Outbreak of severe community-acquired bacterial infections among children in North Rhine-Westphalia (Germany), October to December 2022.

PURPOSE: In late 2022, a surge of severe S. pyogenes infections was reported in several European countries. This study assessed hospitalizations and disease severity of community-acquired bacterial infections with S. pyogenes, S. pneumoniae, N. meningitidis, and H. influenzae among children in North Rhine-Westphalia (NRW), Germany, during the last quarter of 2022 compared to long-term incidences. METHODS: Hospital cases due to bacterial infections between October and December 2022 were collected in a multicenter study (MC) from 59/62 (95%) children's hospitals in NRW and combined with surveillance data (2016-2023) from the national reference laboratories for streptococci, N. meningitidis, and H. influenzae. Overall and pathogen-specific incidence rates (IR) from January 2016 to March 2023 were estimated via capture-recapture analyses. Expected annual deaths from the studied pathogens were calculated from national death cause statistics. RESULTS: In the MC study, 153 cases with high overall disease severity were reported with pneumonia being most common (59%, n = 91). IRs of bacterial infections declined at the beginning of the COVID-19 pandemic and massively surged to unprecedented levels in late 2022 and early 2023 (overall hospitalizations 3.5-fold), with S. pyogenes and S. pneumoniae as main drivers (18-fold and threefold). Observed deaths during the study period exceeded the expected number for the entire year in NRW by far (7 vs. 0.9). DISCUSSION: The unprecedented peak of bacterial infections and deaths in late 2022 and early 2023 was caused mainly by S. pyogenes and S. pneumoniae. Improved precautionary measures are needed to attenuate future outbreaks.

The Relationship between School Infrastructure and School Nutrition Program Participation and Policies in New York City.

School nutrition programs (SNP) provide much needed access to fruits, vegetables, and other healthy foods at low or no cost. Yet, the infrastructure of school kitchens and cafeteria vary across schools, potentially contributing to systematic barriers for SNP operation and equity. The purpose of this paper is to examine the association between school infrastructure and outcomes including meal participation, untraditional lunch periods, and having an open campus. Regression analyses were conducted using administrative data for 1804 schools and school nutrition manager survey data (n = 821) in New York City (NYC). Co-location was significantly associated with open campus status (OR = 2.84, CI: 1.11, 7.26) and high school breakfast participation (ß = -0.056, p = 0.003). Overcrowding was associated with breakfast (elementary: ß = -0.046, p = 0.03; middle: ß = 0.051, p = 0.04; high: ß = 0.042, p = 0.04) and lunch participation (elementary: ß = -0.031, p = 0.01) and untraditional lunchtimes (elementary: OR = 2.47, CI: 1.05, 5.83). Higher enrollment to cafeteria capacity ratios was associated with breakfast (elementary: ß = -0.025, p = 0.02) and lunch (elementary: ß = -0.015, p = 0.001; high: ß = 0.014, p = 0.02) participation and untraditional lunchtimes (middle: OR = 1.66, CI: 1.03, 2.68). Infrastructure characteristics are an important source of variation across NYC schools that may hinder the equity of school nutrition programs across the city.

Plasmodium falciparum coinfection is associated with improved IgE and IgG3 response against hookworm antigens.

Background: Plasmodium falciparum and Hookworm infections are prevalent in West Africa and they cause iron deficiency anemia and protein malnutrition in Children. Immune response of these parasites interact and their interactions could have repercussions on vaccine development and efficacy. The current goal of hookworm eradication lies on vaccination. We evaluated the effect of P. falciparum coinfection and albendazole treatment on naturally acquired antibody profile against hookworm L3 stage larvae antigen. Methods: In a longitudinal study, 40 individuals infected with Necator americanus only, 63 participants infected with N. americanus and P. falciparum, and 36 nonendemic controls (NECs) were recruited. The study was done in the Kintampo North Metropolis of Ghana. Stool and blood samples were taken for laboratory analyses. Serum samples were obtained before hookworm treatment and 3 weeks after treatment. Results: The malaria-hookworm (N. americanus and P. falciparum) coinfected subjects had significantly higher levels of IgE (ß = 0.30, 95% CI = [0.12, 0.48], p = 0.023) and IgG3 (ß = 0.15, 95% CI = [0.02, 0.52], p = 0.004) compared to those infected with hookworm only (N. americanus). The N. americanus groups had significantly higher levels of IgG3 (ß = 0.39, 95% CI = [0.14-0.62], p = 0.002) compared to the control group. Similarly, N. americanus and P. falciparum coinfected participants had significantly higher levels of IgE (ß = 0.35, 95% CI = [0.70-0.39], p = 0.002) and IgG3 (ß = 0.54, 95% CI = [0.22-0.76], p = 0.002). Moreover, albendazole treatment led to a significant reduction in IgE, IgA, IgM, and IgG3 antibodies against hookworm L3 stage larvae (p < 0.05). Conclusion: P. falciparum is associated with improved IgE and IgG response against hookworm L3 stage larvae. Treatment with single dose of albendazole led to reduction in naturally acquired immune response against hookworm infection. Thus, P. falciparum infection may have a boosting effect on hookworm vaccine effectiveness.

The Antitumor Mechanism of Paeonol on CXCL4/CXCR3-B Signals in Breast Cancer Through Induction of Tumor Cell Apoptosis.

BACKGROUND: Paeonol, a phenolic component from the root bark of Paeonia moutan, has been identified to possess antitumor effects. However, the effect of paeonol and the mechanism of CXCL4/CXCR3-B signals in paeonol-induced breast cancer cell remain unknown. MATERIALS AND METHODS: After MDA-MB-231 cells were pretreated with paeonol or DMSO, the proliferation activity was detected by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide), Hoechst, Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), and Annexin-V/propidium iodide staining flow cytometry. Western blot and immunohistochemistry of human breast cancer and noncancerous tissues were performed to determine the molecular alteration of CXCL4/CXCR3-B signals. RESULTS: Compared with the control, paeonol-treated breast cancer cells had low proliferation activity and high apoptotic index, indicating that paeonol induces breast cancer cell apoptosis. Western blot and immunohistochemistry showed that paeonol increased CXCR3-B signal, downregulated CXCL4, heme oxygenase (HO-1) with a corresponding increased BACH1, and decreased nuclear factor E2-related factor 2 (Nrf2). CONCLUSIONS: Thus, CXCL4/CXCR3-B may be involved in the mechanism of apoptosis induced by paeonol in breast cancer cells by regulating the expression of BACH1 and Nrf2 to downregulating HO-1 and promote apoptosis. Therefore, the authors suggest paeonol has a significant growth inhibitory effect on breast cancer cells, which may be related to the induction of apoptosis.

Disruption of autophagy by the histone deacetylase inhibitor MGCD0103 and its therapeutic implication in B-cell chronic lymphocytic leukemia.

Evading apoptosis is a hallmark of B-cell chronic lymphocytic leukemia (CLL) cells and an obstacle to current chemotherapeutic approaches. Inhibiting histone deacetylase (HDAC) has emerged as a promising strategy to induce cell death in malignant cells. We have previously reported that the HDAC inhibitor MGCD0103 induces CLL cell death by activating the intrinsic pathway of apoptosis. Here, we show that MGCD0103 decreases the autophagic flux in primary CLL cells. Activation of the PI3K/AKT/mTOR pathway, together with the activation of caspases, and to a minor extent CAPN1, resulting in cleavage of autophagy components, were involved in MGCD0103-mediated inhibition of autophagy. In addition, MGCD0103 directly modulated the expression of critical autophagy genes at the transcriptional level that may contribute to autophagy impairment. Besides, we demonstrate that autophagy is a pro-survival mechanism in CLL whose disruption potentiates cell death induced by anticancer molecules including HDAC and cyclin-dependent kinase inhibitors. In particular, our data highlight the therapeutic potential of MGCD0103 as not only an inducer of apoptosis but also an autophagy suppressor in both combination regimens with molecules like flavopiridol, known to induce protective autophagy in CLL cells, or as an alternative to circumvent undesired immunomodulatory effects seen in the clinic with conventional autophagy inhibitors.

In vitro anticancer activity and biologically relevant metabolization of organometallic ruthenium complexes with carbohydrate-based ligands.

The synthesis and in vitro anticancer activity of dihalogenido(eta6-p-cymene)(3,5,6-bicyclophosphite-alpha-D-glucofuranoside)ruthenium(II) complexes are described. The compounds were characterized by NMR spectroscopy and ESI mass spectrometry, and the molecular structures of dichlorido-, dibromido- and diiodido(eta6-p-cymene)(3,5,6-bicyclophosphite-1,2-O-isopropylidene-alpha-D-glucofuranoside)ruthenium(II) were determined by X-ray diffraction analysis. The complexes were shown to undergo aquation of the first halido ligand in aqueous solution, followed by hydrolysis of a P--O bond of the phosphite ligand, and finally formation of dinuclear species. The hydrolysis mechanism was confirmed by DFT calculations. The aquation of the complexes was markedly suppressed in 100 mM NaCl solution, and notably only very slow hydrolysis of the P--O bond was observed. The complexes showed affinity towards albumin and transferrin and monoadduct formation with 9-ethylguanine. In vitro studies revealed that the 3,5,6-bicyclophosphite-1,2-O-cyclohexylidene-alpha-D-glucofuranoside complex is the most cytotoxic compound in human cancer cell lines (IC50 values from 30 to 300 microM depending on the cell line).

Synthesis, structure, spectroscopic properties, and antiproliferative activity in vitro of novel osmium(III) complexes with azole heterocycles.

Reactions of (H 2azole) 2[OsCl 6], where Hazole = pyrazole, Hpz, ( 1), indazole, Hind, ( 2), imidazole, Him, ( 3) and benzimidazole, Hbzim, ( 4) with the corresponding azole heterocycle in 1:4 molar ratio in boiling isoamyl alcohol or hexanol-1 afforded novel water-soluble osmium(III) complexes of the type trans-[OsCl 2(Hazole) 4]Cl, where Hazole = Hpz ( 5a), Hind ( 6a), Him ( 7a), and Hbzim ( 9a) in 50-70% ( 5a, 7a, 9a) and 5% ( 6a) yields. The synthesis of 7a was accompanied by a concurrent reaction which led to minor formation (<4%) of cis-[OsCl 2(Him) 4]Cl ( 8). The complexes were characterized by elemental analysis, IR spectroscopy, UV-vis spectroscopy, ESI mass spectrometry, cyclic voltammetry, and X-ray crystallography. 5a, 7a, and 9a were found to possess remarkable antiproliferative activity in vitro against A549 (non-small cell lung carcinoma), CH1 (ovarian carcinoma), and SW480 (colon carcinoma) cells, which was compared with that of related ruthenium compounds trans-[RuCl 2(Hazole) 4]Cl, where Hazole = Hpz (5b), Hind (6b), Him (7b), and Hbzim (9b).

Surveillance of transmitted HIV drug resistance among women attending antenatal clinics in Dar es Salaam, Tanzania.

BACKGROUND: In resource-limited settings where antiretroviral treatment (ART) access is being scaled-up, the World Health Organization (WHO) recommends surveillance of transmitted HIV drug resistance (HIVDR). We used the WHO HIVDR threshold survey method to assess transmitted HIVDR in Dar es Salaam where ART was introduced in 1995 and where approximately 11,000 people are currently on ART. METHODS: From November 2005 to February 2006, dried blood spot (DBS) specimens were made from remnant specimens collected during the national HIV serosurvey from 60 primagravidas <25 years old attending six antenatal clinics for routine syphilis testing. Genotyping was performed at the Centers for Disease Control and Prevention, Atlanta, Georgia, USA. Protease and reverse transcriptase drug resistance mutations were identified using the Stanford University HIV drug resistance database. We used the National Institutes of Health genotyping tool for HIV-1 subtyping. HIVDR prevalence categorization was based on the WHO threshold survey binomial sequential sampling method. RESULTS: Among the 60 eligible specimens collected, 50 DBS were successfully amplified using RT-PCR. Sequencing was performed on the first 39 specimens: 13 (33.3%) were subtype A1, 13 (33.3%) subtype C, and 4 (10.3%) subtype D, the remainder differed in the closest subtype based on protease versus reverse transcriptase. No resistance mutations were seen; HIVDR to all drug classes was categorized as <5%. CONCLUSIONS: Our survey indicates that prevalence of transmitted HIVDR among recently infected pregnant women in Dar es Salaam is low (<5/%). The survey should be repeated during the next HIV sentinel survey in Dar es Salaam and extended to other regions where ART is being scaled up.

Metal-based paullones as putative CDK inhibitors for antitumor chemotherapy.

Paullones constitute a class of potent cyclin-dependent kinase inhibitors. To overcome the insufficient solubility and bioavailability, which hamper their potential medical application, we aim at the development of metal-based derivatives. Two types of paullone ligands, L (1) - L (3) and L (4) , with different locations of metal-binding sites, were prepared. They were found to form organometallic complexes of the general formula [M (II)Cl(eta (6)- p-cymene)L]Cl ( 1- 4, L = L (1) - L (4) ; a, M = Ru; b, M = Os). The complexes were characterized by X-ray crystallography, one- and two-dimensional NMR spectroscopy and other physical methods. Complexes 1- 3, with a coordinated amidine unit, were found to undergo E/ Z isomerization in solution. The reaction was studied by NMR spectroscopy, and activation parameters Delta H (double dagger) and Delta S (double dagger) were determined. Antiproliferative activity in the low micromolar range was observed in vitro in three human cancer cell lines by means of MTT assays. (3)H-Thymidine incorporation assays revealed the compounds to lower the rate of DNA synthesis, and flow cytometric analyses showed cell cycle arrest mainly in G 0/ G 1 phase.

The first ruthenium-based paullones: syntheses, X-ray diffraction structures, and spectroscopic and antiproliferative properties in vitro.

Two novel paullone derivatives, namely, 6-(alpha-picolylamino)-7,12-dihydroindolo[3,2-d][1]benzazepine (L1) and 9-bromo-6-(alpha-picolylamino)-7,12-dihydroindolo[3,2-d][1]benzazepine (L2), have been prepared. The reaction of cis-[RuCl2(DMSO)4] (DMSO=dimethyl sulfoxide) with L1 and L2 in a 1:1 molar ratio in dry ethanol at 50 degrees C afforded the complexes trans-[RuIICl2(DMSO)2L1] (1a) and trans-[RuIICl2(DMSO)2L2] (1b) in 26 and 30% yield, respectively. The reaction carried out from the same starting compounds in a 1:2 molar ratio at 75 degrees C led to the formation of [RuIICl(DMSO)(L1)2]Cl (2a) and [RuIICl(DMSO)(L2)2]Cl (2b) in 16 and 23% yield, correspondingly. The products were characterized by elemental analysis, one- and two-dimensional NMR spectroscopy, electrospray ionization mass spectrometry, IR spectroscopy, electronic spectra, cyclic voltammetry, and X-ray crystallography (L1, L2, 1a, and 2b). Complexes 2a and 2b exhibit remarkable antiproliferative activity in three human carcinoma cell lines, A549 (non-small cell lung carcinoma), CH1 (ovarian carcinoma), and SW480 (colon carcinoma). The novel complexes show an intercalative mode of interaction with DNA, which may render them attractive alternatives to metal compounds with a coordinative mode of interaction.

Estimating and projecting HIV prevalence and AIDS deaths in Tanzania using antenatal surveillance data.

BACKGROUND: The Estimations and Projections Package (EPP 2005) for HIV/AIDS estimates and projects HIV prevalence, number of people living with HIV and new HIV infections and AIDS cases using antenatal clinic (ANC) surveillance data. The prevalence projection produced by EPP can be transferred to SPECTRUM, a demographic projection model, to calculate the number of AIDS deaths. This paper presents estimates and projections of HIV prevalence, new cases of HIV infections and AIDS deaths in Tanzania between 2001 and 2010 using the EPP 2005 and SPECTRUM soft-wares on ANC data. METHODS: For this study we used; the 1985-2004 ANC data set, the 2005 UN population estimates for urban and rural adults, which is based on the 2002 population census, and results of the 2003 Tanzania HIV Indicator Survey. The ANC surveillance sites were categorized into urban and rural areas on the basis of the standard national definitions of urban and rural areas, which led to 40 urban and 35 rural clinic sites. The rural and urban epidemics were run independently by fitting the model to all data and on level fits. RESULTS: The national HIV prevalence increased from 0% in 1981 to a peak of 8.1% in 1995, and gradually decreased to 6.5% in 2004 which stabilized until 2010. The urban HIV epidemic increased from 0% in 1981 peaking at 12.6% in 1992 and leveled to between 10.9% and 11.8% from 2003 to 2010. The rural epidemic peaked in 1995 at 7.0% and gradually declined to 5.2% in 2004, and then stabilized at between 5.1% and 5.3% from 2005 to 2010. New infections are projected to rise steadily, resulting in 250,000 new cases in 2010. Deaths due to AIDS started in 1985 and rose steadily to reach 120,000 deaths in 2010, with more females dying than men. CONCLUSION: The fact that the number of new infections is projected to increase steadily to reach 250,000 per year in 2010 calls for more concerted efforts to combat the spread of HIV infection particularly in the rural areas where the infrastructure needed for prevention programmes such as counseling and testing, condom accessibility and AIDS information is less developed.

Surveillance of HIV and syphilis infections among antenatal clinic attendees in Tanzania-2003/2004.

BACKGROUND: This paper presents the prevalence of human immunodeficiency virus (HIV) and syphilis infections among women attending antenatal clinics (ANC) in Tanzania obtained during the 2003/2004 ANC surveillance. METHODS: Ten geographical regions; six of them were involved in a previous survey, while the remaining four were freshly selected on the basis of having the largest population among the remaining 20 regions. For each region, six ANC were selected, two from each of three strata (urban, peri-urban and rural). Three of the sites did not participate, resulting into 57 surveyed clinics. 17,813 women who were attending the chosen clinics for the first time for any pregnancy between October 2003 and January 2004. Patient particulars were obtained by interview and blood specimens were drawn for HIV and syphilis testing. HIV testing was done anonymously and the results were unlinked. RESULTS: Of the 17,813 women screened for HIV, 1,545 (8.7% (95% CI = 8.3-9.1)) tested positive with the highest prevalence in women aged 25-34 years (11%), being higher among single women (9.7%) than married women (8.6%) (p < 0.07), and increased with level of education from 5.2% among women with no education to 9.3% among those at least primary education (p < 0.001). Prevalence ranged from 4.8% (95% CI = 3.8%-9.8%) in Kagera to 15.3% (95% CI = 13.9%-16.8%) in Mbeya and was; 3.7%, 4.7%, 9.1%, 11.2% and 15.3% for rural, semi-urban, road side, urban and 15.3% border clinics, respectively (p < 0.001). Of the 17,323 women screened for syphilis, 1265 (7.3% (95%CI = 6.9-7.7)) were positive, with highest prevalence in the age group 35-49 yrs (10.4%) (p < 0.001), and being higher among women with no education than those with some education (9.8% versus 6.8%) (p < 0.0001), but marital status had no influence. Prevalence ranged from 2.1% (95% CI = 1.4%-3.0%) in Kigoma to 14.9% (95% CI = 13.3%-16.6%) in Kagera and was 16.0% (95% CI = 13.3-18.9), 10.5% (95% CI = 9.5-11.5) and 5.8% (95% CI = 5.4-6.3) for roadside, rural and urban clinics, respectively. Syphilis and HIV co-infection was seen in 130/17813 (0.7%). CONCLUSION: The high HIV prevalence observed among the ANC clinic attendees in Tanzania call for expansion of current voluntary counselling and testing (VCT) services and access to antiretroviral drugs (ARV) in the clinics. There is also a need for modification of obstetric practices and infant feeding options in HIV infection in order to prevent mother to child transmission of HIV. To increase uptake to HIV testing the opt-out strategy in which all clients are offered HIV testing is recommended in order to meet the needs of as many pregnant women as possible.

Prognostic value of ambulatory blood-pressure recordings in patients with treated hypertension.

BACKGROUND: It is uncertain whether ambulatory blood-pressure measurements recorded for 24 hours in patients with treated hypertension predict cardiovascular events independently of blood-pressure measurements obtained in the physician's office and other cardiovascular risk factors. METHODS: We assessed the association between base-line ambulatory blood pressures in treated patients and subsequent cardiovascular events among 1963 patients with a median follow-up of 5 years (range, 1 to 66 months). RESULTS: We documented new cardiovascular events in 157 patients. In a Cox proportional-hazards model with adjustment for age, sex, smoking status, presence or absence of diabetes mellitus, serum cholesterol concentration, body-mass index, use or nonuse of lipid-lowering drugs, and presence or absence of a history of cardiovascular events, as well as blood pressure measured at the physician's office, higher mean values for 24-hour ambulatory systolic and diastolic blood pressure were independent risk factors for new cardiovascular events. The adjusted relative risk of cardiovascular events associated with a 1-SD increment in blood pressure was 1.34 (95 percent confidence interval, 1.11 to 1.62) for 24-hour ambulatory systolic blood pressure, 1.30 (95 percent confidence interval, 1.08 to 1.58) for ambulatory systolic blood pressure during the daytime, and 1.27 (95 percent confidence interval, 1.07 to 1.57) for ambulatory systolic blood pressure during the nighttime. For ambulatory diastolic blood pressure, the corresponding relative risks of cardiovascular events associated with a 1-SD increment were 1.21 (95 percent confidence interval, 1.01 to 1.46), 1.24 (95 percent confidence interval, 1.03 to 1.49), and 1.18 (95 percent confidence interval, 0.98 to 1.40). CONCLUSIONS: In patients with treated hypertension, a higher ambulatory systolic or diastolic blood pressure predicts cardiovascular events even after adjustment for classic risk factors including office measurements of blood pressure.