Notch-3 affects chemoresistance in colorectal cancer via DNA base excision repair enzymes.

Colon cancer is the second leading cause of cancer death. With over 153,000 new CRC cases predicted, it is the third most commonly diagnosed cancer. Early detection can lead to curative surgical intervention, but recurrent and late metastatic disease is frequently treated with chemotherapeutic options based on induction of DNA damage. Understanding mechanism(s) that regulate DNA damage repair within colon tumor cells is essential to developing effective therapeutic strategies. The Notch signaling pathway is known to participate in normal colon development and we have recently described a pathway by which Notch-1, Notch-3 and Smad may regulated EMT and stem-like properties in colon tumor cells, promoting tumorigenesis. Little is known about how Notch may regulate drug resistance. In this study, we used shRNA to generate colon tumor cells with loss of Notch-3 expression. These cells exhibited reduced expression of the base-excision repair proteins PARP1 and APE1, along with increased sensitivity to ara-c and cisplatin. These data point to a pathway in which Notch-3 signaling can regulate DNA repair within colon tumor cells and suggests that targeting Notch-3 may be an effective approach to rendering colon tumors sensitive to chemotherapeutic drugs.

Management of Traumatic Nerve Palsies in Paediatric Supracondylar Humerus Fractures: A Systematic Review.

Purpose: Up to 12% of paediatric supracondylar humerus fractures (SCHFs) have an associated traumatic nerve injury. This review aims to summarize the evidence and guide clinicians regarding the timing of investigations and/or surgical interventions for traumatic nerve palsies after this injury. Methods: A formal systematic review was undertaken in accordance with the Joanna Briggs Institute (JBI) methodology for systematic reviews and PRISMA guidelines. Manuscripts were reviewed by independent reviewers against the inclusion and exclusion criteria, and data extraction, synthesis, and assessment for methodological quality were undertaken. Results: A total of 51 manuscripts were included in the final evaluation, reporting on a total of 510 traumatic nerve palsies in paediatric SCHFs. In this study, 376 nerve palsies recovered without any investigation or intervention over an average time of 19.5 weeks. Comparatively, 37 went back to theatre for exploration beyond the initial treatment due to persistent deficits, at an average time of 4 months. The most common finding at the time of exploration was entrapment of the nerve requiring neurolysis. A total of 27 cases did not achieve full recovery regardless of management. Of the 15 reports of nerve laceration secondary to paediatric SCHFs, 13 were the radial nerve. Conclusions: Most paediatric patients who sustain a SCHF with associated traumatic nerve injury will have full recovery. Delayed or no recovery of the nerve palsy should be considered for exploration within four months of the injury; earlier exploration should be considered for radial nerve palsies.

Immunisation used for offensive and defensive purposes during the Second World War.

The best defence against natural or intentional biological agents during armed conflict is usually immunisation, as with typhoid fever, but exceptional circumstances are informative. A large iatrogenic epidemic of hepatitis B occurred in 1942 due to contaminated lots of yellow fever (YF) vaccine used in the US military, even though there was no natural risk of infection. YF vaccine was intended to protect against Japanese Army's use of YF as a biowarfare agent, which did not eventuate. Salmonella typhi was used to infect German soldiers in a Paris café during Christmas 1941 in the knowledge that the café staff but not the soldiers were likely to be immunised against typhoid fever. German Army use of the Weil-Felix reaction to eliminate civilians likely to be typhus infected was subverted by Polish medical officers. They immunised civilians with locally produced Proteus antigens to create false-positive Weil-Felix reactions in order to exempt men from forced labour schemes. Immunisation against biowarfare agents has a mixed record, indicating that vaccines rarely cover well for intelligence gaps.

Management of iatrogenic ulnar nerve palsies after cross pinning of pediatric supracondylar humerus fractures: A systematic review.

Purpose: Up to 4% of patients who undergo cross pinning of a pediatric supracondylar humerus fracture sustain an iatrogenic ulnar nerve palsy (IUNP). This study aims to summarize the evidence regarding the management of IUNP in this setting, and to identify if early intervention (early wire removal or exploration) leads to faster and/or more complete recovery of the ulnar nerve. Methods: A formal systematic review was undertaken, with databases searched including Ovid Medline, Embase and Cochrane central. This was performed in accordance with JBI methodology and PRISMA guidelines. Results: In all, 26 articles were included in final evaluation, reporting a total of 179 IUNP. In all, 153 cases (85%) were managed expectantly, reporting full recovery at final follow-up (average 4.5 months) in 140 cases (91%). There were 26 cases of IUNP which were managed with early wire removal and/or exploration, of which 22 had full recovery (85%). There were 17 cases of 179 (9%) which did not have full recovery. Conclusion: The majority of IUNP are managed expectantly, with approximately 90% achieving full recovery at final follow-up. The literature does not support early wire removal and/or exploration, possibly because the damage to the nerve is done at the time of wire placement.

Liberty ship sinking disrupts military medical mobilisation in 1942.

Medical mobilisation is vital to support tropical campaigns where many disease casualties are expected. Much of the medical supplies and equipment for nine station and three general hospitals that were being placed in Australia were aboard the Liberty Ship SS Rufus King when it went aground off Moreton Island on 7 July 1942. A concerted salvage operation rescued 85% of the stores from the freighter that had broken in half on the Amity sandbar. This emergency effort allowed medical support to New Guinea to proceed without delays due to medical supplies that were nearly lost at sea.

A multi-component tailored intervention in family childcare homes improves diet quality and sedentary behavior of preschool children compared to an attention control: results from the Healthy Start-Comienzos Sanos cluster randomized trial.

BACKGROUND: Childcare settings are important environments for influencing child eating and physical activity (PA). Family childcare homes (FCCH) care for many children of low-income and diverse racial/ethnic backgrounds who are at greater risk for poor diet quality, low PA, and obesity, but few interventions have targeted this setting. The aim of this study was to assess the efficacy of a multicomponent intervention conducted in FCCH on the diet quality and PA of 2-5 year old children in their care. TRIAL DESIGN: Cluster randomized trial. METHODS: The cluster-randomized trial, Healthy Start/Comienzos Sanos (2015-2019) evaluated an 8-month nutrition and PA intervention that included four components: (1) monthly telephone calls from a support coach using brief motivational interviewing, (2) tailored reports, newsletters and videos, (3) group support meetings, and (4) active play toys. After completing baseline measurement, FCCH were randomized into intervention or comparison groups in matched pairs. Both groups received the same intervention components but on different topics (intervention: nutrition/PA vs. comparison: reading readiness/literacy). Evaluation staff were blinded to group assignment. Child primary outcome measures collected at baseline and 8-months included: 1) Healthy Eating Index (HEI-2015) scores calculated from diet observation, and 2) accelerometer measurement of PA. Process measures were collected from field data and provider surveys. Generalized Estimating Equation Models assessed changes in HEI-2015 scores and PA over time by experimental condition. RESULTS: Ethnically diverse FCCH providers (n = 119) and 2-to-5-year-old children in their care (n = 377) were included in the final analysis. Process evaluation showed high participation in all intervention components except for group meetings. Compared to children in comparison group FCCH, children in intervention FCCH increased total HEI-2015 scores by 7.2 points (p < .001) including improvement in component scores for vegetables (0.84 points, p = .025) and added sugar (0.94 points, p = .025). For PA, compared to children in the comparison group, children in intervention FCCH decreased sedentary time by 5.7% (p = .021). CONCLUSIONS: The multicomponent Healthy Start intervention was effective in improving diet quality and sedentary behavior of children in FCCH, which demonstrates the promise of obesity prevention interventions in this setting. Future research could include enhancing the Healthy Start intervention to strengthen the PA component, considering virtual peer support, and determining how to best translate and disseminate the intervention into FCCH nationally. TRIAL REGISTRATION: National Institutes of Health, NCT02452645 . Registered 5 May 2015.

Reintroduced malaria in Queensland, Australia during the Second World War.

A malaria epidemic arose in 1942 in Cairns, which was the evacuation point from the Japanese offensive in New Guinea. Health authorities made great efforts to suppress parasites in transiting soldiers and to position them south of 19°S latitude away from most vectors. Queensland experienced some scattered locally transmitted epidemics in 1943-1944 but by 1945 malaria transmission had largely been eliminated.

Decreased Mortality of falciparum Malaria in Anemic Prisoners of War?

Modern clinical trials have suggested that anemia protects against malaria mortality. Military records of the Second World War in Asia were examined to see if there was support for this hypothesis. When relatively well-nourished Imperial Japanese Navy sailors captured on Nauru (n = 799) were imprisoned on the Fauro Islands, 26% died from falciparum malaria. Similarly treated but very malnourished colocated Imperial Army soldiers experienced low stable malaria mortality. One-fifth of previously healthy Australian Army soldiers (n = 252) retreating from New Britain died largely because of malaria in April 1942. Malnourished prisoners of war, who were as a group very anemic, both Australian Army soldiers in Thailand and Japanese Army soldiers in Papua New Guinea, had high malaria rates but very low (< 3%) mortality rates. Malaria immunity does not adequately explain this dichotomy, suggesting that severe nutritional deprivation may be protective against malaria mortality possibly because of iron-deficiency anemia.

Effectiveness of operative versus expectant management on recovery of nerve palsies in pediatric supracondylar fractures: a systematic review protocol.

OBJECTIVE: The objective of this review is to evaluate the effectiveness of operative versus expectant management on recovery of nerve palsies after pediatric supracondylar fracture of the humerus or after surgery for supracondylar fracture of the humerus. INTRODUCTION: Supracondylar humerus fractures are the most common fracture of the elbow in children. These fractures have a high risk of complications from both the trauma itself and the treatment. Up to 12% of patients will have associated nerve injury, but there is insufficient information regarding the timing of investigation of and intervention in a persistent nerve palsy. This review aims to summarize the evidence and guide clinicians regarding the timing of investigation and/or surgical intervention for persistent nerve palsies after supracondylar humerus fractures in the pediatric population. INCLUSION CRITERIA: This review will include pediatric patients with ipsilateral upper limb nerve palsy after supracondylar fracture of the humerus or after surgery for a supracondylar fracture of the humerus without preexisting nerve palsies. METHODS: A comprehensive database search will be undertaken in MEDLINE, Embase, and Cochrane Central Register of Controlled Trials. The trial registers to be searched will include PROSPERO and AllTrials. The search strategy will include the keywords pediatric/paediatric, supracondylar, nerve injury/palsy/palsies, fracture, and humerus. Titles and abstracts will be screened by independent reviewers for suitability against the inclusion criteria, with accepted publications then being assessed in full with data extraction, synthesis, and assessment of methodological quality, using standardized critical appraisal tools from JBI. SYSTEMATIC REVIEW REGISTRATION NUMBER: PROSPERO CRD42019121581.

Epidemiological Isolation as an Infection Mortality Risk Factor in U.S. Soldiers from Late Nineteenth to Early Twentieth Centuries.

It remains uncertain why most infectious disease mortalities disappeared before modern medical interventions. Historical epidemiology using prospectively collected U.S. Army data from the Civil War (1860-1861), Spanish-American War (1898-1899), and First World War (1917-1918) suggests that epidemiological isolation was a major mortality risk factor for soldiers. Morbidity and mortality due to common infections decreased progressively from 1860 to 1918, except for influenza during the 1918 pandemic. Adult measles or mumps infections are indicative of isolated rural populations and correlated with disease mortality by U.S. state. Experiencing infections before adulthood may equip the immune system to better resist infections and decrease mortality rates.

Malaria-Associated Mortality in Australian and British Prisoners of War on the Thai-Burma Railway 1943-1944.

During the building of the Thai-Burma railway in 1943 Australian and British prisoners of war died at high rates from tropical infections and nutritional deficiencies. Mortality records from "F" Force (n = 7,000) showed nearly half (44%) of the soldiers perished in a single year, yet only 4% of these deaths were primarily attributed to malaria, with another 7% where malaria was listed as a major contributing cause. Case fatality rates were < 1%, with nearly all soldiers chronically infected with Plasmodium vivax > Plasmodium falciparum. Separate labor camp point prevalence malaria rates by microscopy ranged from 28% to 69% (median 54%) despite intermittent quinine suppression. During complex public health emergencies, malaria mortality may be disguised by its combination with other common infections and nutritional deficiencies.

Tolerance May Be More Appropriate Than Immunity When Describing Chronic Malaria Infections.

Adults who have not grown up in a malaria-endemic area may experience severe malaria soon after entering a malarious area. Such mortality is usually limited to a short period of time (months), after which they are thought to be "immune." Such anti-disease immunity may be more accurately considered as tolerance. Malaria rates of British soldiers during the Second World War reflected their time with suppressed infections and the transmission levels. Black workers from non-endemic areas on the Panama Canal experienced higher initial mortality and infection rates than co-located white workers for Plasmodium falciparum, whereas the known genetic resistance of blacks to Plasmodium vivax reversed these rates. The ethnic differences observed in malaria rates may have more to do with acquired tolerance than genetic resistance. Long-term (years) sub-patent infections may maintain host tolerance, and elimination of malaria infections may place these adults at subsequent risk of severe malaria.

The Notch pathway in colorectal cancer.

Colorectal cancer (CRC) is the third leading cause of cancer death worldwide. It is also the third most common cancer diagnosis among men, and the second most common cancer diagnosis among women. Globally, CRC can account for nearly 694,000 annual deaths. It is widely appreciated that CRC is the result of dysregulated cellular pathways that promote an inappropriate stem-cell-like phenotype, apoptotic resistance, unchecked proliferation and metastatic spread. While no single pathway is responsible for all of these attributes, an array of recent studies suggests a pivotal role for abnormal Notch-1 signaling in CRC, in part due to interconnectivity of Notch with other pathways. This review will summarize recent evidence for a role of Notch signaling in CRC, will consider interconnectivity between Notch and other pathways involved in CRC and will discuss the possible utility of targeting Notch as a CRC therapeutic.

Clinical MRSA isolates from skin and soft tissue infections show increased in vitro production of phenol soluble modulins.

BACKGROUND: Phenol-soluble modulins (PSMs) are amphipathic, pro-inflammatory proteins secreted by most Staphylococcus aureus isolates. This study tested the hypothesis that in vitro PSM production levels are associated with specific clinical phenotypes. METHODS: 177 methicillin-resistant S. aureus (MRSA) isolates from infective endocarditis (IE), skin and soft tissue infection (SSTI), and hospital-acquired/ventilator-associated pneumonia (HAP) were matched by geographic origin, then genotyped using spa-typing. In vitro PSM production was measured by high performance liquid chromatography/mass spectrometry. Statistical analysis was performed using Chi-squared or Kruskal-Wallis tests as appropriate. RESULTS: Spa type 1 was significantly more common in SSTI isolates (62.7% SSTI; 1.7% IE; 16.9% HAP; p < 0.0001) while HAP and IE isolates were more commonly spa type 2 (0% SSTI; 37.3% IE; 40.7% HAP; p < 0.0001). USA300 isolates produced the highest levels of PSMs in vitro. SSTI isolates produced significantly higher quantities of PSMα1-4, PSMß1, and δ-toxin than other isolates (p < 0.001). These findings persisted when USA300 isolates were excluded from analysis. CONCLUSIONS: Increased in vitro production of PSMs is associated with an SSTI clinical source. This significant association persisted after exclusion of USA300 genotype isolates from analysis, suggesting that PSMs play a particularly important role in the pathogenesis of SSTI as compared to other infection types.

Mass drug administration for the control and elimination of Plasmodium vivax malaria: an ecological study from Jiangsu province, China.

BACKGROUND: Recent progress in malaria control has caused renewed interest in mass drug administration (MDA) as a potential elimination strategy but the evidence base is limited. China has extensive experience with MDA, but it is not well documented. METHODS: An ecological study was conducted to describe the use of MDA for the control and elimination of Plasmodium vivax in Jiangsu Province and explore the association between MDA and malaria incidence. Two periods were focused on: 1973 to 1983 when malaria burden was high and MDA administered to highly endemic counties province-wide, and 2000 to 2009, when malaria burden was low and a focal approach was used in two counties. All available data about the strategies implemented, MDA coverage, co-interventions, incidence, and adverse events were collected and described. Joinpoint analysis was used to describe trends in incidence and the relationship between MDA coverage and incidence was explored in negative binomial regression models. RESULTS: From 1973 to 1983, MDA with pyrimethamine and primaquine was used on a large scale, with up to 30 million people in target counties covered in a peak year (50% of the total population). Joinpoint analyses identified declines in annual incidence, -56.7% (95% CI -75.5 to -23.7%) from 1973-1976 and -12.4% (95% CI -24.7 to 2.0%) from 1976-1983. Population average negative binomial models identified a relationship between higher total population MDA coverage and lower monthly incidence from 1973-1976, IRR 0.98 (95% CI 0.97 to 1.00), while co-interventions, rainfall and GDP were not associated. From 2000-2009, incidence in two counties declined (annual change -43.7 to -14.0%) during a time when focal MDA using chloroquine and primaquine was targeted to villages and/or individuals residing near passively detected index cases (median 0.04% of total population). Although safety data were not collected systematically, there were rare reports of serious but non-fatal events. CONCLUSIONS: In Jiangsu Province, China, large-scale MDA was implemented and associated with declines in high P. vivax malaria transmission; a more recent focal approach may have contributed to interruption of transmission. MDA should be considered a potential key strategy for malaria control and elimination.

Prediction of microcystis blooms based on TN:TP ratio and lake origin.

We evaluated the relationship between TN:TP ratio and Microcystis growth via a database that includes worldwide lakes based on four types of lake origin (dammed, tectonic, coastal, and volcanic lakes). We used microcosm and mesocosm for the nutrient elution tests with lake water and four kinds of sediment (nontreated, MgO sprinkling treated, dissolved air flotation [DAF] treated, and combined treated sediment) in order to control TN:TP ratio and to suppress Microcystis growth. Microcystis growth was related to TN:TP ratio, with the maximum value at an optimum TN:TP ratio and the minimum values when the TN:TP ratios reached to 0 or "V. The kurtosis of the distribution curve varied with the type of lake origin; the lowest kurtosis was found in dammed lakes, while the highest was found in volcanic lakes. The lake trophic state could affect the change in the kurtosis, providing much lower kurtosis at eutrophic lakes (dammed lakes) than that at oligotrophic lakes (volcanic lakes). The relationship between TN:TP ratio and Microcystis growth could be explained by the nutrient elution tests under controlled TN:TP ratios through the various sediment treatments. A significant suppression of Microcystis growth of 70% could be achieved when the TN:TP ratios exceeded 21. Lake origin could be regarded as an index including morphological and geographical factors, and controlling the trophic state in lakes. The origin rather than trophic state for lakes could be considered as an important factor of TN:TP influences on Microcystis growth.