A deep learning pipeline to simulate fluorodeoxyglucose (FDG) uptake in head and neck cancers using non-contrast CT images without the administration of radioactive tracer.

OBJECTIVES: Positron emission tomography (PET) imaging is a costly tracer-based imaging modality used to visualise abnormal metabolic activity for the management of malignancies. The objective of this study is to demonstrate that non-contrast CTs alone can be used to differentiate regions with different Fluorodeoxyglucose (FDG) uptake and simulate PET images to guide clinical management. METHODS: Paired FDG-PET and CT images (n = 298 patients) with diagnosed head and neck squamous cell carcinoma (HNSCC) were obtained from The cancer imaging archive. Random forest (RF) classification of CT-derived radiomic features was used to differentiate metabolically active (tumour) and inactive tissues (ex. thyroid tissue). Subsequently, a deep learning generative adversarial network (GAN) was trained for this CT to PET transformation task without tracer injection. The simulated PET images were evaluated for technical accuracy (PERCIST v.1 criteria) and their ability to predict clinical outcome [(1) locoregional recurrence, (2) distant metastasis and (3) patient survival]. RESULTS: From 298 patients, 683 hot spots of elevated FDG uptake (elevated SUV, 6.03 ± 1.71) were identified. RF models of intensity-based CT-derived radiomic features were able to differentiate regions of negligible, low and elevated FDG uptake within and surrounding the tumour. Using the GAN-simulated PET image alone, we were able to predict clinical outcome to the same accuracy as that achieved using FDG-PET images. CONCLUSION: This pipeline demonstrates a deep learning methodology to simulate PET images from CT images in HNSCC without the use of radioactive tracer. The same pipeline can be applied to other pathologies that require PET imaging.

Rates of Bile Acid Diarrhoea After Cholecystectomy: A Multicentre Audit.

INTRODUCTION: Bile acid diarrhoea (BAD) can occur due to disruption to the enterohepatic circulation, e.g. following cholecystectomy. Post-cholecystectomy diarrhoea has been reported in 2.1-57.2% of patients; however, this is not necessarily due to BAD. The aim of this study was to determine the rates of bile acid diarrhoea diagnosis after cholecystectomy and to consider investigation practices. METHODS: A retrospective analysis of electronic databases from five large centres detailing patients who underwent laparoscopic cholecystectomy between 2013 and 2017 was cross-referenced with a list of patients who underwent 75SeHCAT testing. A 7-day retention time of <15% was deemed to be positive. Patient demographics and time from surgery to investigation were collected and compared for significance (p < 0.05). RESULTS: A total of 9439 patients underwent a laparoscopic cholecystectomy between 1 January 2013 and 31 December 2017 in the five centres. In total, 202 patients (2.1%) underwent investigation for diarrhoea via 75SeHCAT, of which 64 patients (31.6%) had a 75SeHCAT test result of >15%, while 62.8% of those investigated were diagnosed with bile acid diarrhoea (BAD). In total, 133 (65.8%) patients also underwent endoscopy and 74 (36.6%) patients had a CT scan. Median time from surgery to 75SeHCAT test was 672 days (SD ± 482 days). DISCUSSION/CONCLUSION: Only a small proportion of patients, post-cholecystectomy, were investigated for diarrhoea with significant time delay to diagnosis. The true prevalence of BAD after cholecystectomy may be much higher, and clinicians need to have an increased awareness of this condition due to its amenability to treatment. 75SeHCAT is a useful tool for diagnosis of bile acid diarrhoea.

Development of a novel index to characterise arterial dynamics using ultrasound imaging.

Abdominal aortic aneurysms (AAA) are associated with systemic inflammation and endothelial dysfunction. We previously reported flow mediated dilatation (FMD) of the brachial artery as a predictor of AAA growth. We hence hypothesised that other physical characteristics of the brachial artery correlate with AAA growth. Using a prospectively cohort of AAA patients, we devised a 'brachial artery relaxation index' (BARI) and examined its role as a biomarker for AAA growth. However, no correlation between BARI and future aneurysm growth was observed (p = 0.45). Therefore, our investigations did not substantiate the hypothesis that other physical characteristics of the brachial artery predicts AAA growth.

Recognizing the Dying Patient, When Less Could be More: A Diagnostic Framework for Shared Decision-Making at the End of Life.

BACKGROUND: Recognizing dying patients is crucial to produce outcomes that are satisfactory to patients, their families, and clinicians. AIM: Earlier discussion of and shared decision-making around dying to improve these outcomes. DESIGN: In this study, we interviewed 16 senior clinicians to develop summaries of palliative care in 4 key specialties: Cardiology, Vascular Surgery, Emergency General Surgery, and Intensive Care. SETTING: Oxford University Hospitals. RESULTS: Based on themes common to our 4 clinical areas, we developed a novel diagnostic framework to support shared palliative decision-making that can be summarized as follows: 1) Is the acute pathology reversible? 2) What is the patient's physiological reserve? 3) What is important to the patient? Will they be fit enough for discharge for a reasonable length of time? CONCLUSIONS: We believe that education using this framework in the medical school and postgraduate curricula would significantly improve recognition of dying patients. This would serve to stimulate earlier conversations, more shared decision-making, and ultimately better outcomes in palliative care and patient experience.

Shared decision making and consent post-Montgomery, UK Supreme Court judgement supporting best practice.

The UK Supreme Court Montgomery judgement marks a decisive shift in the legal test of duty of care in the context of consent to treatment from the perspective of the clinician (as represented by Bolam rules) to that of the patient. This has important implications in the surgical field worldwide, where informed consent is critical. This paper aims to explain the ruling and how it impacts the consent process. The case and ruling are outlined and summarised as pertaining to consent and requirements for validity; a shift from the clinician's interpretation about what would be best for patients to the values of the particular patient concerned in the decision in question. A sample of recent commentaries is reviewed. Four examples illustrate some of the practical applications of the Montgomery ruling on consent and how the ruling can empower doctors and patients to make mutually beneficial shared decisions. Future consent should be obtained using a Montgomery compliant strategy in accordance with the principles of shared decision making.

Shared decision making in chronic medication use: Scenarios depicting exemplary care.

Patient-centred care includes patients and their values in the healthcare decision-making process. Shared decision-making is essential for patient satisfaction, medication adherence, and positive clinical outcomes. It also empowers patients to play an active role in managing their health condition by improving their sense of agency, allowing them to personalise their care. Long-term prescriptions are an unexplored area where shared decision-making could be impactful. This paper provides 5 common clinical prescription scenarios pertaining to route of administration, medication timing, side effects, and length of prescription. Minor tailoring of treatment plans could significantly improve clinical outcomes. These serve as exemplars as to how to personalise prescriptions through shared decision making in accordance with patient values.

Shared decision-making across the specialties: Much potential but many challenges.

Shared decision-making (SDM) is a collaborative process through which patients and clinicians work together to arrive at a mutually agreed-upon treatment plan. The use of SDM has gathered momentum, with it being legally mandated in some areas; however, despite being a ubiquitously applicable intervention, its maturity in use varies across the specialties and requires an appreciation of the nuanced and different challenges they each present. It is therefore our aim in this paper to review the current and potential use of SDM across a wide variety of specialties in order to understand its value and the challenges in its implementation. The specialties we consider are Primary Care, Mental Health, Paediatrics, Palliative Care, Medicine, and Surgery. SDM has been demonstrated to improve decision quality in many scenarios across all of these specialties. There are, however, many challenges to its successful implementation, including the need for high-quality decision aids, cultural shift, and adequate training. SDM represents a paradigm shift towards more patient-centred care but must be implemented with continued people centricity in order to realize its full potential.

'The House of God': reflections 40 years on, in conversation with author Samuel Shem.

The House of God is a seminal work of medical satire based on the gruelling internship experiences of Samuel Shem at the Beth Israel Hospital. Thirteen 'Laws' were offered to rationalise the seemingly chaotic patient management and flow. There have been large shifts in the healthcare landscape and practice since, so we consider whether these medical truisms are still applicable to contemporary National Health Service practice and propose updates where necessary:People are sometimes allowed to die.GOMERs (Get Out of My Emergency Room) still go to ground.Master yourself, join the multidisciplinary team.The patient is the one with the disease, but not the only one suffering.Placement (discharge planning) comes first.There is no body cavity that cannot be reached with a gentle arm and good interventional radiologists.Fit the rule to the patient rather than the patient to the rule.They can always pay you less.The only bad admission is a futile one.If you don't take a temperature you can't find a fever and if you are not going to act on it, don't do the test.Show me a BMS (best medical student) who ONLY triples my work, and I'll show you a future Foundation Year 1 doctor (FY1) who is an asset to the firm.Interpret radiology freely, but share your clinical findings with the radiologist and in a timely fashion.Doing nothing can be a viable option. These were developed in conversation with Samuel Shem, who also offers further insight on the creation of the original laws.

Improving routine outpatient monitoring for patients with sickle-cell disease on hydroxyurea.

Hydroxyurea is the gold standard treatment for prevention of vaso-occlusive crises in patients with sickle-cell anaemia. It has a narrow therapeutic index and dangerous side effects including cytopenias. There is high variation in dose-response across the population. Therefore, a robust outpatient monitoring programme is crucial to ensure efficacy and safety of treatment. However, there has historically been difficulty engaging the target population in regular laboratory test monitoring programmes. This project aimed to ensure that all patients on hydroxyurea had routine blood tests at least once every 2 months which were reviewed and acted upon within the 3-year project life cycle. A specialist haematology nurse prescriber clinic service was introduced, first informally, and then formally to take blood tests, alter medication dosing, prescribe it and then write a clinic letter. The mean number of tests per patient per year rose from 0.21 at baseline to 9.05 after 2 years of the formal nurse prescriber clinic. This led to an associated increase in dose changes from 0.23 to 1.45 per patient per year. This improved the number of patients on the optimum dose of hydroxyurea. Furthermore, due to increased confidence in the outpatient monitoring, the total number of people being prescribed hydroxyurea increased from 26 to 42. Restriction of prescriptions to only those enrolled in the service has prevented unmonitored patients being at risk of the potential toxicities associated with doses that are too high. The introduction of a formal nurse-led clinic has improved the safety, efficacy and compliance and increased the number of patients on the gold standard preventative treatment for vaso-occlusive crises in sickle-cell anaemia.

Inactivated polio vaccines from three different manufacturers have equivalent safety and immunogenicity when given as 1 or 2 additional doses after bivalent OPV: Results from a randomized controlled trial in Latin America.

BACKGROUND: Since April 2016 inactivated poliovirus vaccine (IPV) has been the only routine source of polio type 2 protection worldwide. With IPV supply constraints, data on comparability of immunogenicity and safety will be important to optimally utilize available supplies from different manufacturers. METHODS: In this multicenter phase IV study, 900 Latin American infants randomly assigned to six study groups received three doses of bOPV at 6, 10 and 14weeks and either one IPV dose at 14weeks (groups SP-1, GSK-1 and BBio-1) or two IPV doses at 14 and 36weeks (groups SP-2, GSK-2 and BBio-2) from three different manufacturers. Children were challenged with mOPV2 at either 18 (one IPV dose) or 40weeks (two IPV doses) and stools were collected weekly for 4weeks to assess viral shedding. Serum neutralizing antibodies were measured at various time points pre and post vaccination. Serious adverse events and important medical events (SAE and IME) were monitored for 6months after last study vaccine. RESULTS: At week 18, 4weeks after one dose of IPV, overall type 2 seroconversion rates were 80.4%, 80.4% and 73.3% for SP-1, GSK-1 and BBio-1 groups, respectively; and 92.6%, 96.8% and 88.0% in those who were seronegative before IPV administration. At 40weeks, 4weeks after a second IPV dose, type 2 seroconversion rates were ≥99% for any of the three manufacturers. There were no significant differences in fecal shedding index endpoint (SIE) after one or two IPV doses (SP: 2.3 [95% CI: 2.1-2.6]); GSK: 2.2 [1.7-2.5]; BBio 1.8 [1.5-2.3]. All vaccines appeared safe, with no vaccine-related SAE or IME. CONCLUSION: Current WHO prequalified IPV vaccines are safe and induce similar humoral and intestinal immunity after one or two doses. The parent study was registered with ClinicalTrials.gov, number NCT01831050.

Purple Urine Bag Syndrome: A Rare Spot Diagnosis.

Purple urine bag syndrome (PUBS) is a complication of urinary tract infections (UTIs) where catheter bags and tubing turn purple. It is alarming for patients, families, and clinicians; however, it is in itself a benign phenomenon. PUBS is the result of UTIs with specific bacteria that produce sulphatases and phosphatases which lead tryptophan metabolism to produce indigo (blue) and indirubin (red) pigments, a mixture of which becomes purple. Risk factors include female gender, immobility, constipation, chronic catheterisation, and renal disease. Management involves reassurance, antibiotics, and regular changing of catheters, although there are debates regarding how aggressively to treat and no official guidelines. Prognosis is good, but PUBS is associated with high morbidity and mortality due to the backgrounds of patients. Here, we review the literature available on PUBS, present a summary of case studies from the last five years, and propose the Oxford Urine Chart as a tool to aid such diagnoses.

Humoral and intestinal immunity induced by new schedules of bivalent oral poliovirus vaccine and one or two doses of inactivated poliovirus vaccine in Latin American infants: an open-label randomised controlled trial.

BACKGROUND: Replacement of the trivalent oral poliovirus vaccine (tOPV) with bivalent types 1 and 3 oral poliovirus vaccine (bOPV) and global introduction of inactivated poliovirus vaccine (IPV) are major steps in the polio endgame strategy. In this study, we assessed humoral and intestinal immunity in Latin American infants after three doses of bOPV combined with zero, one, or two doses of IPV. METHODS: This open-label randomised controlled multicentre trial was part of a larger study. 6-week-old full-term infants due for their first polio vaccinations, who were healthy on physical examination, with no obvious medical conditions and no known chronic medical disorders, were enrolled from four investigational sites in Colombia, Dominican Republic, Guatemala, and Panama. The infants were randomly assigned by permuted block randomisation (through the use of a computer-generated list, block size 36) to nine groups, of which five will be discussed in this report. These five groups were randomly assigned 1:1:1:1 to four permutations of schedule: groups 1 and 2 (control groups) received bOPV at 6, 10, and 14 weeks; group 3 (also a control group, which did not count as a permutation) received tOPV at 6, 10, and 14 weeks; group 4 received bOPV plus one dose of IPV at 14 weeks; and group 5 received bOPV plus two doses of IPV at 14 and 36 weeks. Infants in all groups were challenged with monovalent type 2 vaccine (mOPV2) at 18 weeks (groups 1, 3, and 4) or 40 weeks (groups 2 and 5). The primary objective was to assess the superiority of bOPV-IPV schedules over bOPV alone, as assessed by the primary endpoints of humoral immunity (neutralising antibodies-ie, seroconversion) to all three serotypes and intestinal immunity (faecal viral shedding post-challenge) to serotype 2, analysed in the per-protocol population. Serious and medically important adverse events were monitored for up to 6 months after the study vaccination. This study is registered with ClinicalTrials.gov, number NCT01831050, and has been completed. FINDINGS: Between May 20, 2013, and Aug 15, 2013, 940 eligible infants were enrolled and randomly assigned to the five treatment groups (210 to group 1, 210 to group 2, 100 to group 3, 210 to group 4, and 210 to group 5). One infant in group 1 was not vaccinated because their parents withdrew consent after enrolment and randomisation, so 939 infants actually received the vaccinations. Three doses of bOPV or tOPV elicited type 1 and 3 seroconversion rates of at least 97·7%. Type 2 seroconversion occurred in 19 of 198 infants (9·6%, 95% CI 6·2-14·5) in the bOPV-only groups, 86 of 88 (97·7%, 92·1-99·4) in the tOPV-only group (p<0·0001 vs bOPV-only), and 156 of 194 (80·4%, 74·3-85·4) infants in the bOPV-one dose of IPV group (p<0·0001 vs bOPV-only). A further 20 of 193 (10%) infants in the latter group seroconverted 1 week after mOPV2 challenge, resulting in around 98% of infants being seropositive against type 2. After a bOPV-two IPV schedule, all 193 infants (100%, 98·0-100; p<0·0001 vs bOPV-only) seroconverted to type 2. IPV induced small but significant decreases in a composite serotype 2 viral shedding index after mOPV2 challenge. 21 serious adverse events were reported in 20 patients during the study, including two that were judged to be possibly related to the vaccines. Most of the serious adverse events (18 [86%] of 21) and 24 (80%) of the 30 important medical events reported were infections and infestations. No deaths occurred during the study. INTERPRETATION: bOPV provided humoral protection similar to tOPV against polio serotypes 1 and 3. After one or two IPV doses in addition to bOPV, 80% and 100% of infants seroconverted, respectively, and the vaccination induced a degree of intestinal immunity against type 2 poliovirus. FUNDING: Bill & Melinda Gates Foundation.

Qualitative and quantitative assessment of meningococcal antigens to evaluate the potential strain coverage of protein-based vaccines.

A unique multicomponent vaccine against serogroup B meningococci incorporates the novel genome-derived proteins fHbp, NHBA, and NadA that may vary in sequence and level of expression. Measuring the effectiveness of such vaccines, using the accepted correlate of protection against invasive meningococcal disease, could require performing the serum bactericidal assay (SBA) against many diverse strains for each geographic region. This approach is impractical, especially for infants, where serum volumes are very limited. To address this, we developed the meningococcal antigen typing system (MATS) by combining a unique vaccine antigen-specific ELISA, which detects qualitative and quantitative differences in antigens, with PorA genotyping information. The ELISA correlates with killing of strains by SBA and measures both immunologic cross-reactivity and quantity of the antigens NHBA, NadA, and fHbp. We found that strains exceeding a threshold value in the ELISA for any of the three vaccine antigens had ≥80% probability of being killed by immune serum in the SBA. Strains positive for two or more antigens had a 96% probability of being killed. Inclusion of multiple different antigens in the vaccine improves breadth of coverage and prevents loss of coverage if one antigen mutates or is lost. The finding that a simple and high-throughput assay correlates with bactericidal activity is a milestone in meningococcal vaccine development. This assay allows typing of large panels of strains and prediction of coverage of protein-based meningococcal vaccines. Similar assays may be used for protein-based vaccines against other bacteria.

Paralytic syndromes in children: epidemiology and relationship to vaccination.

Acute flaccid paralysis is a standard outcome for detection of poliomyelitis globally and an ongoing potential vaccine-associated adverse event concern for polio, influenza, and meningococcal vaccines. No systematic population-based data on the epidemiologic and clinical features of this condition, or its potential association with immunization, have been reported from the United States. The present retrospective cohort study of acute flaccid paralysis in the Southern and Northern California Kaiser Permanente Health Care Plans was conducted using computerized diagnosis data and medical record review of potential cases among children aged 1 month to <15 years and diagnosed from January 1, 1992 through December 31, 1998. In all, 3297 potential cases were identified; of these, 2682 cases (81%) did not meet the case definition, and of the remaining 615 cases, 245 (7% of the total) were included. The incidence of disease was 1.4 per 100,000 children/year (95% confidence interval = 1.2-1.6); predicting approximately 844 children/year in the United States. Disease incidence did not vary with season or sex, varied inversely with age, and declined 28% during the study period. No cases of vaccine-associated acute flaccid paralysis were identified. In nonendemic countries, ongoing acute flaccid paralysis surveillance is often conducted, because of the risk of poliovirus importation, but this practice may be difficult to justify, given low disease incidence and breadth of clinical presentation.

Immunosuppression impairs response to pneumococcal polysaccharide vaccination in patients with inflammatory bowel disease.

OBJECTIVES: The treatment of inflammatory bowel disease (IBD) often includes immunosuppressive medications, which may increase the risk of vaccine-preventable illnesses. We aimed to assess the impact of immunosuppression on immune responses to pneumococcal vaccination in patients with IBD. METHODS: The study design consists of a prospective controlled clinical trial. This study was carried out at a tertiary-care IBD clinic. The subjects for the study belonged to one of the following three groups: adult patients with IBD on combination TNF-blockers and immunomodulators (Group A), those without immunosuppressive therapy (Group B), and age-matched healthy controls (Group C). The treatment consisted of immunization with 23-valent pneumococcal polysaccharide vaccines (PSVs). The main outcome was immune response for five serotypes defined as a twofold or greater increase from pre-vaccination titers and > or =1 microg post-vaccination titer. RESULTS: Sixty-four subjects participated in the study: 20 in Group A, 25 in Group B, and 19 in Group C. Pre-vaccination titers were similar among the three groups. Vaccine responses were lower in Group A than in Group B (P< or =0.01 for four out of five antigens) and Group C (P<0.01 for all five antigens). Overall vaccine response was seen in 45, 80, and 85% of Groups A, B, and C (P=0.01), respectively. CONCLUSIONS: Immune response to PSV-23 is impaired in Crohn's disease (CD) patients on combination immunosuppressive therapy but is normal among non-immunosuppressed patients. Given the unpredictable likelihood for immunosuppressive therapy, newly diagnosed patients with IBD should undergo vaccination before the initiation of immunosuppressive therapy.

Evaluation of vaccine coverage for low birth weight infants during the first year of life in a large managed care population.

OBJECTIVE: There are few recent population-based assessments of vaccine coverage in premature infants available. This study assesses and compares age- and dose-specific immunization coverage in children of different birth weight categories during the first year of life. METHODS: We performed a retrospective cohort analysis of computerized vaccination data from a large managed care organization in southern California. The participants were children born between January 1, 1997, and December 31, 2002, and continuously enrolled from birth to at least 12 months of age in the Southern California Kaiser Permanente health plan. We measured age-specific up-to-date and age-appropriate immunization rates according to birth weight (extremely low birth weight: <1000 g; very low birth weight: 1000-1499 g; low birth weight: 1500-2499 g; normal birth weight: >/=2500 g) for 4 vaccines (hepatitis B, diphtheria and tetanus toxoids with pertussis, Haemophilus influenzae type b, and poliovirus) through the first year of life. RESULTS: We identified 127 833 infants born during the study period and continuously enrolled through the first year of life; 120 048 were normal birth weight infants; 6491 were low birth weight infants; 788 were very low birth weight infants; and 506 were extremely low birth weight infants. Vaccine-specific age-appropriate immunization rates were 3% to 15% lower for low birth weight infants and 17% to 33% lower for extremely low birth weight infants compared with the rates for normal birth weight infants in the first 6 months of life. Extremely low birth weight infants had the lowest age-specific up-to-date immunization levels (5%-31% lower) compared with normal birth weight infants at each age assessed. By 12 months, extremely low birth weight infants still had significantly lower up-to-date levels (87%) compared with very low birth weight, low birth weight, and normal birth weight infants (91%-92%). CONCLUSIONS: Despite recommendations that lower birth weight infants be vaccinated as the same chronological age as normal birth weight infants, extremely low birth weight and very low birth weight infants are immunized at significantly lower rates relative to low birth weight and normal birth weight infants at 2, 4, and 6 months of age. However, by 12 months of age this finding persists only in extremely low birth weight infants.

A population-based, postlicensure evaluation of the safety of a combination diphtheria, tetanus, acellular pertussis, hepatitis B, and inactivated poliovirus vaccine in a large managed care organization.

BACKGROUND: Prelicensure studies of diphtheria, tetanus, acellular pertussis, hepatitis B, inactivated polio virus vaccine suggested that there were higher rates of fever after its administration than when its component antigens were given separately. METHODS: We conducted an open, controlled, cohort study to evaluate selected potential adverse events after receipt of diphtheria, tetanus, acellular pertussis, hepatitis B, inactivated poliovirus vaccine in the Southern California Kaiser Permanente Health Care Plan. From April 2003 through June 2005, we identified 61,004 infants who received >or=1 dose of vaccine (120000 total doses). This group was compared with a previous cohort of 58,251 age-, gender-, and medical center-matched infants (116,637 doses) who received diphtheria, tetanus, acellular pertussis vaccine and separate doses of hepatitis B and inactivated poliovirus vaccines from January 2002 through March 2003. We compared the incidence of seizures, medically attended events that were associated with fever, and other selected adverse outcomes. RESULTS: We identified 16 infants (8 with fever) who had a seizure in the diphtheria, tetanus, acellular pertussis, hepatitis B, inactivated poliovirus cohort and 15 infants (6 with fever) among control subjects in the 8-day period after receipt of any dose of vaccine. The incidence of all seizures or seizures associated with fever was not significantly different between cohorts. The incidence of medically attended events that were associated with fever in the 4-day period after any dose of vaccine was also similar in both cohorts. As well, no significant differences between the diphtheria, tetanus, acellular pertussis, hepatitis B, inactivated poliovirus and control cohorts, were noted in the incidence of allergic reactions within 48 hours of any dose of vaccine, outpatient visits within 21 days, hospitalizations within 21 days, or death within 1 year. CONCLUSIONS: We did not observe a statistically significant increase in any of several clinically important safety events after diphtheria, tetanus, acellular pertussis, hepatitis B, inactivated poliovirus vaccination compared with a historical cohort who received separate component vaccines.