NKX2-5 regulates the expression of beta-catenin and GATA4 in ventricular myocytes.

BackgroundThe molecular pathway that controls cardiogenesis is temporally and spatially regulated by master transcriptional regulators such as NKX2-5, Isl1, MEF2C, GATA4, and beta-catenin. The interplay between these factors and their downstream targets are not completely understood. Here, we studied regulation of beta-catenin and GATA4 by NKX2-5 in human fetal cardiac myocytes.Methodology/principal findingsUsing antisense inhibition we disrupted the expression of NKX2-5 and studied changes in expression of cardiac-associated genes. Down-regulation of NKX2-5 resulted in increased beta-catenin while GATA4 was decreased. We demonstrated that this regulation was conferred by binding of NKX2-5 to specific elements (NKEs) in the promoter region of the beta-catenin and GATA4 genes. Using promoter-luciferase reporter assay combined with mutational analysis of the NKEs we demonstrated that the identified NKX2-5 binding sites were essential for the suppression of beta-catenin, and upregulation of GATA4 by NKX2-5.ConclusionsThis study suggests that NKX2-5 modulates the beta-catenin and GATA4 transcriptional activities in developing human cardiac myocytes

Pan-resistant Acinetobacter infection in neonates in Karachi, Pakistan.

Background: Pan-resistant Acinetobacter infection has emerged as an important nosocomial pathogen in our inPatient neonates over the past few years. Methodology: We performed a retrospective chart review during a five-year period (July 2003 - June 2008) of all neonates hospitalized in our neonatal intensive care unit (NICU) who developed Acinetobacter infection to identify mortality-associated risk factors in Acinetobacter neonatal infection. Results: During the five-year study period, 122 cultures from 78 neonates grew Acinetobacter. Source sites of positive culture were in the following descending order: blood (n = 57), trachea (n = 55), tissue/wound/body fluids (n = 4), eye (n = 4), urine (n = 1), and cerebrospinal fluid (n = 1). Twenty-four (31%) Patients had Acinetobacter isolated from more than one site. At the time of admission the mean age was 2.08 +/- 4 days and mean weight was 1.77 +/- 0.88 kg, 75% were premature. Pan-resistance (87/122, sensitive only to Polymyxin) was present in 71% of Acinetobacter isolates. Crude mortality rate of this cohort was 47%, while 70% of Patients died within four days after positive Acinetobacter culture. We identified weight of less than 1 kg on admission (p 0.06, adjusted Odds Ratio (AOR) 1.53), gestational age 28 weeks or less (p 0.011, AOR 2.88), poor perfusion (p 0.007, AOR 2.4), thrombocytopenia (p 0.01, AOR 1.6) and metabolic acidosis (p 0.01, AOR 1.67) as predictors associated with poor outcome. Conclusion: Pan-resistant Acinetobacter infection is exceedingly fatal in newborns, particularly in premature and very low-birth weight neonates. Rational antibiotic use and vigilant infection control in NICUs are key to controlling multi-drug resistant Acinetobacter infection and improving clinical outcome

A comparison of fluoroquinolones versus other antibiotics for treating enteric fever: meta-analysis

Objectives To review evidence supporting use of fluoroquinolones as first line agents over other antibiotics for treating typhoid and paratyphoid fever (enteric fever)

Incidence and etiology of omphalitis in Pakistan: a community-based cohort study

Introduction: Although omphalitis (umbilical infections) among newborns is common and a major cause of neonatal deaths in developing countries, information on its burden and etiology from community settings is lacking. This study aimed to determine the incidence and etiology of omphalitis in newborns in high neonatal mortality settings in Karachi, Pakistan. Methodology: Trained community health workers surveyed all new births in three low-income areas from September 2004 to August 2007. Pus samples from the umbilical stumps were obtained from babies with pre-defined signs of illness and subjected to culture and antimicrobial susceptibility testing. Results: Among 6904 births, 1501 (21.7%) newborns were diagnosed with omphalitis. Of these, 325 (21.6%) were classified as mild, 1042 (69.4%) as moderate, and 134 (8.9%) as severe, 141 (9.3%) were associated with clinical signs of sepsis. The incidence of omphalitis was 217.4/1000 live births, moderate-severe omphalitis 170.3 per 1000 live births, and associated with sepsis 20.4 per 1000 live births. Of 853 infants with purulent umbilical discharge, 64% yielded 583 isolates. The most common pathogens were Staphylococcus aureus, of which 291 (95.7%) were methicillin-susceptible Staphylococcus aureus (MSSA) and 13 (4.2%) methicillin-resistant S. aureus (MRSA), Streptococcus pyogenes 105 (18%), Group B beta-hemolytic streptococci 59 (10 %), Pseudomonas spp., 52 (8.9 %), Aeromonas spp. 19 (3.2%), and Klebsiella spp. 12 (2%). Conclusions: A high burden of omphalitis can be associated with sepsis among newborns in low-income communities in Pakistan. S. aureus is the most common pathogen isolated from umbilical pus. Appropriate low-cost prevention strategies need to be implemented

RSV associated hospitalizations in children in Karachi, Pakistan: Implications for vaccine prevention strategies

Major progress is being made in vaccines against Respiratory Syncytial Virus (RSV), with multiple vaccine candidates currently in the clinical phase of development. Making an investment case for public sector financing of RSV vaccine will require estimation of burden, cost-effectiveness, and impact. The aim of this study is to determine the proportion, age distribution and clinical spectrum of RSV associated hospitalizations in children in Karachi, Pakistan. A three years prospective study was conducted at the Aga Khan University Hospital in Karachi, a city of 20 million in south Pakistan, from August 2009 to June 2012. Children less than five years old admitted with acute respiratory infections (ARI) were enrolled. Throat swabs were collected and tested for RSV using real-time PCR. Multivariable log binomial regression analysis was performed to identify the associated factors of RSV infection. Out of 1150 children enrolled, RSV was detected among 223 (19%). Highest rate of RSV detection was in young infants less than 3 months of age (48/168, 29%), which accounted for 22% of all RSV detected. Most common diagnosis in RSV positive infants (age) was bronchiolitis followed by pneumonia, while in older children between the ages of one and 5 years of age, pneumonia and asthma were the most common diagnosis. Although identified year-round, RSV was most prevalent from August to October with peak in September, coinciding with the rainy season. This study identified RSV to be independently associated with younger age (P = 0.036), rainy season (P \u3c 0.001), post-tussive emesis (P = 0.008), intubation (P = 0.003), and discharge diagnosis of bronchiolitis (P = 0.004). Vaccines against RSV that target this age group are likely to yield remarkable benefit

Evaluation of vaccine derived poliovirus type 2 outbreak response options: A randomized controlled trial, Karachi, Pakistan

Background: Outbreaks of circulating vaccine derived polioviruses type 2 (cVDPV2) remain a risk to poliovirus eradication in an era without live poliovirus vaccine containing type 2 in routine immunization. We evaluated existing outbreak response strategies recommended by the World Health Organization (WHO) for control of cVDPV2 outbreaks.Methods: Seronegative children for poliovirus type 2 (PV2) at 22 weeks of life were assigned to one of four study groups and received respectively (1) one dose of trivalent oral poliovirus vaccine (tOPV); (2) monovalent OPV 2 (mOPV2); (3) tOPV together with a dose of inactivated poliovirus vaccine (IPV); or (4) mOPV2 with monovalent high-potency IPV type 2. Stool and blood samples were collected and assessed for presence of PV2 (stool) and anti-polio antibodies (sera).Results: We analyzed data from 265 children seronegative for PV2. Seroconversion to PV2 was achieved in 48, 76, 98 and 100% in Groups 1–4 respectively. mOPV2 was more immunogenic than tOPV alone (p \u3c 0.001); and OPV in combination with IPV was more immunogenic than OPV alone (p \u3c 0.001). There were 33%, 67%, 20% and 43% PV2 excretors in Groups 1–4 respectively. mOPV2 resulted in more prevalent shedding of PV2 than when tOPV was used (p \u3c 0.001); and tOPV together with IPV resulted in lower excretion of PV2 than tOPV alone (p = 0.046).Conclusion: mOPV2 was a more potent vaccine than tOPV. Adding IPV to OPV improved immunological response; adding IPV also seemed to have shortened the duration of PV2 shedding. mIPV2 did not provide measurable improvement of immune response when compared to conventional IPV. WHO recommendation to use mOPV2 as a vaccine of first choice in cVDPV2 outbreak response was supported by our findings

Effectiveness of 10-valent pneumococcal conjugate vaccine against vaccine-type invasive pneumococcal disease in Pakistan

Objective: To assess the effectiveness of 10-valent pneumococcal conjugate vaccine (PCV10) against invasive pneumococcal disease (IPD) due to vaccine serotypes of Streptococcus pneumoniae post introduction of the vaccine into the routine immunization program in Pakistan.Methods: A matched case-control study was conducted at 16 hospitals in Sindh Province, Pakistan. Children aged (eligible to receive PCV10) who presented with radiographically confirmed pneumonia and/or meningitis were enrolled as cases. PCR for the lytA gene was conducted on blood (for radiographic pneumonia) and cerebrospinal fluid (for meningitis) samples to detect S. pneumoniae. The proportion of IPD due to vaccine serotypes (including vaccine-related serogroups) was determined through serial multiplex PCR. For each case, at least five controls were enrolled from children hospitalized at the same institution, matched for age, district, and season.Results: Of 92 IPD patients enrolled during July 2013 to March 2017, 24 (26.0%) had disease caused by vaccine serotypes. Most case (87.5% of 24) and control (66.4% of 134) children had not received any PCV10 doses. The estimated effectiveness of PCV10 against vaccine-type IPD was 72.7% (95% confidence interval (CI) -7.2% to 92.6%) with at least one dose, 78.8% (95% CI -11.9% to 96.0%) for at least two doses, and 81.9% (95% CI -55.7% to 97.9%) for all three doses of vaccine.Conclusion: The vaccine effectiveness point estimates for PCV10 were high and increased with increasing number of doses. However, vaccine effectiveness estimates did not reach statistical significance, possibly due to low power. The findings indicate the likely impact of vaccine in reducing the burden of vaccine-type IPD if vaccine uptake can be improved

Effect of case management on neonatal mortality due to sepsis and pneumonia

<p>Abstract</p> <p>Background</p> <p>Each year almost one million newborns die from infections, mostly in low-income countries. Timely case management would save many lives but the relative mortality effect of varying strategies is unknown. We have estimated the effect of providing oral, or injectable antibiotics at home or in first-level facilities, and of in-patient hospital care on neonatal mortality from pneumonia and sepsis for use in the Lives Saved Tool (LiST).</p> <p>Methods</p> <p>We conducted systematic searches of multiple databases to identify relevant studies with mortality data. Standardized abstraction tables were used and study quality assessed by adapted GRADE criteria. Meta-analyses were undertaken where appropriate. For interventions with biological plausibility but low quality evidence, a Delphi process was undertaken to estimate effectiveness.</p> <p>Results</p> <p>Searches of 2876 titles identified 7 studies. Among these, 4 evaluated oral antibiotics for neonatal pneumonia in non-randomised, concurrently controlled designs. Meta-analysis suggested reductions in all-cause neonatal mortality (RR 0.75 95% CI 0.64- 0.89; 4 studies) and neonatal pneumonia-specific mortality (RR 0.58 95% CI 0.41- 0.82; 3 studies). Two studies (1 RCT, 1 observational study), evaluated community-based neonatal care packages including injectable antibiotics and reported mortality reductions of 44% (RR= 0.56, 95% CI 0.41-0.77) and 34% (RR =0.66, 95% CI 0.47-0.93), but the interpretation of these results is complicated by co-interventions. A third, clinic-based, study reported a case-fatality ratio of 3.3% among neonates treated with injectable antibiotics as outpatients. No studies were identified evaluating injectable antibiotics alone for neonatal pneumonia. Delphi consensus (median from 20 respondents) effects on sepsis-specific mortality were 30% reduction for oral antibiotics, 65% for injectable antibiotics and 75% for injectable antibiotics on pneumonia-specific mortality. No trials were identified assessing effect of hospital management for neonatal infections and Delphi consensus suggested 80%, and 90% reductions for sepsis and pneumonia-specific mortality respectively.</p> <p>Conclusion</p> <p>Oral antibiotics administered in the community are effective for neonatal pneumonia mortality reduction based on a meta-analysis, but expert opinion suggests much higher impact from injectable antibiotics in the community or primary care level and even higher for facility-based care. Despite feasibility and low cost, these interventions are not widely available in many low income countries.</p> <p>Funding</p> <p>This work was supported by the Bill & Melinda Gates Foundation through a grant to the US Fund for UNICEF, and to Saving Newborn Lives Save the Children, through Save the Children US.</p

Associations between eight earth observation-derived climate variables and enteropathogen infection: An independent participant data meta-analysis of surveillance studies with broad spectrum nucleic acid diagnostics

Diarrheal disease, still a major cause of childhood illness, is caused by numerous, diverse infectious microorganisms, which are differentially sensitive to environmental conditions. Enteropathogen‐specific impacts of climate remain underexplored. Results from 15 studies that diagnosed enteropathogens in 64,788 stool samples from 20,760 children in 19 countries were combined. Infection status for 10 common enteropathogens—adenovirus, astrovirus, norovirus, rotavirus, sapovirus, Campylobacter, ETEC, Shigella, Cryptosporidium and Giardia—was matched by date with hydrometeorological variables from a global Earth observation dataset—precipitation and runoff volume, humidity, soil moisture, solar radiation, air pressure, temperature, and wind speed. Models were fitted for each pathogen, accounting for lags, nonlinearity, confounders, and threshold effects. Different variables showed complex, non‐linear associations with infection risk varying in magnitude and direction depending on pathogen species. Rotavirus infection decreased markedly following increasing 7‐day average temperatures—a relative risk of 0.76 (95% confidence interval: 0.69–0.85) above 28°C—while ETEC risk increased by almost half, 1.43 (1.36–1.50), in the 20–35°C range. Risk for all pathogens was highest following soil moistures in the upper range. Humidity was associated with increases in bacterial infections and decreases in most viral infections. Several virus species\u27 risk increased following lower‐than‐average rainfall, while rotavirus and ETEC increased with heavier runoff. Temperature, soil moisture, and humidity are particularly influential parameters across all enteropathogens, likely impacting pathogen survival outside the host. Precipitation and runoff have divergent associations with different enteric viruses. These effects may engender shifts in the relative burden of diarrhea‐causing agents as the global climate changes

Psychosocial factors in patients with kidney failure and role for social worker : a secondary data audit

Background: People with kidney failure face a multitude of psychosocial stressors that affect disease trajectory and health outcomes. Objectives: To investigate psychosocial factors affecting people with kidney failure before or at start of kidney replacement therapy (KRT) and kidney supportive and palliative care (KSPC) phases of illness and to explore role of social worker during the illness trajectory. Methods: We conducted a secondary data audit of patients either before or at start of KRT (Phase 1) and at the KSPC (Phase 2) of illness and had psychosocial assessments between March 2012 and March 2020 in an Australian setting. Results: Seventy-nine individuals, aged 70 ± 12 years, had at least two psychosocial assessments, one in each of the two phases of illness. The median time between social worker evaluations in Phase 1 and Phase 2 was 522 (116−943) days. Adjustment to illness and treatment (90%) was the most prevalent psychosocial issue identified in Phase 1, which declined to 39% in Phase 2. Need for aged care assistance (7.6%−63%; p < 0.001) and carer support (7.6%−42%; p < 0.001) increased significantly from Phase 1 to Phase 2. There was a significant increase in psychosocial interventions by the social worker in Phase 2, including supportive counselling (53%−73%; p < 0.05), provision of education and information (43%−65%; p < 0.01), and referrals (28%−62%; p < 0.01). Conclusion: Adults nearing or at the start of KRT experience immense psychosocial burden and adaptive demands that recognisably change during the course of illness. The positive role played by the nephrology social worker warrants further investigation