WHO Guidelines for IPT and ICF Reuben Granich

WHO Guidelines for IPT and ICF Reuben Granich

WHO Guidelines for IPT and ICF Reuben Granich HIV/AIDS Department World Health Organization Haileyesus Getahun STOP TB Department World Health Organization Outline Background Evidence Recommendations Adults and adolescents Children Conclusions WHO 2004 Interim Policy on Collaborative TB/HIV Activities A. Establish NTP-NACP collaborative mechanisms

Set up coordinating bodies for effective TB/HIV activities at all levels Conduct surveillance of HIV prevalence among TB cases Carry out joint TB/HIV planning Monitor and evaluate collaborative TB/HIV activities B. Decrease burden of TB among PLHIV (the "Three I's") Establish intensified TB case finding Introduce INH preventive therapy Ensure TB infection control in health care and congregate settings

C. Decrease burden of HIV among TB patients Provide HIV testing and counselling Introduce HIV prevention methods Introduce co-trimoxazole preventive therapy Ensure HIV/AIDS care and support Introduce ARVs WHO/UNAIDS 1998 IPT Policy Statement Key IPT recommendations (1993-2009) IPT should be provided to TST positives If TST is not feasible IPT should be given to: PLHIV in areas >30% MTB infection in population Health workers, prisoners, contacts, miners Mandatory CXR to exclude active TB Self administered for 6 months

Implementation progress ICF among people living with HIV, 2005-2009 * Data as per June 2010 IPT provision for people living with HIV, 2005-2009 * Data as per June 2010 People living with HIV receiving IPT 2009 <1% 1% 9% 10% 19% 20% and higher Data not available * Data as per October 2010 IPT policy in Country X, 2006

Eligibility criteria for a facility to offer IPT Minimum requirements to offer IPT Human resource: Medical Officer Laboratory assistant Trained counselor Pharmacy technician Adherence supporters Infrastructure: Functional Laboratory X-ray or access to x-ray services Counseling room/space Consultation room Equipment and logistics: Facilities for TB microscopy Facilities for skin testing (mantoux) Cold chain system Facilities for HIV testing Sustainable supply of anti-TB drugs including Isoniazid Sustainable supply of HIV test kits Other key issues: If an organization has a TB default rate

of greater than 5% it will not be eligible to provide IPT WHO meeting on Three I's for HIV/TB April 2008 Conclusion: reconceptualised IPT as part of TB screening and requested WHO to revise the IPT policy WHO GRC recommended policy development: quality of evidence Judgments on strength of recommendation: criteria to consider for WHO Factors Comments Quality of the evidence Higher the quality of the evidence the more likely a strong recommendation can be made Balance between desirable and

undesirable effects Larger the gap or gradient between these then more likely a strong recommendation will be made Values and preferences If there is a great deal of variability or strong reasons that the recommended course of action is unlikely to be accepted then it is more likely a weak recommendation will be made. Costs/financial implications (resource use) Higher the cost both financial and in terms of infrastructure, equipment or requirements, and more resource intensive requirements, then less likely to make a strong recommendation Feasibility Is the intervention possible and practical in the settings where greatest impact is likely to be attained

or is being sought Strength of recommendations Strong: the desirable effects of a recommendation outweigh the undesirable effects. Conditional: the desirable effects probably outweigh the undesirable effects. However, Data are scant or Only applicable to specific group/population or setting or New evidence may change risk to benefit balance or Benefits may not warrant the cost or resources required Risk and benefit summary WHO 2010 IPT/ICF Recommendations Use four symptom screen to rule in for IPT No need for TST or chest radiography Simplified algorithm

HIV program leadership Rationale Ruling out TB is major barrier to implementing IPT Chronic cough more than 2 or 3 wks alone is insensitive predictor of TB in people living with HIV TB screening tools are not standardised and vary from country to country Role of CXR is not clear and inconsistent Demand from countries for evidence-based TB screening algorithm IPT/ICF Guidelines Preparation Process: HIV/AIDS & Stop TB Departments 1. Scoping the document: reasons for choosing the topic, problems with existing guidelines, variations and gaps, 2. Group composition Reporting standard and process 3. Conflict of interest 4. Formulations of the questions and choice of the relevant outcomes 5. Evidence retrieval, evaluation and

synthesis (balance sheet, evidence table) 6. Benefit/risk profile: integrating evidence with values and preferences, equity and costs Standards for evidence: GRADE system Benefit/risk profile: affected community 7. Formulation of the recommendations 8. Committee review/finalization (January 25th 2010) 9. Submission to GRC for approval 10. Dissemination Reporting standard and process Individual patient meta-analysis (12 studies) Total patients in the 12 datasets (n=29,523) 29,523

HIV-uninfected patients or those with unknown HIV status (n=19,466) 10,057 HIV-infected patients (n=10,057) Patients receiving TB disease or TB infection treatment at screening (n=187) Patients not receiving TB treatment (n=9,870) Unknown smear results or sputum smear positive with no culture or negative culture or culture grew NTM (n=160) Patients with sputum smear results (n=9,710) Patients with unknown TB status (n=84) Patients with known TB status (n=9,626) 9,626 Patients with TB (n=557) Patients without TB (n=9,069) Top 5 Best Performing Rules (1 of m) in all Subjects (n = 8173)

NPV (95% CI) Combination Rule Sen (%) Spe (%) LR- CC, F, NS, WL 85 53 0.29 98.5 (98.1 - 98.8) H, F, NS, WL

82 56 0.32 98.4 (97.9 - 98.7) CC, F, WL 81 57 0.33 98.3 (97.9 - 98.6) CC, NS, WL 81 57

0.34 98.3 (97.9 - 98.6) H, F, NS, WL 81 62 0.31 97.4 (98 - 98.7) 5% TB Prevalence CC: Cough in the last 24 hours; F: Fever; H: Haemoptysis; NS: Night sweats; WL: Weight loss Performance of the Best Rule (one of the current cough, fever, night sweats or weight loss) NPV (95% CI) Setting

Sen (%) Spe (%) LR(%) 5% TB prevalence Community 76 61 0.39 98.0 (97.4 - 98.4) Clinical 89

38 0.50 97.4 (96.7 - 98.8) CD4 < 200 94 27 0.45 97.7 (95.8 - 99.5) CD4> 200 83 34 0.49

97.6 (95.3 - 98.7) CC: cough in the last 24 hours; F: Fever; H: Haemoptysis; NS: Night sweats; WL: Weight loss Top 5 Best Performing Rules (1 of m) in all subjects with abnormal CXR ( n = 2805) NPV (95% CI) Combination Rule Sen (%) Spe (%) LR- CC, F, NS, WL, X 93 40

0.17 99.1 (98.4 - 99.5) CC, F, NS, X 92 50 0.16 99.2 (98.5 - 99.5) H, F, NS, WL, X 92 43 0.2 99.0 (98.2 - 99.4)

H. F, NS, WL, X 91 44 0.2 99.0 (98.2 - 99.4) CC, NS, W, LX 91 45 0.2 99.0 (98.2 99.4) 5% TB prevalence CC: cough in the last 24 hours; F: Fever; H: Haemoptysis; NS: Night sweats; WL: Weight loss

TB prevalence and the number of diagnostic Evaluations required to yield one TB case TB Prevalence 1% CXR No CXR All study subjects* 56 63 Community 51 Clinical TB Prevalence 20% CXR

No CXR CXR 11 12 2 2 75 10 14 2 3

75 83 14 16 3 3 CD4 < 200 82 70 16 13 3

3 CD4> 200 76 75 15 14 3 3 Setting No CXR TB Prevalence 5%

*Number of PLHIV TB suspects that need to be investigated to get one TB case (FP/TP) Evidence for efficacy of different drug regimens Intervention Comparator RR (95% Cl) Quality of evidence INH Rifampicin and pyrazinamide 1.03 (0.751.4) Moderate INH

INH and rifampicin 0.97 (0.521.83) Moderate INH INH, rifampicin and pyrazinamide 0.69 (0.231.57) Low INH and rifampicin INH, rifampicin and pyrazinamide 0.75 (0.211.82) Moderate INH and rifapentine INH

1.05 (0.561.97) Moderate IPT for people living with HIV: Evidence for recommendations 3, 4 and 5 Outcome Studies Patients RR (95% CI) Probable, confirmed or possible TB 8 4136 0.67 (0.51,0.87) - TST positive 4

1311 0.36 (0.22,0.61) - TST negative 7 2490 0.86 (0.59,1.26) - TST unknown 2 335 0.86 (0.48,1.52) 4 2063

0.72 (0.47,1.11) - TST positive 1 112 0.13 (0.01, 2.32) - TST negative 3 1021 0.76 (0.36,1.61) - TST unknown 2 930

0.79 (0.46,1.36) Confirmed TB The effect of IPT is more in TST positives than TST negatives and unknowns (Akolo et al 2010 Cochrane Review) GRADE analysis table: 36 months vs. 6 month IPT RR for Probable TB (95% CI) = 0.50 (0.29 to 0.84) RR for Confirmed TB (95% CI) = 0.48 (0.26 to Samanadari et al, unpublished, 2010 0.9) Martinson et al, unpublished, 2010 Settings for 36 months should be determined by national guidelines Local context (feasibility, resources, safety and relevance) Higher TB prevalence and transmission IPT and drug resistance

RR 95% CI 1.45 (0.85-2.47) (Balcell's et al, GRADE analysis table: IPT and drug resistance RR 95% CI= 1.87 (0.65 - 5.38) Prevalence of INH resistance among IPT exposed is similar to background population Van Halsema et al, 2010 Concomitant use of IPT with ART (Strong recommendation, low quality evidence) No study directly address the issue Contrasting results on immune status and IPT effect No difference by HIV stage at baseline (Gordin, 1997) Greater effect when TLC >2/L (Mwinga, 1998) Not affected by CD4 count (Churchyard, 2003) IPT+ART= TB IRR 0.20 (0.090.91) (Golub, 2007-Brazil) IPT+ART= TB IRR 0.15 (0.0040.85) (Golub, 2009-SA)

Recommendation 1 : TB screening for adults and adolescents Adults and adolescents living with HIV should be screened with a clinical algorithm and those who do not report any one of; current cough, fever, weight loss or night sweats are unlikely to have active TB and should be offered IPT. (Strong recommendation, moderate quality evidence) Recommendation 2 : TB screening for adults and adolescents Adults and adolescents living with HIV screened with a clinical algorithm and reported one of the following; current cough, fever, weight loss or night sweats may have active TB and should be evaluated to TB and other diseases.

(Strong recommendation, moderate quality evidence) Recommendation 3: IPT 6 months for adults and adolescents Adults and adolescents who are living with HIV and: have unknown or positive TST status and; unlikely to have active TB should receive IPT for at least 6 months IPT should be given to such individuals irrespective of the degree of immunosuppression, and also to those on ART, those who have previously been treated for TB and pregnant women (Strong recommendation, high quality evidence) Recommendation 4: IPT 36 months for adults and adolescents Adults and adolescents who are living with HIV in settings with higher TB transmission and: have unknown or positive TST status and; unlikely to have active TB should receive IPT for at least 36 months IPT should be given to such individuals irrespective of the degree of immunosuppression, and also to those on ART, those

who have previously been treated for TB and pregnant women (Conditional recommendation, low quality evidence) Recommendation 5: TST Tuberculin skin test is not a requirement for initiating IPT for people living with HIV (Strong recommendation, moderate quality evidence) People living with HIV who have a positive TST benefit more from IPT; TST can be used where feasible to identify such individuals (Strong recommendation, high quality of evidence) Recommendation 6: INH resistance Providing IPT to people living with HIV does not increase the risk of developing INH resistant TB. Therefore concerns regarding the development of INH resistance should not be a barrier to providing IPT. (Strong recommendation, moderate quality evidence) TB screening and IPT algorithm Person living with HIV Screen for TB with any one of the following:** Current cough; Fever Weight loss; Night Sweats

No Assess IPT contraindications No Give IPT Yes Defer IPT Yes Investigate for TB & other disease Other diagnosis Appropriate treatment & consider IPT Screen for TB regularly Not TB Follow up & consider IPT TB Treat for

TB Literature search strategy (Children) Search criteria: PubMed Search ("Child"[Mesh] OR "Child, Preschool"[Mesh]) OR "Infant"[Mesh]) AND "Tuberculosis"[Mesh]) AND "HIV Infections"[Mesh]) AND "Diagnosis"[Mesh]) OR (TB screening, Children, HIV) 546 Limits: Clinical Trial, Meta-Analysis, Randomized Controlled Trial, Review, Clinical Trial, Phase I, Clinical Trial, Phase II, Clinical Trial, Phase III, Clinical Trial, Phase IV, Comparative Study, Controlled Clinical Trial, Evaluation Studies, Multicenter Study, MEDLINE, PubMed Central, All Infant: birth-23 months, Newborn: birth-1 month, Infant: 1-23 months, Preschool Child: 2-5 years, Child: 6-12 years 161 By title 57 (+ 17 added) By abstract 20 (+10 added from references)

Of interest 15 International conferences (CROI, IAS, International AIDS conference): CROI 2008, 2009: 0 IAS 2009: 2 IAC 2008: 2 Abstracts of Interest: 1 16 Studies of interest: A total of 16 articles/ abstracts provided information about clinical presentation of tuberculosis among HIV-infected children or utility of TB scoring system in HIV-infected children or combination of signs and symptoms or diagnostic tests among HIV-infected children. TB screening for IPT for children Quality assessment No. of studies Design (number of participants) Limitations

Other considerations Quality of evidence Inconsistency Indirectness Imprecision No serious inconsistency No serious indirectness No serious imprecision# No serious inconsistency

No serious indirectness No serious imprecision# No serious inconsistency No serious indirectness No serious imprecision# Low No serious inconsistency No serious indirectness No serious

imprecision# Low Any one of cough 2 weeks, fever or failure to thrive Negative predictive value 0.99 1 Observational study Serious limitation* (303) Low Sensitivity 0.90 1 Observational study Serious limitation* (303) Low

Specificity 0.65 1 Observational study Serious limitation* (303) Positive predictive value 0.15 1 Observational study Serious limitation* (303) A combination of culture and radiological appearance was used as a gold standard, which is not a perfect gold standard. The study did not qualify for the highest quality of evidence since it was an observational study and did not have a well-defined gold standard. * The reference standard used is unlikely to correctly classify all the children with disease as having the disease. Moreover, sputum was collected only from children having signs and symptoms suggestive of TB or abnormal chest X-ray findings. # Confidence intervals for sensitivity and specificity were not reported. Bibliography: Song et al. 2009

Recommendations for children: TB screening Strong recommendation, low quality evidence Children living with HIV who do not have poor weight gain*, fever or current cough are unlikely to have active tuberculosis TB. Strong recommendation, low quality of evidence Children living with HIV who have any one of the following symptoms poor weight gain, fever, current cough or contact history with a TB case may have TB and should be evaluated for TB and other conditions. If the evaluation shows no TB, such children should be offered IPT regardless of their age. *Poor weight gain is defined as reported weight loss, or very low weight (weight-for-age less than -3 z-score), or underweight (weight-for-age less than -2 z-score), or confirmed weight loss (>5%) since the last visit, or growth curve flattening Recommendations for children: IPT Strong recommendation, moderate quality of evidence Children living with HIV who are more than 12 months of age and who are unlikely to have active TB on symptom-based screening, and have no contact with a TB case should receive

six months of IPT (10 mg/kg) as part of a comprehensive package of HIV prevention and care services Strong recommendation, low quality of evidence In children living with HIV who are less than 12 months of age, only those children who have contact with a TB case and who are evaluated for TB (using investigations) should receive six months of IPT if the evaluation shows no TB disease Conditional recommendation, low quality of evidence All children living with HIV who have successfully completed treatment for TB disease should receive INH for an additional six months. Secondary prophylaxis No evidence on the use of IPT in children living with HIV after successful completion of TB treatment Children living with HIV are exposed to reinfection and recurrence of TB Conditional recommendation All children living with HIV who have been successfully treated for TB and are living in settings with a high TB prevalence and transmission should receive IPT for an additional six months. (IPT can be started after the last dose of anti-TB therapy or at a later date)

Role of TST and IGRA: Children TST is not required to initiate IPT in children and should not be routinely used as part of the process to determine eligibility for IPT TST may provide important additional information in assessing a child with suspected TB, especially if there is no positive contact history The main limitation of TST in the diagnosis of TB in HIVinfected children is its variable sensitivity In settings where it is available, TST may be used for the diagnosis of active TB in children and may also have a role in screening for LTBI. No role for IGRA IPT and ART: Children No data regarding the efficacy of IPT for children stratified by degree of immunosuppression. Biological plausibility in extrapolating what is known for adults and adolescents to children Conditionally recommended the combined use of IPT with ART for all children (ART

priority). Algorithm for TB screening in children more than one year of age and living with HIV Child more than 12 months of age and living with HIV* Screen for TB with any one of the following symptoms: Poor weight gain Fever Current cough Contact with a TB case No Assess for contraindications to IPT*** No Give IPT Yes Defer IPT Yes

Investigate for TB and other diseases**** Other diagnosis Give appropriate treatment and consider IPT Screen regularly for TB Not TB Follow up and consider IPT TB Treat for TB Summary: what is new in 2010? Screening for TB only by using symptom based algorithm is sufficient to start IPT for PLHIV No mandatory CXR and TST requirement for IPT

Regular screening of those on IPT at every visit Pregnant women, children, those on ART and those who completed TB treatment should receive IPT Conditional recommendation of 36 months IPT for settings with high TB transmission among PLHIV Conclusions The analysis represent the best available evidence from Asia and Africa The recommended rule perform consistently across different settings, populations and CD4 count The rule entail replacement of longer duration cough with current cough among PLHIV CXR improves the sensitivity of the rule by 13-16% The trade offs to the health system are similar to the expected practice at 5% TB prevalence The ultimate solution lies in the better point of care TB diagnostics (TB dipstick test). RESEARCH Conclusions Screening rule is applicable to those living with HIV in resource limited settings The screening rule can be effectively used among people living with HIV, including during HIV testing campaigns

The rule is not practical for TB screening among those without HIV as the numbers of false positives would be very high Further research in children is needed to build evidence base Laws, like sausages, cease to inspire respect in proportion as we know how they are made. Otto von Bismarck 1930 Thank you Review Team: Georgina Russell (NHS) Date, Anand (CDC/CCID/NCHHSTP) Abhishek Sharma Martina Penazatto Co-Chairs: Kevin De Cock, Holger Schunemann, Suzanne Hill WHO Committee Haileyesus Getahun (STOP TB Co-lead) Andrew Doupe (HIV/AIDS) Christian Gunneberg (STOP TB) Lulu Mussa Muhe (HIV/AIDS and CAH)

Malgorzata Grzemska (STOP TB) Reuben Granich (HIV/AIDS) Siobhan Crowley (HIV/AIDS) Caoimhe Smyth (HIV/AIDS) Evidence for TB screening recommendations (1 and 2) Individual patient data meta-analysis What is the most sensitive clinical algorithm to screen for culture-confirmed TB in people living HIV? Inclusion with criteria for studies Collected sputum specimens from PLHIV regardless of signs or symptoms; Used mycobacterial culture of at least one specimen to diagnose TB and;

Collected data about signs and symptoms. Methods Clinical symptoms that can be assessed at any level of the health system Analysis of common variables across studies: Cough (4 wks, 2 wks and last 24 hours) Night sweats Fever Weight loss Hemoptysis Only observations with no missing data included Impact of adding CXR was also examined Systematic search of studies

Database searching (n=2352) Other sources (n=18) Records (n=2119) Screened (n=53) Excluded (n=32) Full text articles (n=21) Full text excluded (n=9) Studies included (n=12) WHO Guidelines for

National TB Programmes on the Management of Children Pediatric dosing chart Weight range (kg) <5 Number of 100 mg tablets of INH to be administered per dose (total dose 10 mg/kg/day) tablet 5.19.9 1 tablet 1013.9 1 tablet 1419.9

2 tablets 2024.9 2 tablets >25 3 tablets or one adult tablet Dose (mg) 50 100 150 200 250 300 Call for Rigor and Transparency &

IPT/ICF guideline preparation process Ideal recommendations Screening algorithm for IPT and further TB evaluation Recommendations regarding diagnostic methods for ruling out TB Preferred regimen for adults and children Answer questions regarding duration, toxicity, cost, and resistance Populations being considered HIV+ adults, adolescents and children HIV+ pregnant women Relevant outcomes Mortality Disease progression (morbidity) Severe or regimen limiting adverse events Adherence and retention on IPT Durability of IPT regimen effect Cost effectiveness P opulation of interest I ntervention to be assessed C omparison with current standard of care Outcomes for patients and community T imeline in which each outcome needs to be assessed PICOT Framework

1. What are the best combination of signs, symptoms and diagnostic procedures (e.g., smear microscopy, radiography, serum-based tests such as IGRA, etc.) as screening tools to determine eligibility for treatment for latent TB infection? 2. What is the optimal duration and drug regimen (e.g., INH, RIF, etc.) for treatment of LTBI to reduce the risk of developing Tuberculosis among PLHIV? 3. What is the optimal time to start considering IPT? (i.e., should immune status be considered and should IPT be started with ART)? 4. Should secondary treatment of LTBI be provided for people living with HIV to prevent re-infection or recurrence of tuberculosis after successful completion of TB treatment? 5.

Does treatment for LTBI among people living with HIV lead to significant developments of mono-resistance against the drug(s) used for LTBI treatment? 6. Will low adherence rates to LTBI treatment be a barrier to implementation of LTBI treatment among PLHIV? 7. Is provision of treatment for LTBI cost-effective? 8. Is the use of tuberculin skin test feasible in resource limited settings? Children living with HIV without poor weight gain*, fever, current cough are unlikely to have active tuberculosis and should be offered IPT Children living with HIV who are over 12 months of age who are unlikely to have active TB should receive 6 months of INH preventive therapy (10mg/kg) as part of a comprehensive package of HIV After successful completion of treatment for TB disease, all children living with HIV who are over 12 months of age should receive INH for an additional 6 months. All children with a history of contact with a TB case should receive 6 months IPT Population: Children living with HIV Intervention: Careful history taking, and clinical assessment

Factor Decision Explanation Quality of evidence The quality of evidence comes from one study by Song et al is low. Low Benefits Simplifies screening and limits the numbers of radiologic and laboratory or desired effects investigations.Identifies children that can benefit from IPT (and thus reduce TB morbidity/mortality) Risks or undesired effects Strong Small number of children with active tuberculosis might be given mono-therapy Increase in time spent by health care workers for screening for TB Values and preferences Strong Costs Weak/

conditional Feasibility Overall ranking of recommendation Weak Parents would like their children to be protected from TB due to IPT especially in high TB burden setting Increased by: Training of clinicians and nurses to perform clinical assessment and correctly determine poor weight gainAdditional staff due to increase in time spent by existing staff for screening Reduced by: Limited resources needed for symptom screening among children already regularly attending clinical services for HIV Avoiding costs of additional diagnostic tests including chest x-ray Avoiding costs that would have been associated with treatment of TB (if latent TB infection is effectively treated) - History taking and clinical assessment would be feasible but would require additional training and time for already overburdened staff. Strength of recommendation

Strong (initial IPT for 6 months) Conditional (post TB treatment) Children living with HIV with any one of the following: poor weight gain, fever of current cough may have active tuberculosis and should be evaluated for TB and other diseases Children living with HIV with any one of the following: poor weight gain, fever of current cough may have active tuberculosis and should be evaluated for TB and other diseases. Population: Children living with HIV Intervention: Careful history taking, and clinical assessment Factor Decision Explanation Quality of The quality of evidence comes from one study by Song et al and the Low evidence quality of evidence is low. Benefits or desired effects Early identification of TB suspects followed by appropriate treatment of identified TB cases can reduce TB-associated morbidity and mortality among children living with HIV.

Risks or undesired Weak effects Increased demand for clinical and laboratory investigations This approach would result in a larger number of children undergoing diagnostic testing, including possible risks (generally not high danger) associated with sample collection (e.g. from lymph nodes or gastric aspirates) Values and preferences Patients/parents generally desire accurate diagnosis of disease and may be willing to undergo diagnostic evaluation or treatment in effort to prevent morbidity/mortality Costs Increased by: Increase in number of children requiring diagnostic evaluation for TB will require resources (staff, reagents, transport, lab capacity) Increased need for quality assurance of diagnostic services.

Need for additional drugs to increase in number of cases Weak/ Decreased by: Decreased costs of managing more severely ill or dying children if TB is recognized Feasibility Weak Overall ranking of recommendation oMay require some additional training and time from overburdened health care workers, laboratory workers and families of affected children. Strength of recommendation Strong

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