Concerning the antileukemic agent jatrophatrione: the first total synthesis of a [5.9.5] tricyclic diterpene.

The highly functionalized [5.9.5] tricyclic framework resident in jatrophatrione (1) has been synthesized. The route begins with the tandem anionic oxy-Cope rearrangement/methylation/transannular ene cyclization of 5 and subsequent introduction of a conjugated enone double bond. Hydroxyl-directed 1,4-reduction of this functionality in 6 with LiAlH4/CuI/HMPA/THF sets the stage for the implementation of a Grob fragmentation and rapid generation of 8. Stereocontrolled intramolecular hydrosilylation allows for the subsequent introduction of a cyclic carbonate as in 11. This intermediate undergoes a remarkably smooth Treibs reaction to generate 12, thus serving as a pivotal step for making 1 available five steps later.